Abstract
BACKGROUND: Medulloblastoma is a common brain malignancy in children. Patients after puberty are rare and bear an intermediate prognosis. Standard treatment consists of maximal resection plus radio-chemotherapy. Treatment toxicity is high and produces disabling long-term side effects. The sonic hedgehog (SHH) subgroup is highly overrepresented in the post-pubertal and adult population and can be targeted by smoothened (SMO) inhibitors. No practice-changing prospective randomized data have been generated in adults so far. MATERIAL AND METHODS: EORTC 1634-BTG/NOA-23 trial randomizes patients between standard-dose vs. reduced-dosed craniospinal radiotherapy and SHH-subgroup patients between the SMO inhibitor sonidegib (OdomzoTM, Sun Pharmaceuticals Industries, Inc., New York, USA) and standard chemotherapy. Based on data that suggest equal efficacy, a reduction of toxicity with dose-reduced CSI while maintaining efficacy is investigated by using 35.2 Gy in the standard vs. 24.6 Gy in the experimental arm. Chemotherapy consists of vincristine during radiotherapy, followed by a maximum of six cycles of lomustine, cisplatin and vincristine of six-weekly cycles. Sonidegib is added for patients with SHH-activated medulloblastoma. An increase in efficacy in the SHH subgroup is the primary efficacy endpoint. A number of translational research projects are performed alongside the trial. RESULTS: The trial aims at developing a personalized, genotype-based, intensity-modulated therapy for post-pubertal and adult patients with newly diagnosed medulloblastoma. We are investigating tumor tissue, blood, and cerebrospinal fluid as well as magnetic resonance imaging and radiotherapy plans to generate information that helps to further improve treatment outcomes. Long-term follow-up is performed to monitor classic side effects of therapy, but also health-related quality of life, cognition, social and professional outcome, and reproduction and fertility. The 1634-BTG/NOA-23 trial started recruitment in November 2022. Updated information on recruitment as well as on demographic data of recruited patients will be presented at the EANO annual meeting. CONCLUSION: EORTC 1634-BTG/NOA-23 is the first trial worldwide that prospectively enrolls post-pubertal and adult patients with medulloblastoma according to their molecular subgroup in a randomized design. Translational subprojects will enable us to evaluate events on several layers to gain deeper insights into subgrouping, risk stratification, therapeutic targets, resistance mechanisms, and the toxicity of treatments. The trial will therefore generate unprecedented data that will be translated into treatment changes in post-pubertal patients with medulloblastoma and will help to design future clinical trials.