Radiation therapy is a part of multidisciplinary management of several childhood cancers. Proton therapy is a new method of irradiation, which uses protons instead of photons. Proton radiation has been used safely and effectively for medulloblastoma, primitive neuro-ectodermal tumors, craniopharyngioma, ependymoma, germ cell intracranial tumors, low-grade glioma, retinoblastoma, rhabdomyosarcoma and other soft tissue sarcomas, Ewing’s sarcoma and other bone sarcomas. Moreover, other possible applications are emerging, in particular for lymphoma and neuroblastoma. Although both photon and proton techniques allow similar target volume coverage, the main advantage of proton radiation therapy is to sparing of intermediate-to-low-dose to healthy tissues. This characteristic could translate into clinical reduction of side effects, including a lower risk for secondary cancers. The following review presents the state of the art of proton therapy in the treatment of pediatric malignancies.

Brain tumors are the most common solid neoplasms of childhood. They are frequently reported in children with Neurofibromatosis type 1 (NF1). The most frequent central nervous system malignancies described in NF1 are optic pathway gliomas and brainstem gliomas. Medulloblastoma (MB) in NF1 patients is extremely rare, and to our knowledge, only 10 cases without molecular characterization are described in the literature to date. We report the case of a 14-year-old girl with NF1 that came to our attention for an incidental finding of a lesion arising from cerebellar vermis. The mass was completely resected, revealing a localized classic medulloblastoma (MB), subgroup 4. She was treated as a standard-risk MB with a dose-adapted personalized protocol. The treatment proved to be effective, with minor toxicity. Brain and spine MRI one year after diagnosis confirmed the complete remission of the disease. To our knowledge, this is the only case of MB reported in a patient with NF1 with molecular characterization by the methylation profile. The association between NF1 and MB, although uncommon, may not be an accidental occurrence.

Background: We applied the strategy for M+ medulloblastoma across all high-risk subgroups, including LC/A histology, TP53 mutations, and MYC/MYCN amplification. Methods: Patients over 3 years old received, after surgery, staging and histo-biological analysis, sequential high-dose-methotrexate(HD-MTX), high-dose-etoposide(HD-VP16), high-dose-cyclophosphamide(HD-Cyclo), and high-dose-carboplatin(HD-Carbo). Hyperfractionated-accelerated-radiotherapy–craniospinal(HART-CSI), administered twice daily 1.3 Gy-fractions reached a total dose tailored to the patients’ age and pre-radiation response to chemotherapy(CT): 31.2 Gy if under 10-years-old and complete response(CR) or partial response(PR) obtained or absence of metastatic disease, 39 Gy in other/older patients. Boosts to posterior fossa/residual metastatic(M+) deposits were given up to a total dose of 60 Gy/9 Gy, respectively, but avoided if metastatic nodules were very big or patients were very young. Two courses of high-dose-thiotepa were delivered in case of not CR/PR after the pre-radiotherapy (RT) phase and in all M0 patients either—pre/post-HART. Subgrouping was performed where the tissue was available. Results: Eighty-nine patients were enrolled, with a median age of 8.8 years, and a median follow-up of 136 months. Overall survival (OS) and event-free survival (EFS) at 5/15 years were 75.9/66.5% and 68.2/65.3%, respectively; 5/28 fatal events were not related to relapse(3 developed secondary malignancies). Sex, age less than 10 years, histological subtype, presence of MYC/MYCN amplification, reduction in CSI dose, omission of RT-boosts, implementation of myeloablative therapy, presence–absence of metastases did not impact prognosis.Patients progressing after pre-HART CT(14/89) and stable-disease(SD)+PD after HART(10/89) negatively affected outcome(P < .001).Subgrouping in 66/89 patients’ samples demonstrated a significantly worse EFS for patients with Sonic Hedgehog(SHH)-tumors(#15, 2 with constitutional TP53-mutations) versus groups 3 and 4(15 and 29 patients, respectively, group3/4 in 7).Patients younger than 10 received lower CSI doses if stratified according to CT response. Conclusions: This strategy, partly adopted in the ongoing SIOPE protocol, confirmed improved EFS and OS over previously reported outcomes in all high-risk categories; SHH tumors appeared the most aggressive.

Background: Several studies have shown that the intensity of treatment in Ewing sarcoma has an impact on outcome. The present trial tested the non‐inferiority of intensive, shorter, induction chemotherapy (25 weeks total treatment time) compared to the standard treatment (37 weeks) in non‐metastatic Ewing sarcoma (ES) at onset.Procedure: This national, multicenter, parallel, randomized, controlled, open‐label, non‐inferiority, phase III trial was conducted in 14 specialized hospitals in Italy. Patients aged 2‐40 years with newly diagnosed localized ES were randomized to receive four courses of induction therapy (one every 21 days) either with a standard arm (Arm A) or with an intensive arm (Arm B). For consolidation therapy, good responders (GRs) in Arm A received nine courses (37 weeks), while Arm B patients received five courses (25 weeks). Poor responders for both arms received four courses followed by high‐dose busulfan/melphalan + autologous stem cell rescue. Follow‐up was 5 years.Results: In the study period 2009–2018, 274 patients with ES at onset were screened, 248 were eligible, 15 refused randomization, and 233 were randomized (Arm A: 113; Arm B: 120). Median age was 14 years. Arm B was not inferior to Arm A: 5‐year EFS was 77.5% and 71.6%, respectively (HR vs. Arm A: 0.74, 90% CI: 0.49–1.14). GRs were 54.9% in Arm A and 62.5% in Arm B. Hematological, gastrointestinal, and cardiovascular Grade ≥3 toxicities had higher frequencies in Arm B.Conclusions: Intensive induction therapy showed non‐inferiority in 5‐year EFS when compared with the standard induction therapy. Higher toxicity was reported in Arm B with similar outcome, counterbalanced in GRs with a shorter treatment plan. ClinicalTrials.gov Identifier: NCT02063022.

Proton beam therapy (PBT) is an effective pediatric brain tumor treatment. However, the resulting microstructural changes within and around irradiated tumors are unknown. We retrospectively applied diffusion tensor imaging (DTI) and free-water imaging (FWI) on diffusion-weighted magnetic resonance imaging (dMRI) data to monitor microstructural changes during the PBT and after 8 months in a pilocytic astrocytoma (PA) and normal-appearing white matter (NAWM). We evaluated the conventional MRI- and dMRI-derived indices from six MRI sessions (t0–t5) in a Caucasian child with a hypothalamic PA: at baseline (t0), during the PBT (t1–t4) and after 8 months (t5). The tumor voxels were classified as “solid” or “fluid” based on the FWI. While the tumor volume remained stable during the PBT, the dMRI analyses identified two different response patterns: (i) an increase in fluid content and diffusivity with anisotropy reductions in the solid voxels at t1, followed by (ii) smaller variations in fluid content but higher anisotropy in the solid voxels at t2–t4. At follow-up (t5), the tumor volume, fluid content, and diffusivity in the solid voxels increased. The NAWM showed dose-dependent microstructural changes. The use of the dMRI and FWI showed complex dynamic microstructural changes in the irradiated mass during the PBT and at follow-up, opening new avenues in our understanding of radiation-induced pathophysiologic mechanisms in tumors and the surrounding tissues.

Purpose The long-term neurocognitive impact of craniospinal irradiation (CSI) in young children with medulloblastoma (MB) has driven the development of alternative strategies aimed at improving survival while delaying or avoiding CSI. Methods We retrospectively analyzed a cohort of patients under 5 years of age with MB treated at Bambino Gesù Children’s Hospital between 2007 and 2023 with intensive chemotherapy regimens according to AIEOP recommendation. Clinical, radiological, histopathological, molecular, neurocognitive, and toxicity data were collected. Results Among 42 patients under 5 years, 25 met inclusion criteria (median age 25.3 months, range 5.0–51.3). Histology included classic (52%), desmoplastic/nodular (20%), extensive nodularity (16%), and large cell/anaplastic (12%). SHH was the most common molecular subgroup (52%), followed by Group 3 (32%) and Group 4 (16%). At a median follow-up of 95.7 months, 68% were alive in complete remission. Two- and 5-year overall survival (OS) were 80.0% (95%CI: 58.4–91.1) and 65.9% (95%CI: 42.8–81.4); progression-free survival (PFS) was 68.0% (95%CI: 46.1–82.5) and 63.8% (95%CI: 41.8–79.2). Survival differed by risk group: low-risk patients achieved 100% OS and PFS, standard-risk intermediate, high-risk lowest. All experienced grade 3–4 hematological toxicity; late endocrine effects occurred in four patients, no other long-term toxicities reported. median IQ was stable from diagnosis (885.3) to last follow-up (8392.5.4). Conclusion Our retrospective study of infants MB treated with first-line intensive chemotherapy shows encouraging survival rates. Importantly, neurocognitive function was preserved over time, supporting radiation-sparing strategies, and toxicity was manageable in all cases.