Abstract
Embryonal tumors with multilayered rosettes (ETMR) are aggressive central nervous system neoplasms with unfavorable prognosis, exhibiting rapid disease progression and frequent post-therapeutic relapse. The rarity of ETMR necessitates global collaboration to advance therapies. Radiotherapy (RT) has been associated with improved survival outcomes in ETMR with case series revealing that nearly half of ETMR patients treated without RT relapse within six months of diagnosis. However, RT is often withheld due to young patient age and neurodevelopmental considerations. This high-rate of on-treatment relapse is unique to ETMR and suggests that radiation-sparing regimens may be suboptimal. PNOC031 is an international collaboration, establishing a global clinical trial to innovate and improve therapeutic interventions for children with ETMR. Eligible patients with newly-diagnosed ETMR are stratified into three cohorts: Cohort 1 - gross total resection/RT-eligible patients to receive early focal radiotherapy (RT); Cohort 2 – gross total resection/not RT-eligible to receive high-dose chemotherapy with autologous stem cell rescue; and Cohort 3 – less than gross total resection or with metastatic disease to receive RT or high-dose chemotherapy per RT eligibility, based on age and tumor location. Cohort 1 will test the hypothesis if early RT improves outcomes in a pilot cohort of 20 patients. Patients will receive six weeks of induction chemotherapy, followed by focal irradiation and an additional six weeks of chemotherapy. Six-month progression-free survival will be assessed to determine the impact of radiotherapy on the rate of early relapse. Cohorts 2 and 3 will allow collection of uniform prospective clinical data using a common treatment backbone, to inform future clinical trial design for ETMR. Incorporating a myriad of correlative studies, including next-generation sequencing, cerebrospinal fluid analyses, microbiome profiles, and evaluations of social determinants of health alongside cognitive outcomes, will enhance comprehensive understanding of clinical responses and advance therapeutic options for this high risk disease.