Comprehensive radiotherapy for pediatric Ewing Sarcoma: Outcomes of a prospective proton study.

BACKGROUND AND PURPOSE: Patients with Ewing Sarcoma (EWS) are treated with multimodality therapy which includes radiation therapy (RT) as an option for local control. We report on the efficacy after proton radiation therapy (PRT) to the primary site for localized and metastatic EWS. MATERIALS AND METHODS: Forty-two children with EWS (33 localized, 9 metastatic) treated between 2007 and 2020 were enrolled on 2 prospective registry protocols for pediatric patients undergoing PRT. PRT was delivered by passive scatter (74 %), pencil-beam scanning (12 %) or mixed technique (14 %). Treated sites included the spine (45 %), pelvis/sacrum (26 %), skull/cranium (14 %), extraosseous (10 %), and chest wall (5 %). Median radiation dose was 54 Gy-RBE (range 39.6-55.8 Gy-RBE). Patients with metastatic disease received consolidative RT to metastatic sites (4 at the time of PRT to the primary site, 5 after completion of chemotherapy). Median follow-up time was 47 months after PRT. RESULTS: The 4-year local control (LC), progression-free survival (PFS), and overall survival (OS) rates were 83 %, 71 %, and 86 %, respectively. All local failures (n = 6) were in-field failures. Tumor size ≥ 8 cm predicted for inferior 4-year LC (69 % vs 95 %, p = 0.04). 4-year PFS and OS rates were not statistically different in patients with localized versus metastatic disease (72 % vs 67 %, p = 0.70; 89 % vs 78 %, p = 0.38, respectively). CONCLUSION: In conclusion, LC for pediatric patients with EWS treated with PRT was comparable to that of historical patients who received photon-RT. Tumor size ≥ 8 cm predicted increased risk of local failure. Patients with metastatic disease, including non-pulmonary only metastases, received radiation therapy to all metastatic sites and had favorable survival outcomes.

ESTRO-SIOPE guideline: Clinical management of radiotherapy in atypical teratoid/rhabdoid tumors (AT/RTs).

BACKGROUND AND PURPOSE: Treatment of patients with atypical teratoid/rhabdoid (AT/RT) is challenging, especially when very young (below the age of three years). Radiotherapy (RT) is part of a complex trimodality therapy. The purpose of this guideline is to provide appropriate recommendations for RT in the clinical management of patients not enrolled in clinical trials. MATERIALS AND METHODS: Nine European experts were nominated to form a European Society for Radiotherapy and Oncology (ESTRO) guideline committee. A systematic literature search was conducted in PubMed/MEDLINE and Web of Science. They discussed and analyzed the evidence concerning the role of RT in the clinical management of AT/RT. RESULTS: Recommendations on diagnostic imaging, therapeutic principles, RT considerations regarding timing, dose, techniques, target volume definitions, dose constraints of radiation-sensitive organs at risk, concomitant chemotherapy, and follow-up were considered. Treating children with AT/RT within the framework of prospective trials or prospective registries is of utmost importance. CONCLUSION: The present guideline summarizes the evidence and clinical-based recommendations for RT in patients with AT/RT. Prospective clinical trials and international, large registries evaluating modern treatment approaches will contribute to a better understanding of the best treatment for these children in future.

Surface guided radiotherapy practice in paediatric oncology: a survey on behalf of the SIOPE Radiation Oncology Working Group.

INTRODUCTION: Surface guided radiotherapy (SGRT) is increasingly being implemented to track patient's surface movement and position during radiation therapy. However, limited information is available on the SGRT use in paediatrics. The aim of this double survey was to map SIOPE (European Society for Paediatric Oncology)-affiliated centres using SGRT and to gain information on potential indications, observed, or expected benefits. METHODS: A double online survey was distributed to 246 SIOPE-affiliated radiotherapy (RT) centres. Multiple choices, yes/no, and open answers were included. The first survey (41 questions) was active from February to March 2021. A shortened version (13 questions) was repeated in March 2023 to detect trends in SGRT use within the same community. RESULTS: Respectively, 76/142 (54%) and 28/142 (20%) responding centres used and planned to use SGRT clinically, including 4/34 (12%) new centres since 2021. Among the SGRT users, 33/76 (43%) already applied this technology to paediatric treatments. The main benefits of improved patient comfort, better monitoring of intrafraction motion, and more accurate initial patient set-up expected by future users did not differ from current SGRT-users (P = .893). Among non-SGRT users, the main hurdles to implement SGRT were costs and time for installation. In paediatrics, SGRT is applied to all anatomical sites. CONCLUSION: This work provides information on the practice of SGRT in paediatrics across SIOPE-affiliated RT centres which can serve as a basis for departments when considering the purchase of SGRT systems. ADVANCES IN KNOWLEDGE: Since little information is available in the literature on the use of SGRT in paediatrics, the results of this double survey can serve as a basis for departments treating children when considering the purchase of an SGRT system.

Linear energy transfer-inclusive models of brainstem necrosis following proton therapy of paediatric ependymoma.

Background and Purpose: Radiation-induced brainstem necrosis after proton therapy is a severe toxicity with potential association to uncertainties in the proton relative biological effectiveness (RBE). A constant RBE of 1.1 is assumed clinically, but the RBE is known to vary with linear energy transfer (LET). LET-inclusive predictive models of toxicity may therefore be beneficial during proton treatment planning. Hence, we aimed to construct models describing the association between brainstem necrosis and LET in the brainstem. Materials and methods: A matched case-control cohort (n = 28, 1:3 case-control ratio) of symptomatic brainstem necrosis was selected from 954 paediatric ependymoma brain tumour patients treated with passively scattered proton therapy. Dose-averaged LET (LETd) parameters in restricted volumes (L50%, L10% and L0.1cm3, the cumulative LETd) within high-dose thresholds were included in linear- and logistic regression normal tissue complication probability (NTCP) models. Results: A 1 keV/µm increase in L10% to the brainstem volume receiving dose over 54 Gy(RBE) led to an increased brainstem necrosis risk [95% confidence interval] of 2.5 [0.0, 7.8] percentage points. The corresponding logistic regression model had area under the receiver operating characteristic curve (AUC) of 0.76, increasing to 0.84 with the anterior pons substructure as a second parameter. 19 [7, 350] patients with toxicity were required to associate the L10% (D > 54 Gy(RBE)) and brainstem necrosis with 80% statistical power. Conclusion: The established models of brainstem necrosis illustrate a potential impact of high LET regions in patients receiving high doses to the brainstem, and thereby support LET mitigation during clinical treatment planning.

Neurocognitive function and health-related quality of life in a nationwide cohort of long-term childhood brain tumor survivors.

Background: Childhood brain tumor survivors are at high risk of late effects, especially neurocognitive impairment. Limited data are available examining neurocognitive function and associations with quality of life (QoL) in childhood brain tumor survivors. Our aim was to examine neurocognitive function in childhood brain tumor survivors, and associations with QoL and symptom burden. Methods: Five-year survivors of brain tumors over the age of 15 were identified in the Danish Childhood Cancer Registry (n = 423). Eligible and consenting participants completed neuropsychological tests and questionnaires assessing QoL, insomnia, fatigue, anxiety, and depression. Survivors treated with radiation (n = 59) were statistically compared with survivors not treated with radiation (n = 102). Results: In total, 170 survivors participated (40.2% participation rate). Sixty-six percent of the survivors who completed neurocognitive tests (n = 161) exhibited overall neurocognitive impairment. Survivors treated with radiation, especially whole-brain irradiation, exhibited poorer neurocognitive outcomes than survivors not treated with radiation. Neurocognitive outcomes for survivors treated with surgery were below normative expectations. Furthermore, a number of survivors experienced significant fatigue (40%), anxiety (23%), insomnia (13%), and/or depression (6%). Survivors treated with radiation reported lower quality of life (QoL) and higher symptom burden scores than survivors not treated with radiation; particularly in physical functioning, and social functioning with symptoms of fatigue. Neurocognitive impairment was not associated with QoL or symptom burden. Conclusions: In this study, a majority of the childhood brain tumor survivors experienced neurocognitive impairment, reduced QoL, and high symptom burden. Although not associated with each other, it is apparent that childhood brain tumor survivors experience not only neurocognitive dysfunction but may also experience QoL impairments and significant symptom burden.

A case-control study of linear energy transfer and relative biological effectiveness related to symptomatic brainstem toxicity following pediatric proton therapy.

BACKGROUND AND PURPOSE: A fixed relative biological effectiveness (RBE) of 1.1 (RBE1.1) is used clinically in proton therapy even though the RBE varies with properties such as dose level and linear energy transfer (LET). We therefore investigated if symptomatic brainstem toxicity in pediatric brain tumor patients treated with proton therapy could be associated with a variable LET and RBE. MATERIALS AND METHODS: 36 patients treated with passive scattering proton therapy were selected for a case-control study from a cohort of 954 pediatric brain tumor patients. Nine children with symptomatic brainstem toxicity were each matched to three controls based on age, diagnosis, adjuvant therapy, and brainstem RBE1.1 dose characteristics. Differences across cases and controls related to the dose-averaged LET (LETd) and variable RBE-weighted dose from two RBE models were analyzed in the high-dose region. RESULTS: LETd metrics were marginally higher for cases vs. controls for the majority of dose levels and brainstem substructures. Considering areas with doses above 54 Gy(RBE1.1), we found a moderate trend of 13% higher median LETd in the brainstem for cases compared to controls (P =.08), while the difference in the median variable RBE-weighted dose for the same structure was only 2% (P =.6). CONCLUSION: Trends towards higher LETd for cases compared to controls were noticeable across structures and LETd metrics for this patient cohort. While case-control differences were minor, an association with the observed symptomatic brainstem toxicity cannot be ruled out.

QUARTET: A SIOP Europe project for quality and excellence in radiotherapy and imaging for children and adolescents with cancer.

The European Society for Paediatric Oncology (SIOPE) Radiation Oncology Working Group presents the QUARTET Project: a centralised quality assurance programme designed to standardise care and improve the quality of radiotherapy and imaging for international clinical trials recruiting children and adolescents with cancer throughout Europe. QUARTET combines the paediatric radiation oncology expertise of SIOPE with the infrastructure and experience of the European Organisation for Research and Treatment of Cancer to deliver radiotherapy quality assurance programmes for large, prospective, international clinical trials. QUARTET-affiliated trials include children and adolescents with brain tumours, neuroblastoma, sarcomas including rhabdomyosarcoma, and renal tumours including Wilms' tumour. With nine prospective clinical trials and two retrospective studies within the active portfolio in March 2022, QUARTET will collect one of the largest repositories of paediatric radiotherapy and imaging data, support the clinical assessment of radiotherapy, and evaluate the role and benefit of radiotherapy quality assurance for this cohort of patients within the context of clinical trials.

Systematic Review: Sleep Disorders Based on Objective Data in Children and Adolescents Treated for a Brain Tumor.

Background: Tumors of the central nervous system (CNS) are the most common solid childhood malignancy. Over the last decades, treatment developments have strongly contributed to the improved overall 5-year survival rate, which is now approaching 75%. However, children now face significant long-term morbidity with late-effects including sleep disorders that may have detrimental impact on everyday functioning and quality of life. The aims of this study were to (1) describe the symptoms that lead to polysomnographic evaluation; (2) describe the nature of sleep disorders diagnosed in survivors of childhood CNS tumor using polysomnography (PSG); and (3) explore the association between tumor location and diagnosed sleep disorder. Methods: An extensive literature search following the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines (PRISMA) was conducted. Inclusion criteria were children and adolescents diagnosed with a CNS tumor age <20 years having a PSG performed after end of tumor treatment. The primary outcome was sleep disorder confirmed by PSG. Results: Of the 1,658 studies identified, 11 met the inclusion criteria. All the included articles were appraised for quality and included in the analysis. Analyses indicated that sleep disorders commonly occur among childhood CNS tumor survivors. Symptoms prior to referral for PSG were excessive daytime sleepiness (EDS), fatigue, irregular breathing during sleep and snoring. The most common sleep disorders diagnosed were sleep-related breathing disorders (i.e., obstructive sleep apnea) and central disorders of hypersomnolence (i.e., narcolepsy). Conclusion: Our findings point to the potential benefit of systematically registering sleep disorder symptoms among CNS tumor patients together with tumor type and treatment information, so that at-risk patients can be identified early. Moreover, future rigorous and larger scale controlled observational studies that include possible modifiable confounders of sleep disorders such as fatigue and obesity are warranted. Clinical Trial Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021243866, identifier [CRD42021243866].

Treatment plan comparison of proton vs photon radiotherapy for lower-grade gliomas.

BACKGROUND AND PURPOSE: Patients with lower-grade gliomas are long-term survivors after radiotherapy and may benefit from the reduced dose to normal tissue achievable with proton therapy. Here, we aimed to quantify differences in dose to the uninvolved brain and contralateral hippocampus and compare the risk of radiation-induced secondary cancer for photon and proton plans for lower-grade glioma patients. MATERIALS AND METHODS: Twenty-three patients were included in this in-silico planning comparative study and had photon and proton plans calculated (50.4 Gy(RBE = 1.1), 28 Fx) applying similar dose constraints to the target and organs at risk. Automatically calculated photon plans were generated with a 3 mm margin from clinical target volume (CTV) to planning target volume. Manual proton plans were generated using robust optimisation on the CTV. Dose metrics of organs at risk were compared using population mean dose-volume histograms and Wilcoxon signed-rank test. Secondary cancer risk per 10,000 persons per year (PPY) was estimated using dose-volume data and a risk model for secondary cancer induction. RESULTS: CTV coverage (V95%>98%) was similar for the two treatment modalities. Mean dose (Dmean) to the uninvolved brain was significantly reduced from 21.5 Gy (median, IQR 17.1-24.4 Gy) with photons compared to 10.3 Gy(RBE) (8.1-13.9 Gy(RBE)) with protons. Dmean to the contralateral hippocampus was significantly reduced from 6.5 Gy (5.4-11.7 Gy) with photons to 1.5 Gy(RBE) (0.4-6.8 Gy(RBE)) with protons. The estimated secondary cancer risk was reduced from 6.7 PPY (median, range 3.3-10.4 PPY) with photons to 3.0 PPY (1.3-7.5 PPY) with protons. CONCLUSION: A significant reduction in mean dose to uninvolved brain and contralateral hippocampus was found with proton planning. The estimated secondary cancer risk was reduced with proton therapy.

A national study on the inter-observer variability in the delineation of organs at risk in the brain.

BACKGROUND: The Danish Neuro Oncology Group (DNOG) has established national consensus guidelines for the delineation of organs at risk (OAR) structures based on published literature. This study was conducted to finalise these guidelines and evaluate the inter-observer variability of the delineated OAR structures by expert observers. MATERIAL AND METHODS: The DNOG delineation guidelines were formed by participants from all Danish centres that treat brain tumours with radiotherapy. In a two-day workshop, guidelines were discussed and finalised based on a pilot study. Following this, the ten participants contoured the following OARs on T1-weighted gadolinium enhanced MRI from 13 patients with brain tumours: optic tracts, optic nerves, chiasm, spinal cord, brainstem, pituitary gland and hippocampus. The metrics used for comparison were the Dice similarity coefficient (Dice), mean surface distance (MSD) and others. RESULTS: A total of 968 contours were delineated across the 13 patients. On average eight (range six to nine) individual contour sets were made per patient. Good agreement was found across all structures with a median MSD below 1 mm for most structures, with the chiasm performing the best with a median MSD of 0.45 mm. The Dice was as expected highly volume dependent, the brainstem (the largest structure) had the highest Dice value with a median of 0.89 whereas smaller volumes such as the chiasm had a Dice of 0.71. CONCLUSION: Except for the caudal definition of the spinal cord, the variances observed in the contours of OARs in the brain were generally low and consistent. Surface mapping revealed sub-regions of higher variance for some organs. The data set is being prepared as a validation data set for auto-segmentation algorithms for use within the Danish Comprehensive Cancer Centre - Radiotherapy and potential collaborators.

Inter-clinician delineation variation for a new highly-conformal flank target volume in children with renal tumors: A SIOP-Renal Tumor Study Group international multicenter exercise.

BACKGROUND AND PURPOSE: Recently, the SIOP-RTSG developed a highly-conformal flank target volume definition for children with renal tumors. The aims of this study were to evaluate the inter-clinician delineation variation of this new target volume definition in an international multicenter setting and to explore the necessity of quality assurance. MATERIALS AND METHODS: Six pediatric renal cancer cases were transferred to ten radiation oncologists from seven European countries ('participants'). These participants delineated the pre- and postoperative Gross Tumor Volume (GTVpre/post), and Clinical Target Volume (CTV) during two test phases (case 1-2 and 3-4), followed by guideline refinement and a quality assurance phase (case 5-6). Reference target volumes (TVref) were established by three experienced radiation oncologists. The Dice Similarity Coefficient between the reference and participants (DSCref/part) was calculated per case. Delineations of case 5-6 were graded by four independent reviewers as 'per protocol' (0-4 mm), 'minor deviation' (5-9 mm) or 'major deviation' (≥10 mm) from the delineation guideline using 18 standardized criteria. Also, a major deviation resulting in underestimation of the CTVref was regarded as an unacceptable variation. RESULTS: A total of 57/60 delineation sets were completed. The median DSCref/part for the CTV was 0.55 without improvement after sequential cases (case 3-4 vs. case 5-6: p = 0.15). For case 5-6, a major deviation was found for 5/18, 12/17, 18/18 and 4/9 collected delineations of the GTVpre, GTVpost, CTV-T and CTV-N, respectively. An unacceptable variation from the CTVref was found for 7/9 participants for case 5 and 6/9 participants for case 6. CONCLUSION: This international multicenter delineation exercise demonstrates that the new consensus for highly-conformal postoperative flank target volume delineation leads to geometrical variation among participants. Moreover, standardized review showed an unacceptable delineation variation in the majority of the participants. These findings strongly suggest the need for additional training and centralized pre-treatment review when this target volume delineation approach is implemented on a larger scale.

Spatial Agreement of Brainstem Dose Distributions Depending on Biological Model in Proton Therapy for Pediatric Brain Tumors.

PURPOSE: During radiation therapy for pediatric brain tumors, the brainstem is a critical organ at risk, possibly with different radio-sensitivity across its substructures. In proton therapy, treatment planning is currently performed using a constant relative biological effectiveness (RBE) of 1.1 (RBE1.1), whereas preclinical studies point toward spatial variability of this factor. To shed light on this biological uncertainty, we investigated the spatial agreement between isodose maps produced by different RBE models, with emphasis on (smaller) substructures of the brainstem. METHODS AND MATERIALS: Proton plans were recalculated using Monte Carlo simulations in 3 anonymized pediatric patients with brain tumors (a craniopharyngioma, a low-grade glioma, and a posterior fossa ependymoma) to obtain dose and linear energy transfer distributions. Doses and volume metrics for the brainstem and its substructures were calculated using a constant RBE1.1, 4 phenomenological RBE models with varying (α/ß)x parameters, and with a simpler linear energy transfer-dependent model. The spatial agreement between the dose distributions of constant RBE1.1 versus the variable RBE models was compared using the Dice similarity coefficient. RESULTS: The spatial agreement between the variable RBE dose distributions and RBE1.1 decreased with increasing isodose levels in all patient cases. The patient with ependymoma showed the greatest variation in dose and dose volumes, where V50Gy(RBE) in the brainstem increased from 32% (RBE1.1) to 35% to 49% depending on the applied model, corresponding to a spatial agreement (Dice similarity coefficient) between 0.79 and 0.95. The remaining patients showed similar trends, however, with lower absolute values due to lower brainstem doses. CONCLUSIONS: All phenomenological RBE models fully enclosed the isodose volumes of the constant RBE1.1, and the volumes based on variable RBE spatially agreed. The spatial agreement was dependent on the isodose level, where higher isodose levels showed larger expansions and less agreement between the variable RBE models and RBE1.1.

Variation in relative biological effectiveness for cognitive structures in proton therapy of pediatric brain tumors.

BACKGROUND: Clinically, a constant value of 1.1 is used for the relative biological effectiveness (RBE) of protons, whereas in vitro the RBE has been shown to vary depending on physical dose, tissue type, and linear energy transfer (LET). As the LET increases at the distal end of the proton beam, concerns exist for an elevated RBE in normal tissues. The aim of this study was therefore to investigate the heterogeneity of RBE to brain structures associated with cognition (BSCs) in pediatric suprasellar tumors. MATERIAL AND METHODS: Intensity-modulated proton therapy (IMPT) plans for 10 pediatric craniopharyngioma patients were re-calculated using 11 phenomenological and two plan-based variable RBE models. Based on LET, tissue dependence and number of data points used to fit the models, the three RBE models considered the most relevant for the studied endpoint were selected. Thirty BSCs were investigated in terms of RBE and dose/volume parameters. RESULTS: For a representative patient, the median (range) dose-weighted mean RBE (RBEd) across all BSCs from the plan-based models was among the lowest (1.09 (1.02-1.52) vs. the phenomenological models at 1.21 (0.78-2.24)). Omitting tissue dependency resulted in RBEd at 1.21 (1.04-2.24). Across all patients, the narrower RBE model selection gave median RBEd values from 1.22 to 1.30. CONCLUSION: For all BSCs, there was a systematic model-dependent variation in RBEd, mirroring the uncertainty in biological effects of protons. According to a refined selection of in vitro models, the RBE variation across BSCs was in effect underestimated when using a fixed RBE of 1.1.