Radiotherapy (RT) is a cornerstone treatment strategy for brain tumours. Besides cytotoxicity, RT can cause disruption of the blood–brain barrier (BBB), resulting in an increased permeability into the surrounding brain parenchyma. Although this effect is generally acknowledged, it remains unclear how and to what extent different radiation schemes affect BBB integrity. The aim of this systematic review and meta-analysis is to investigate the effect of photon RT regimens on BBB permeability, including its reversibility, in clinical and preclinical studies. We systematically reviewed relevant clinical and preclinical literature in PubMed, Embase, and Cochrane search engines. A total of 69 included studies (20 clinical, 49 preclinical) were qualitatively and quantitatively analysed by meta-analysis and evaluated on key determinants of RT-induced BBB permeability in different disease types and RT protocols. Qualitative data synthesis showed that 35% of the included clinical studies reported BBB disruption following RT, whereas 30% were inconclusive. Interestingly, no compelling differences were observed between studies with different calculated biological effective doses based on the fractionation schemes and cumulative doses; however, increased BBB disruption was noted during patient follow-up after treatment. Qualitative analysis of preclinical studies showed RT BBB disruption in 78% of the included studies, which was significantly confirmed by meta-analysis (p < 0.01). Of note, a high risk of bias, publication bias and a high heterogeneity across the studies was observed. This systematic review and meta-analysis sheds light on the impact of RT protocols on BBB integrity and opens the discussion for integrating this factor in the decision-making process of future RT, with better study of its occurrence and influence on concomitant or adjuvant therapies.

To assess the feasibility of magnetic resonance imaging (MRI)-only treatment planning for photon and proton radiotherapy in children with abdominal tumours. The study was conducted on 66 paediatric patients with Wilms' tumour or neuroblastoma (age 4 ± 2 years) who underwent MR and computed tomography (CT) acquisition on the same day as part of the clinical protocol. MRI intensities were converted to CT Hounsfield units (HU) by means of a UNet-like neural network trained to generate synthetic CT (sCT) from T1- and T2-weighted MR images. The CT-to-sCT image similarity was evaluated by computing the mean error (ME), mean absolute error (MAE), peak signal-to-noise ratio (PSNR) and Dice similarity coefficient (DSC). Synthetic CT dosimetric accuracy was verified against CT-based dose distributions for volumetric-modulated arc therapy (VMAT) and intensity-modulated pencil-beam scanning (PBS). Relative dose differences (Ddiff) in the internal target volume and organs-at-risk were computed and a three-dimensional gamma analysis (2 mm, 2%) was performed. The average ± standard deviation ME was -5 ± 12 HU, MAE was 57 ± 12 HU, PSNR was 30.3 ± 1.6 dB and DSC was 76 ± 8% for bones and 92 ± 9% for lungs. Average Ddiff were 99% (range [85; 100]%) for VMAT and >96% (range [87; 100]%) for PBS. The deep learning-based model generated accurate sCT from planning T1w- and T2w-MR images. Most dosimetric differences were within clinically acceptable criteria for photon and proton radiotherapy, demonstrating the feasibility of an MRI-only workflow for paediatric patients with abdominal tumours.

Dose prediction using deep learning networks prior to radiotherapy might lead tomore efficient modality selections. The study goal was to predict proton and photon dose distributions based on the patient-specific anatomy and to assess their clinical usage for paediatric abdominal tumours. Data from 80 patients with neuroblastoma or Wilms' tumour was included. Pencil beam scanning (PBS) (5 mm/ 3%) and volumetric-modulated arc therapy (VMAT) plans (5 mm) were robustly optimized on the internal target volume (ITV). Separate 3-dimensional patch-based U-net networks were trained to predict PBS and VMAT dose distributions. Doses, planning-computed tomography images and relevant optimization masks (ITV, vertebra and organs-at-risk) of 60 patients were used for training with a 5-fold cross validation. The networks' performance was evaluated by computing the relative error between planned and predicted dose-volume histogram (DVH) parameters for 20 inference patients. In addition, the organs-at-risk mean dose difference between modalities was calculated using planned and predicted dose distributions (ΔDmean = DVMAT-DPBS). Two radiation oncologists performed a blind PBS/VMAT modality selection based on either planned or predicted ΔDmean. Average DVH differences between planned and predicted dose distributions were ≤ |6%| for both modalities. The networks classified the organs-at-risk Dmean difference as a gain (ΔDmean > 0) with 98% precision. An identical modality selection based on planned compared to predicted ΔDmean was made for 18/20 patients. Deep learning networks for accurate prediction of proton and photon dose distributions for abdominal paediatric tumours were established. These networks allowing fast dose visualisation might aid in identifying the optimal radiotherapy technique when experience and/or resources are unavailable.

Background. SIOP PNET5 MB was initiated in 2014 as the first European trial using clinical, histological, and molecular parameters to stratify treatments for children and adolescents with standard-risk medulloblastoma. Methods. Stratification by upfront assessment of molecular parameters requires the timely submission of adequate tumour tissue. In the standard-risk phase-III cohort, defined by the absence of high-risk criteria (M0, R0), pathological (non-LCA), and molecular biomarkers (MYCN amplification in SHH–MB or MYC amplification), a randomized intensification by carboplatin concomitant with radiotherapy is investigated. In the LR stratum for localized WNT-activated medulloblastoma and age <16 years, a reduction of craniospinal radiotherapy dose to 18 Gy and a reduced maintenance chemotherapy are investigated. Two additional strata (WNT-HR, SHH-TP53) were implemented during the trial. Results. SIOP PNET5 MB is actively recruiting. The availability of adequate tumour tissue for upfront real-time biological assessments to assess inclusion criteria has proven feasible. Conclusion. SIOP PNET5 MB has demonstrated that implementation of biological parameters for stratification is feasible in a prospective multicentre setting, and may improve risk-adapted treatment. Comprehensive research studies may allow assessment of additional parameters, e.g., novel medulloblastoma subtypes, and identification and validation of biomarkers for the further refinement of risk-adapted treatment in the future.

To reduce relapse risk, Total Body Irradiation (TBI) is part of conditioning regimens for hematopoietic stem cell transplantation (HSCT) in pediatric acute leukemia. The study purpose was to evaluate clinical practices regarding TBI, such as fractionation, organ shielding and delivery techniques, among SIOPE affiliated radiotherapy centers. An electronic survey was sent out to 233 SIOPE affiliated centers, containing 57 questions about clinical practice of TBI. Surveys could be answered anonymously. From over 25 countries, 82 responses were collected. For TBI-performing centers, 40/48 irradiated ≤10 pediatric patients annually (range: 1-2 to >25). Most indications concerned acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Four different fractionation schedules were used, of which 12 Gy in 6 fractions was applied in 91% for ALL and 86% for AML. Dose reduction to the lungs, mostly to a mean dose of 8-10 Gy, was applied by 28/33 centers for ALL and 19/21 centers for AML, in contrast to much less applied dose reduction to the kidneys (7/33 ALL and 7/21 AML), thyroid (2/33 ALL and 2/21 AML), liver (4/33 ALL and 3/21 AML) and lenses (4/33 ALL and 4/21 AML). Conventional TBI techniques were used by 24/29 responding centers, while 5/29 used advanced optimized planning techniques. Across SIOPE, there is a high level of uniformity in fractionation and use of lung shielding. Practices vary regarding other organs-at-risk shielding and implementation of advanced techniques. A SIOPE radiotherapy working group will be established to define international guidelines for pediatric TBI.