Abstract
Simple SummaryMedulloblastoma is rare after puberty. Among several molecular subgroups that have been described, the sonic hedgehog (SHH) subgroup is highly overrepresented in the post-pubertal population and can be targeted with smoothened (SMO) inhibitors. However, no practice-changing prospective clinical trials have been published in adults to date. Tumors often recur, and treatment toxicity is relevant. Thus, the EORTC 1634-BTG/NOA-23 trial for post-pubertal patients with standard risk medulloblastoma will aim to increase treatment efficacy and to decrease treatment toxicity. Patients will be randomized between standard-dose vs. reduced-dosed radiotherapy, and SHH-subgroup patients will also be randomized between the SMO inhibitor sonidegib (OdomzoTM,, Sun Pharmaceuticals Industries, Inc., New York, USA) in addition to standard radio-chemotherapy vs. standard radio-chemotherapy alone. In ancillary studies, we will investigate tumor tissue, blood and cerebrospinal fluid samples, magnetic resonance images, and radiotherapy plans to gain information that may improve future treatment. Patients will also be monitored long-term for late side effects of therapy, health-related quality of life, cognitive function, social and professional live outcomes, and reproduction and fertility. In summary, EORTC 1634-BTG/NOA-23 is a unique multi-national effort that will help to council patients and clinical scientists for the appropriate design of treatments and future clinical trials for post-pubertal patients with medulloblastoma.Medulloblastoma is a rare brain malignancy. 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. The EORTC 1634-BTG/NOA-23 trial will randomize 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) in addition to standard radio-chemotherapy vs. standard radio-chemotherapy alone to improve outcomes in view of decreased radiotherapy-related toxicity and increased efficacy. We will further investigate 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. Given that treatment side effects typically occur late, long-term follow-up will monitor classic side effects of therapy, but also health-related quality of life, cognition, social and professional outcome, and reproduction and fertility. In summary, we will generate unprecedented data that will be translated into treatment changes in post-pubertal patients with medulloblastoma and will help to design future clinical trials.
Highlights
Medulloblastoma is a rare condition in adult neuro-oncology practice [1]
We aim to identify and establish novel innovative biomarkers for response prediction and treatment monitoring to inform EORTC 1634-BTG/NeuroOnkologische Arbeitsgemeinschaft in der Deutschen Krebsgesellschaft (NOA)-23 trial interpretation, and future refined clinical trials
Its main objectives will be to investigate if there is increased efficacy in the sonic hedgehog (SHH) subgroup due to the addition of the SMO inhibitor, sonidegib, and to assess in the whole population whether a reduction in radiotherapy toxicity can be attained without compromising efficacy by using a lower dose of radiotherapy
Summary
Medulloblastoma is a rare condition in adult neuro-oncology practice [1]. Of cases occur in patients under 15 years of age, and the peak incidence is around 5 years of age [2]. (SEER) database reported that the incidence of medulloblastoma was 0.6 cases per million in adults [3]. In post-pubertal patients, medulloblastoma is distributed between sexes [1,4]. A staging system was introduced by Chang et al in 1969 to describe the extent of tumoral infiltration (T1–T4) and metastases (M0-M4) in medulloblastoma [5]. T-stage likely has a prognostic role in adults [6,7]. Whether M1 disease has prognostic value in post-pubertal patients and adults is, still a matter of debate
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