Low-grade gliomas of the brainstem in children: stratification into risk groups and the assessment of the effectiveness of targeted therapy

Low-grade gliomas (LGG) of the brainstem remain a therapeutic challenge due to the impossibility of radical tumor resection and unsatisfactory results of standard treatment. We aimed to analyse clinical molecular genetic characteristics of patients with LGG of the brainstem and the results of standard treatment according to the SIOP-LGG protocol as well as targeted therapy with BRAF and MEK inhibitors. The study included 59 patients with sporadic (non-neurofibromatosis type I) LGG of the brainstem. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. The patients' legal representatives gave their informed consent to the use of the patients' data for research purposes and in publications. The 8-year overall survival rates were 68% (47–96%) and the 5-year progression-free survival (PFS) rates were 38% (26–57%). The medulla oblongata was the most common tumor site (n = 25; 40%), in 21 (35.5%) cases, the tumor spread to the adjacent structures of the brainstem and brain. Radical resection of the tumor was performed in 14 patients, subtotal resection – in 15 patients, partial resection – in 14, and 16 patients underwent biopsy. In most cases, the histological type of the tumor was pilocytic astrocytoma (n = 49; 83%). The KIAA1549::BRAF chimeric transcript was detected in the majority of patients (n = 33; 56%). The BRAFV600E mutation was found in 12 (22%) patients, the H3K27M mutation – in 4 (7%) patients. Twelve patients received chemotherapy according to the SIOP-LGG protocol (carboplatin + vincristine). The 2-year PFS rates were 44% (22–87%). Local radiotherapy was performed in 12 patients. The 2-year PFS rates were 44% (22–87%). Targeted therapy with the MEK inhibitor (trametinib) was prescribed to 13 patients, combination therapy with the BRAF and MEK inhibitors – to 9 patients, and one patient was prescribed BRAF inhibitor (vemurafenib) monotherapy. The 2-year PFS in the patients treated with first-line targeted therapy was 88% (67–100%). The most common adverse event of targeted therapy was skin toxicity (70%). A multivariate analysis revealed that the prognostically significant factors influencing PFS were the extent of resection and a molecular genetic driver: biopsy and partial resection of the tumor, as well as the presence of the BRAFV600E and H3K27M mutations demonstrated an independent negative prognostic value.