Central nervous system (CNS) tumors are the most common solid malignancies in children and adolescents and young adults (C-AYAs). Craniospinal irradiation (CSI) is an essential treatment component for some malignancies, but it can also lead to important toxicity. Pencil beam scanning proton therapy (PBSPT) allows for a minimization of dose delivered to organs at risk and, thus, potentially reduced acute and late toxicity. This study aims to report the clinical outcomes and toxicity rates after CSI for C-AYAs treated with PBSPT. Seventy-one C-AYAs (median age: 7.4 years) with CNS tumors were treated with CSI between 2004 and 2021. Medulloblastoma (n = 42: 59%) and ependymoma (n = 8; 11%) were the most common histologies. Median prescribed total PBSPT dose was 54 Gy RBE (range: 18-60.4), and median prescribed craniospinal dose was 24 Gy RBE (range: 18-36.8). Acute and late toxicities were coded according to Common Terminology Criteria for Adverse Events. After a median follow-up of 24.5 months, the estimated 2-year local control, distant control, and overall survival were 86.3%, 80.5%, and 84.7%, respectively. Late grade ≥3 toxicity-free rate was 92.6% at 2 years. Recurrent and metastatic tumors were associated with worse outcome. In conclusion, excellent tumor control with low toxicity rates was observed in C-AYAs with brain tumors treated with CSI using PBSPT. K E Y W O R D Sadolescents and young adults, brain tumors, children, patient-related outcomes, pencil beam scanning, proton therapy, toxicity INTRODUCTIONCraniospinal irradiation (CSI) is an essential treatment component along with surgery and chemotherapy for many children, adolescents

BACKGROUND: Craniospinal irradiation (CSI) is an essential treatment component to achieve cure for some brain tumors in children and young adults/adolescents (C-AYAs). Multimodal treatment approaches are however associated with treatment-related late toxicities in these developing patients. Pencil beam scanning proton therapy (PBSPT) allows for a minimization of dose delivered to organs at risk and the brain integral dose and, thus, potentially also a reduction of radiation-induced adverse events. We report the clinical outcome and toxicity rates after CSI for C-AYAs treated with PBSPT. METHODS: We reviewed 71 C-AYAs with a median age of 7.4 years (1.7 – 21.3) who received CSI with PBSPT. Medullobastoma (n=42, 59%) and ependymoma (n=8, 11%) were the most common histologies. Thirty-four (48%) patients presented with metastatic disease at diagnosis. Sixteen (23%) patients were treated for tumor recurrence/progression and 9 (13%) patients underwent re-irradiation. Median prescribed total dose was 54 GyRBE (18 – 60.4) and median craniospinal dose 24 GyRBE (18 – 36.8). Toxicities were recorded according to CTCAE v5.0. RESULTS: With a median follow-up time of 24 months (2 – 195), 12 (17%) patients died due to progressive disease. Eight (11%) patients experienced local failure and 15 (21%) distant failure after PBSPT. Estimated 2-year OS, LC and DC was 86.9%, 86.0% and 80.4%, respectively. Grade 3 acute toxicity (thrombocytopenia, neutropenia, nausea) was observed in 5 (7%) patients. Late grade 3 toxicities (stroke, cataract and CNS necrosis) were observed in 3 (4%) patients, 8, 9 and 16 months after PBSPT, respectively. One (1%) patient developed grade 4 CNS necrosis 8 months after CSI. Late grade ≥3 toxicity free rate was 92.3% at 2 years. No radiation-induced secondary cancer was observed. CONCLUSION: Excellent tumor and brain/spinal distant control and a low late grade ≥3 toxicity rate after CSI were observed in our cohort of C-AYAs treated with PBSPT.