Background and aims Ultra-high dose rate (FLASH) irradiation is a promising technique to reduce radiation-induced normal tissue toxicities while preserving antitumor efficacy. We evaluated the feasibility and intestinal sparing potential of FLASH irradiation using a clinical synchrocyclotron-based proton therapy system generating a pulsed beam. Material and methods C57BL/6J mice received abdominal irradiation (2×2 cm) in transmission mode at FLASH (>60 Gy/s) or conventional (CONV, 0.5 Gy/s) dose rates using a 230 MeV superconducting synchrocyclotron proton pencil beam scanning (PBS) system. Two independent irradiation rounds were performed. Endpoints included 75-day survival, regenerating crypt counts, whole blood counts at day 4, and intestinal wall thickness, cyst-like structures, and cytokine levels at day 75. Results In the first irradiation round, survival after 14.5 Gy FLASH was markedly improved (5/8 survivors) compared to CONV (0/8), whereas in the second round, survival rates were identical (2/7 per group). Overall, pooled data indicated improved survival with 14.5 Gy FLASH. The LD50 was 13.74 Gy in CONV and 14.48 Gy in FLASH mode, corresponding to a FLASH modifying factor of 0.95. FLASH at 14.5 Gy increased regenerating crypt numbers compared to CONV, but only in the first round, supporting survival outcomes. No significant differences were observed in whole blood counts, cytokine profiles, or long-term intestinal structural changes between groups. Conclusion FLASH proton therapy delivered with a clinical synchrocyclotron PBS system can reduce short-term gastrointestinal toxicity in mice. However, inconsistent results across irradiation rounds highlight limitations of this model for reliable FLASH studies. ### Competing Interest Statement Conflict of interest: Nicolas Gerard, Jarrick Nys, Valentin Hamaide, Alexis Warnier, Rudi Labarbe, Swati Girdhani and Stephane Lucas are employees of Ion Beam Application S.A. (Louvain-La-Neuve, Belgium). Edmond Sterpin collaborates with Ion Beam Application S.A. (Louvain-La-Neuve, Belgium) on related research but received no financial compensation for this study. Walloon region, 8341, C7289

Objectives Survivors of pediatric brain tumors are at an increased risk of developing neurovascular disease, with radiotherapy being a major determinant. The aim of this project was to map how the risk of neurovascular late effects is considered when treating pediatric patients with a brain or skull base tumor with radiotherapy. Methods A web-based survey, prepared in the frame of the HARMONIC project (harmonicproject.eu) together with the SIOPE radiotherapy working group (ROWG) was distributed to ROWG members throughout Europe. The survey included 33 questions about neurovascular structures at risk, screening and information of the patients, recommendations, and follow-up programs. Results 47 participants from 18 European countries completed the survey, with 87% of them treating patients with photon therapy. 39 of the respondents (83%) never delineated specific structures for large vessel disease, mainly because no dose constraints exist (31/39, 79%) and neurovascular structures are not traditionally integrated into pediatric radiotherapy protocols (28/39, 71%). 35 of the respondents (74%) did not screen patients for risk factors of neurovascular disease before radiotherapy. Of the respondents, 22 (47%) informed all patients with a brain or skull base tumor of the risk of large vessel disease after radiotherapy, and 24 (55%) informed all patients of the risk of small vessel disease. 26 (55%) didn't have a follow-up imaging program for neurovascular disease after radiotherapy in pediatric patients, and 32 (68%) didn't have a follow-up program with blood sampling for seromarkers of risks of neurovascular disease. Of note, 94% of the respondents expressed interest in participating in a follow-up workshop on neurovascular disease after radiotherapy in pediatric patients. Conclusion Despite a general agreement on the importance of this topic, neurovascular late effects are currently not well included in the clinical practice of European radiotherapy centers.

BACKGROUND AND PURPOSE:Ultra-high dose rate (UHDR) irradiation induces less normal tissues toxicities compared to conventional dose rate (CONV) irradiation. We aimed to assess whether UHDR and CONV proton irradiation result in different levels of DNA damage in zebrafish embryos. Moreover, we studied the downstream transcriptional activation and functional changes following both modalities. MATERIALS AND METHODS:Zebrafish embryos received 30 Gy UHDR (>5100 Gy/s) or CONV (0.18 Gy/s) proton irradiation at 28 h post-fertilization on a 68 MeV cyclotron. DNA damage was assessed at 4 h post-irradiation. Gene expression changes were assessed at 6 and 24 h post-irradiation. Apoptosis, proliferation and neutrophil migration were investigated at 6 h and 20 h post-irradiation. Survival and morphological abnormalities were assessed at 4 days post-irradiation. RESULTS:No significant differences in morphological abnormalities were found between treatment groups. Conversely, significantly higher levels of DNA damage were observed in CONV- versus UHDR-irradiated embryos. CONV irradiation resulted in higher expression levels of genes involved in cell cycle arrest (cdkn1a) and p53 regulation (mdm2). Lastly, CONV irradiation resulted in higher levels of apoptosis in the embryonic tail compared to UHDR irradiation. Comparable cell proliferation and neutrophil migration to the sites of injury was found between treatments. CONCLUSION:UHDR proton irradiation induces less DNA damage and less downstream transcriptional activation of DNA damage response pathways in zebrafish embryos compared to CONV irradiation, resulting in reduced embryonic cell death. However, the magnitude of observed differences might not always be high enough to translate into significant differences in developmental abnormalities.

Most radiotherapy treatments are nowadays delivered with linear accelerators producing photons. This robust radiation technique improved outstandingly during the last three decades, allowing treatments for most tumoural indications with an exquisite accuracy, a formidable effectiveness, a low toxicity, and a very low cost for the society. Therefore, the reasons for using and developing the more expensive hadron therapy and more particularly proton therapy may seem futile. In the current article targeting the general practitioners readership, we look at the principles of this innovative technique, its inherent advantages and limitations, the current and future indications, the challenges and perspectives for the future. We conclude with an overview of the Belgian landscape in terms of installation, operation, access and reimbursement procedures.

•Empirical evidence about late outcomes of contemporary radiotherapy in paediatrics is needed.•HARMONIC-RT registers patients under 22 years of age treated since 2000 with first external beam radiotherapy in the participating European centres.•HARMONIC-RT is conducting sub-studies and collecting biological samples for detailed investigation of endocrine disorders, neuro- and cardio-vascular damages, second primary cancers and quality of life.

Background The addition of an integrated focal boost to the intraprostatic lesion is associated with improved biochemical disease-free survival (bDFS) in patients with intermediate- and high-risk prostate cancer (PCa) in conventionally fractionated radiotherapy. Furthermore, whole gland stereotactic body radiotherapy (SBRT) demonstrated to be non-inferior to conventional radiotherapy for low- and intermediate-risk PCa. To investigate the combination of ultra-hypofractionated prostate SBRT with iso-toxic focal boosting for intermediate- and high-risk PCa, we performed the hypo-FLAME trial. Methods Patients with intermediate- or high-risk PCa were enrolled in the phase II hypo-FLAME trial. All patients were treated with 35 Gy in 5 weekly fractions to the whole prostate gland with an iso-toxic integrated boost up to 50  Gy to the multiparametric MRI-defined tumor(s). If the dose constraints to the normal tissues would be exceeded, these were prioritised over the focal boost dose. The current analysis reports on the 5-year bDFS, late toxicity and health-related quality of life (HRQoL). Results Between 2016 and 2018, 100 men were treated with a median follow-up of 61 months. The estimated 5-year bDFS (95 % CI) was 93 % (86 % to 97 %). At 5 years, the prevalence of grade 2 + genitourinary and gastrointestinal toxicity was 12 % and 4 %, respectively. Conclusion Ultra-hypofractionated focal boost SBRT is associated with encouraging biochemical control rates up to 5-year follow-up in patients with intermediate- and high-risk PCa. Furthermore, prostate SBRT with iso-toxic focal boosting is associated with acceptable late genitourinary and gastrointestinal toxicity rates.

BACKGROUND:Radiotherapy is a frequently utilized palliative treatment for cancer patients. Electronic Patient-Reported Outcome Measures (ePROMs) offer a method for patients to communicate their symptoms and concerns to healthcare providers (HCPs) remotely. While ePROMs have demonstrated significant benefits for oncology patient care, their integration into routine clinical practice of palliative radiotherapy (PRT) poses challenges. The current study aimed to evaluate the implementation of an ePROM-intervention after PRT. METHODS:We conducted a two-phase study to evaluate the implementation of a self-developed ePROM intervention, known as the ePRomT diary, for symptom monitoring post-PRT. This diary offered automated self-management advice for mild symptoms and also guided patients to contact an HCP for severe symptoms. We assessed various implementation aspects using the RE-AIM framework and collected data through surveys, interviews, electronic health records, and field notes. Quantitative data analysis employed descriptive statistics, while qualitative data underwent thematic analysis using NVivo. Recruitment periods for both phases spanned 10 weeks. RESULTS:In Phase I, 37 out of 87 eligible patients (43%) participated, a number that rose to 40 out of 49 eligible patients (82%) in Phase II. Among participating patients, 93% in Phase I and 98% in Phase II reported the ePRomT diary as a valuable addition to their care. Additionally, 75% and 84% expressed willingness to reuse it, while 70% and 80% would recommend it to others in Phases I and II, respectively. In Phase I, 17 out of 39 patients (44%) completed at least one ePROM assessment, increasing to 26 out of 40 patients (65%) in Phase II. While patients found the self-management advice generally correct and relevant, they noted its somewhat generic nature. Moreover, while the advice to contact an HCP was deemed appropriate, adherence to it varied. HCPs expressed satisfaction with the intervention, deeming it valuable in patient care, and believed that integrating it into routine clinical practice would enhance patient acceptability with minimal workflow disruptions. CONCLUSIONS:Despite certain limitations, including participant bias, our study offers valuable insights into the implementation and potential implications of an ePROM intervention for symptom follow-up post-PRT, framed within the RE-AIM framework. ePROM interventions like the ePRomT diary show promise and are well-received by both patients and HCPs. However, optimizing such interventions to better align with patient needs and seamlessly integrating them into clinical workflows within the context of PRT warrants further investigation.

Background and purpose: The hypo-FLAME trial showed that once-weekly (QW) focal boosted prostate stereotactic body radiotherapy (SBRT) is associated with acceptable acute genitourinary (GU) and gastrointestinal (GI) toxicity. Currently, we investigated the safety of reducing the overall treatment time (OTT) of focal boosted prostate SBRT from 29 to 15 days.Material and methods: Patients with intermediate-and high-risk prostate cancer were treated with SBRT delivering 35 Gy in 5 fractions to the whole prostate gland with an iso-toxic boost up to 50 Gy to the intraprostatic lesion(s) in a semi-weekly (BIW) schedule. The primary endpoint was radiation-induced acute toxicity (CTCAE v5.0). Changes in quality of life (QoL) were examined in terms of proportions achieving a minimal clinically important change (MCIC). Finally, acute toxicity and QoL scores of the BIW schedule were compared with the results of the prior QW hypo-FLAME schedule (n = 100). Results: Between August 2020 and February 2022, 124 patients were enrolled and treated BIW. No grade >3 GU or GI toxicity was observed. The 90-days cumulative incidence of grade 2 GU and GI toxicity rates were 47.5% and 7.4%, respectively. Patients treated QW scored significant less grade 2 GU toxicity (34.0%, p = 0.01). No significant differences in acute GI toxicity were observed. Furthermore, patients treated QW had a superior acute bowel and urinary QoL.Conclusion: Semi-weekly prostate SBRT with iso-toxic focal boosting is associated with acceptable acute GU and GI toxicity. Based on the comparison between the QW and BIW schedule, patients should be counselled regarding the short-term advantages of a more protracted schedule.Registration number ClinicalTrials.gov: NCT04045717.& COPY; 2023 Elsevier B.V. All rights reserved. Radiotherapy and Oncology 185 (2023) 1-8

Purpose:To report on the accuracy of automated delineation, treatment plan quality, and duration of an in-silico "scan-(pre)plan-treat" (SPT) workflow for vertebral bone metastases using a 1 × 8 Gy regimen. Method and Materials:The cloud-based emulator system of the Ethos therapy system was used to adapt an organ-at-risk-sparing preplan created on the diagnostic CT to the anatomy-of-the-day using the cone beam CT made before treatment. Results:SPT using the Ethos emulator system resulted in relatively good coverage of the PTV and acceptable dose to the OAR. Delivery time and plan homogeneity was the best for 7-field IMRT plan template. Conclusions:A SPT workflow formula results in a highly conformal treatment delivery while maintaining an acceptable timeframe for the patient on the treatment couch.

Background: Trimodality treatment, i.e., neoadjuvant chemoradiotherapy (nCRT) followed by surgery, for locally advanced esophageal cancer (EC) improves overall survival but also increases the risk of postoperative pulmonary complications. Here, we tried to identify a relation between dose to functional lung volumes (FLV) as determined by 4D-CT scans in EC patients and treatment-related lung toxicity. Materials and methods: All patients with EC undergoing trimodality treatment between 2017 and 2022 in UZ Leuven and scanned with 4D-CT-simulation were selected. FLVs were determined based on Jacobian determinants of deformable image registration between maximum inspiration and expiration phases. Dose/volume parameters of the anatomical lung volume (ALV) and FLV were compared between patients with versus without postoperative pulmonary complications. Results of pre- and post-nCRT pulmonary function tests (PFTs) were collected and compared in relation to radiation dose. Results: Twelve out of 51 EC patients developed postoperative pulmonary complications. ALV was smaller while FLV10Gy and FLV20Gy were larger in patients with complications (respectively 3141 +/- 858mL vs 3601 +/- 635mL, p = 0.025; 360 +/- 216mL vs 264 +/- 139mL, p = 0.038; 166 +/- 106mL vs 118 +/- 63mL, p = 0.030). No differences in ALV dose-volume parameters were detected. Baseline FEV1 and TLC were significantly lower in patients with complications (respectively 90 +/- 17%pred vs 102 +/- 20%pred, p = 0.033 and 93 +/- 17%pred vs 110 +/- 13%pred, p = 0.001), though no other PFTs were significantly different between both groups. DLCO was the only PFT that had a meaningful decrease after nCRT (85 +/- 17%pred vs 68 +/- 15%pred, p< 0.001) but was not related to dose to ALV/FLV. Conclusion: Small ALV and increasing FLV exposed to intermediate (10 to 20 Gy) dose are associated to postoperative pulmonary complications. Changes of DLCO occur during nCRT but do not seem to be related to radiation dose to ALV or FLV. This information could attribute towards toxicity risk prediction and reduction strategies for EC.

PURPOSE:The FLAME trial (NCT01168479) showed that isotoxic focal boosting to the intraprostatic lesion(s) in patients with intermediate- and high-risk prostate cancer improves 5-year disease-free survival (DFS). Although the near-minimum dose to the gross tumor volume (D98%) was associated with improved outcomes, a closer look suggested that this might not be the same for all patients. Therefore, we investigated whether risk factors that are associated with a benefit of focal boosting can be identified. METHODS AND MATERIALS:We described the distribution of clinical characteristics and the number of high-risk factors with respect to the D98% in 526 FLAME trial patients. We used penalized Cox regression to develop a prediction model. To investigate a potential benefit in patient subgroups, we compared the model-based predictions of 5-year DFS assuming standard whole-gland radiation therapy of 77 Gy to the predictions assuming an additional focal boost with D98% of 95 Gy. RESULTS:Patients with high-risk factors were well represented in the group of 120 patients that received D98% > 85 Gy and showed fewer recurrences compared with the group that received 77 Gy. Applying the model simulating a standard dose of 77 Gy, we predicted a high DFS for grade group (GG) 1 patients, whereas patients with high-risk characteristics appeared to show a low DFS. All risk groups showed a high level of DFS when simulating D98% of 95 Gy. CONCLUSIONS:Our results suggest that GG 1 patients already show a low level of failure at a standard dose of 77 Gy, limiting the additional benefit of focal boosting. In contrast, patients with high-risk characteristics, especially GG 4 or 5, show a low 5-year DFS, while focal boosting might improve this substantially. This suggests that reaching a high focal boost dose may be particularly beneficial for these patients.

Objective: Electronic Patient-Reported Outcome Measures (ePROMs) could be used to monitor patients' symptoms after treatment. However, ePROM implementation in clinical practice has been challenging, especially in (palliative) radiation oncology. The aim of this study was to explore the opinions of healthcare providers (HCP) active in radiation oncology in Belgium on the use of ePROMs for symptom follow-up after palliative radiotherapy. Methods: An anonymous online survey was conducted with different HCP in radiation oncology in Belgium. Participants were recruited through several professional organizations with approximately 390 members actively working in the field of radiation oncology. The survey used was a self-developed questionnaire, based on existing literature on implementation of (e)PROMs in cancer care, our previous research on this topic as well as our personal experience in the field of oncology and palliative care. Results: Of the 128 respondents, 26% had experience with ePROMs in clinical practice. Eighty-four percent considered ePROMs beneficial for patients' health and symptom knowledge, symptom self-management and active participation in care. ePROMs could help HCP to focus on detection of relevant symptoms and improve their management. Almost 75% were willing to implement and use ePROMs. Assigning ePROM introduction and follow-up to a dedicated person, such as a nurse navigator, was suggested to promote ePROM implementation and use in clinical practice. Conclusion: Despite limited experience with ePROMs in clinical care for palliative radiotherapy patients, the majority of respondents is willing to implement and use ePROMs for this particular patient population. Innovation: This is one of the first studies specifically focusing on experiences and opinions of HCP in radiation oncology on the use of ePROMs for symptom follow-up in palliative radiotherapy. HCP should be actively involved in implementation of ePROMs after palliative radiotherapy, to translate their vision of their ideals in practice.