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Objectives: To identify variables predicting interfractional anatomical variations measured with cone-beam CT (CBCT) throughout abdominal paediatric radiotherapy, and to assess the potential of surface-guided radiotherapy (SGRT) to monitor these changes. Methods: Metrics of variation in gastrointestinal (GI) gas volume and separation of the body contour and abdominal wall were calculated from 21 planning CTs and 77 weekly CBCTs for 21 abdominal neuroblastoma patients (median 4 years, range: 2 – 19 years). Age, sex, feeding tubes, and general anaesthesia (GA) were explored as predictive variables for anatomical variation. Furthermore, GI gas variation was correlated with changes in body and abdominal wall separation, as well as simulated SGRT metrics of translational and rotational corrections between CT/CBCT. Results: GI gas volumes varied 74 ± 54 ml across all scans, while body and abdominal wall separation varied 2.0 ± 0.7 mm and 4.1 ± 1.5 mm from planning, respectively. Patients < 3.5 years (p = 0.04) and treated under GA (p < 0.01) experienced greater GI gas variation; GA was the strongest predictor in multivariate analysis (p < 0.01). Absence of feeding tubes was linked to greater body contour variation (p = 0.03). GI gas variation correlated with body (R = 0.53) and abdominal wall (R = 0.63) changes. The strongest correlations with SGRT metrics were found for anterior-posterior translation (R = 0.65) and rotation of the left-right axis (R = −0.36). Conclusions: Young age, GA, and absence of feeding tubes were linked to stronger interfractional anatomical variation and are likely indicative of patients benefiting from adaptive/robust planning pathways. Our data suggest a role for SGRT to inform the need for CBCT at each treatment fraction in this patient group. Advances in knowledge: This is the first study to suggest the potential role of SGRT for the management of internal interfractional anatomical variation in paediatric abdominal radiotherapy.

Background Medullary thyroid carcinoma (MTC) in the context of multiple endocrine neoplasia type 2 (MEN2) is caused by mutations in the RET proto-oncogene. Therefore, in children with MEN2 and advanced MTC, the RET tyrosine kinase (TK) pathway is a target for treatment with selpercatinib, a selective RET TK inhibitor. Patients and methods A retrospective review of the clinical, genetic, biochemical (calcitonin and carcinoembryonic antigen [CEA]) and imaging data of six medically untreated children with MEN2 and recurrent and or progressive MTC. The main parameters were safety and objective treatment response to selpercatinib. Results Six children (three males and three females, aged 3–12 years), four with MEN2B and two MEN2A, are reported. All had initial total thyroidectomy and extensive neck dissections but subsequently developed recurrent and progressive disease. All experienced an improvement in clinical symptoms with a concomitant biochemical response evidenced by significant fall in serum calcitonin and CEA concentrations. The fall in serum calcitonin was evident within 2 weeks of the start of selpercatinib, and responses were ongoing at a median follow-up of 13 months (range, 11–22 months). Four children with measurable radiological disease had good volume reduction. The most common adverse effects were transient but reversible grade 1 or 2 increase in alanine aminotransferase, serum bilirubin and constipation. No child required a dose modification or had to discontinue selpercatinib because of a drug-related adverse event. Conclusion Selpercatinib has shown excellent therapeutic efficacy with minimal toxicity in children with MEN2 and progressive metastatic RET-mutated MTC.

Peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues such as 177-lutetium DOTATATE is an effective treatment modality for neuroendocrine tumours, paragangliomas, and neuroblastomas. However, renal and haematopoietic toxicities are the major limitations of this therapeutic approach. The renal toxicity of PRRT is mediated by renal proximal tubular reabsorption and interstitial retention of the radiolabelled peptides resulting in excessive renal irradiation that can be dose-limiting. To protect the kidneys from PRRT-induced radiation nephropathy, basic amino acids are infused during PRRT as they competitively bind to the proximal tubular cells and prevent uptake of the radionuclide. In adults, 1 L of a basic amino acid solution consisting of arginine and lysine is infused over 4 h commencing 30 min prior to PRRT. However, this volume of amino acids infused over 4 h is excessive in small children and can result in hemodynamic overload. This is all the more relevant in paediatric oncology, as many of the children may have been heavily pretreated and so may have treatment-related renal and or cardiac impairment. We have therefore developed the following guidelines for safe paediatric dosing of renal protective amino acid infusions during PRRT. Our recommendations have been made taking into consideration the renal physiology in small children and the principles of safe fluid management in children.

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 inter-national clinical trials recruiting children and adolescents with cancer throughout Europe. QUARTET combines the paediatric radiation oncology expertise of SIOPE with the infra-structure 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 tu-mours, 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 radio-therapy 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. 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

PURPOSE Relative stopping powers (RSPs) for proton therapy are estimated using single-energy computed tomography (SECT), calibrated with standardized tissues of the adult male. It is assumed that those tissues are representative of tissues of all age and sex. Female, male, and pediatric tissues differ from one another in density and composition. In this study, we use tabulated pediatric tissues and computational phantoms to investigate the impact of this assumption on pediatric proton therapy. The potential of dual-energy CT (DECT) to improve the accuracy of these calculations is explored. METHODS We study 51 human body tissues, categorized into male/female for the age groups newborn, 1-, 5-, 10-, and 15-year-old children, and adult, with given compositions and densities. CT numbers are simulated and RSPs are estimated using SECT and DECT methods. Estimated tissue RSPs from each method are compared to theoretical RSPs. The dose and range errors of each approach are evaluated on three computational phantoms (Ewing's sarcoma, salivary sarcoma, and glioma) derived from pediatric proton therapy patients. RESULTS With SECT, soft tissues have mean estimation errors and standard deviation up to (1.96 ± 4.18)% observed in newborns, compared to (0.20 ± 1.15)% in adult males. Mean estimation errors for bones are up to (-3.35 ± 4.76)% in pediatrics as opposed to (0.10 ± 0.66)% in adult males. With DECT, mean errors reduce to (0.17 ± 0.13)% and (0.23 ± 0.22)% in newborns (soft tissues/bones). With SECT, dose errors in a Ewing's sarcoma phantom are exceeding 5 Gy (10% of prescribed dose) at the distal end of the treatment field, with volumes of dose errors >5 Gy of Vdiff>5=4630.7 mm3 . Similar observations are made in the head and neck phantoms, with overdoses to healthy tissue exceeding 2 Gy (4%). A systematic Bragg peak shift resulting in either over- or underdosage of healthy tissues and target volumes depending on the crossed tissues RSP prediction errors is observed. Water equivalent range errors of single beams are between -1.53 and 5.50 mm (min, max) (Ewing's sarcoma phantom), -0.78 and 3.62 mm (salivary sarcoma phantom), and -0.43 and 1.41 mm (glioma phantom). DECT can reduce dose errors to

Background and purpose State-of-the-art radiotherapy modalities have the potential of reducing late effects of treatment in childhood cancer survivors. Our aim was to investigate the carcinogenic risk associated with 3D conformal (photon) radiation (3D-CRT), intensity modulated arc therapy (IMAT) and pencil beam scanning proton therapy (PBS-PT) in the treatment of paediatric abdominal neuroblastoma. Materials and methods The risk of radiation-induced second malignant neoplasm (SMN) was estimated using the concept of organ equivalent dose (OED) for eleven organs (lungs, rectum, colon, stomach, small intestine, liver, bladder, skin, central nervous system (CNS), bone, and soft tissues). The risk ratio (RR) between radiotherapy modalities and lifetime absolute risks (LAR) were reported for twenty abdominal neuroblastoma patients (median, 4y; range, 1-9y) historically treated with 3D-CRT that were also retrospectively replanned for IMAT and PBS-PT. Results The risk of SMN due to primary radiation was reduced in PBS-PT against 3D-CRT and IMAT for most patients and organs. The RR across all organs ranged from 0.38 ± 0.22 (bladder) to 0.98 ± 0.04 (CNS) between PBS-PT and IMAT, and 0.12 ± 0.06 (rectum and bladder) to 1.06 ± 0.43 (bone) between PBS-PT and 3D-CRT. The LAR for most organs was within 0.01-1% (except the colon) with a cumulative risk of 21 ± 13%, 35 ± 14% and 35 ± 16% for PBS-PT, IMAT and 3D-CRT, respectively. Conclusions PBS-PT was associated with the lowest risk of radiation-induced SMN compared to IMAT and 3D-CRT in abdominal neuroblastoma treatment. Other clinical endpoints and plan robustness should also be considered for optimal plan selection.

This guideline is written as a reference document for clinicians presented with the challenge of managing paediatric patients with differentiated thyroid carcinoma up to the age of 19 years. Care of paediatric patients with differentiated thyroid carcinoma differs in key aspects from that of adults, and there have been several recent developments in the care pathways for this condition; this guideline has sought to identify and attend to these areas. It addresses the presentation, clinical assessment, diagnosis, management (both surgical and medical), genetic counselling, follow-up and prognosis of affected patients. The guideline development group formed of a multi-disciplinary panel of sub-speciality experts carried out a systematic primary literature review and Delphi consensus exercise. The guideline was developed in accordance with The Appraisal of Guidelines Research and Evaluation Instrument II criteria, with input from stakeholders including charities and patient groups. Based on scientific evidence and expert opinion, 58 recommendations have been collected to produce a clear, pragmatic set of management guidelines. It is intended as an evidence base for future optimal management and to improve the quality of clinical care of Paediatric patients with differentiated thyroid carcinoma.

Aims Virtual simulation (VSim) of tangential photon fields is a common method of field localisation for breast radiotherapy. Heart and ipsilateral lung dose is unknown until the dosimetric plan is produced. If heart and ipsilateral lung tolerance doses are exceeded, this can prolong the pre-treatment pathway, particularly if a change of technique is required. The aim of this study was to identify predictive surrogates for heart and ipsilateral lung dose during VSim to aid optimum field placement and treatment modality selection. Materials and methods Computed tomography data from 50 patients referred for left breast/chest wall radiotherapy were retrospectively analysed (model-building cohort). The prescribed dose was 40.05 Gy in 15 fractions using a tangential photon technique. The heart and ipsilateral lung contours were duplicated, cropped to within the field borders and labelled heart-in-field (HIF) and ipsilateral lung-in-field (ILF). The percentage of HIF (%HIF) and ILF (%ILF) was calculated and correlated with mean heart dose (MHD) and volume of the ipsilateral lung receiving 18 Gy (V18Gy). Linear regression models were calculated. A validation cohort of 10 left- and 10 right-sided cases with an anterior supraclavicular fossa (SCF) field, and 10 left- and 10 right-sided cases including the internal mammary nodes using a wide tangential technique and anterior SCF field, tested the predictive model. Threshold values for %HIF and %ILF were calculated for clinically relevant MHD and ipsilateral lung V18Gy tolerance doses. Results For the model-building cohort, the median %HIF and MHD were 2.6 (0.4–16.7) and 2.3 (1.2–8) Gy. The median %ILF and ipsilateral lung V18Gy were 12.1 (2.8–33.6) and 12.6 (3.3–35) %. There was a statistically significant strong positive correlation of %HIF with MHD (r2 = 0.97, P Discussion The ability to VSim breast radiotherapy (±nodal targets) and accurately predict the heart and ipsilateral lung doses on the dosimetric plan will ensure that tolerance doses are not exceeded, and identify early in the pre-treatment pathway those cases where alternative techniques or modalities should be considered.

AIM Differentiated thyroid cancer (DTC) in children and adolescents is rare and data about its presentation and management are not well known. The aim of this study was to provide evidence of the current practice in the United Kingdom before the launch of the Rare National Paediatric Endocrine Tumours Guidelines (to be published in 2020). METHODS Seventy-two children and adolescents with DTC (

Objective. Adaptive radiotherapy workflows require images with the quality of computed tomography (CT) for re-calculation and re-optimisation of radiation doses. In this work we aim to improve the quality of on-board cone beam CT (CBCT) images for dose calculation using deep learning. Approach. We propose a novel framework for CBCT-to-CT synthesis using cycle-consistent Generative Adversarial Networks (cycleGANs). The framework was tailored for paediatric abdominal patients, a challenging application due to the inter-fractional variability in bowel filling and small patient numbers. We introduced to the networks the concept of global residuals only learning and modified the cycleGAN loss function to explicitly promote structural consistency between source and synthetic images. Finally, to compensate for the anatomical variability and address the difficulties in collecting large datasets in the paediatric population, we applied a smart 2D slice selection based on the common field-of-view (abdomen) to our imaging dataset. This acted as a weakly paired data approach that allowed us to take advantage of scans from patients treated for a variety of malignancies (thoracic-abdominal-pelvic) for training purposes. We first optimised the proposed framework and benchmarked its performance on a development dataset. Later, a comprehensive quantitative evaluation was performed on an unseen dataset, which included calculating global image similarity metrics, segmentation-based measures and proton therapy-specific metrics. Main results. We found improved performance for our proposed method, compared to a baseline cycleGAN implementation, on image-similarity metrics such as Mean Absolute Error calculated for a matched virtual CT (55.0 ± 16.6 HU proposed versus 58.9 ± 16.8 HU baseline). There was also a higher level of structural agreement for gastrointestinal gas between source and synthetic images measured using the dice similarity coefficient (0.872 ± 0.053 proposed versus 0.846 ± 0.052 baseline). Differences found in water-equivalent thickness metrics were also smaller for our method (3.3 ± 2.4% proposed versus 3.7 ± 2.8% baseline). Significance. Our findings indicate that our innovations to the cycleGAN framework improved the quality and structure consistency of the synthetic CTs generated.

Radiation may cause long-term splenic dysfunction, risking potentially fatal late sepsis. We aimed to review this complication's magnitude in paediatric radiotherapy and gauge the level of awareness of the spleen as an organ at risk.Clinical trial protocols and radiotherapy guidelines, patient/parent information sheets, and professional guidance documents were reviewed to assess the perceived risk of radiotherapy-related splenic dysfunction. Paediatric oncologists and paediatric radiation oncologists across Europe were surveyed to estimate the level of understanding of this risk and to ascertain current practice. Spleen doses received in practice were examined. A systematic review of relevant publications was undertaken.The risk is not mentioned in most clinical trials, patient information leaflets, or professional guidance documents. When mentioned, a threshold dose of 40 Gy is cited. The survey showed only limited awareness. More than half of patients assessed received spleen doses in excess of 10 Gy. The systematic review identified one paper reporting a relative mortality risk of 5.5 with spleen doses in the 10-20 Gy range.The risk of mortality from overwhelming infection is poorly recognised. We therefore recommend routine delineation of the spleen. Protocols and guidelines should give a spleen dose objective as low as reasonably achievable, ideally mean10 Gy without compromise to target volumes. Revised evidence-based guidelines and continuing professional development activities should inform oncologists. Patient/parent information should mention the risk and the dose received be communicated to colleagues. Antibiotic prophylaxis and/or (re)vaccination should be considered if the mean spleen dose is ≥10 Gy.

Rhabdomyosarcoma of the extremities present with two main challenges: correct evaluation of initial regional nodal involvement and define adequate local treatment. Methods Pediatric patients with localized rhabdomyosarcoma of the extremity included in the EpSSG‐RMS2005 study between 2005 and 2014 were evaluated for staging, treatment, and survival. The outcome was compared to the preceding European SIOP‐MMT studies. Results Of the 162 patients included, histology was unfavorable in 113 (70%), 124 (77%) were younger than 10 years, 128 (79%) were IRS III, and 47 (29%) were node‐positive. A regional node biopsy was performed in 97 patients (60%) and modified the lymph node stage in 15/97 (16%). Primary and delayed surgery was performed in 155 (96%) and radiotherapy delivered in 118 (73%) patients. Relapse occurred in 61 cases (38%), local in 14 (23%), regional in 13 (21%), distant in 22 (36%), and combined relapse in 12 (20%) with five progressive diseases (8%) and four secondary tumors (7%). Five‐year event free (EFS) and overall survival (OS) were 58.4% (95%CI, 50.3‐65.7) and 71.7% (63.6‐78.4), respectively. In the previous studies MMT89 and MMT95, tumor surgery was performed in 32/53 (60%) and 74/82(90%), respectively, and radiotherapy delivered in 13/53 (25%) and 26/82 (30%), respectively. Five‐year EFS and OS were 35.6%, and 50.3% in MMT89 and 54.3% and 68.2% in the MMT95 study. Conclusions Even if the lymph node staging was not always complete according to the RMS2005 protocol, node sampling changed lymph node status in a significant number of patients. Despite the higher rate of patients treated with locoregional radiotherapy, survival in RMS2005 did not improve compared to the previous European SIOP‐MMT95 study., Adequate staging is important for the treatment of extremity RMS. Despite local therapy intensification, survival in RMS2005 did not improve compared to the previous European SIOP‐MMT95 study.

The objective of this phase IIa, open-label, single-centre, single-arm, two-stage clinical trial was to evaluate the safety and activity of 177-lutetium DOTATATE (LuDO) molecular radiotherapy in neuroblastoma. Children with relapsed or refractory metastatic high-risk neuroblastoma were treated with up to four courses of LuDO. The administered activity was 75 to 100 MBq kg−1 per course, spaced at 8- to 12-week intervals. Outcomes were assessed by the International Neuroblastoma Response Criteria (primary outcome), progression-free survival (PFS), and overall survival (OS). The trial recruited 21 patients; eight received the planned four courses. There was dose-limiting haematologic toxicity in one case, but no other significant haematologic or renal toxicities. None of 14 evaluable patients had an objective response at 1 month after completion of treatment (Wilson 90% CI 0.0, 0.16; and 95% CI is 0.0, 0.22). The trial did not therefore proceed to the second stage. The median PFS was 2.96 months (95% CI 1.71, 7.66), and the median OS was 13.0 months (95% CI 2.99, 21.52). In the absence of any objective responses, the use of LuDO as a single agent at the dose schedule used in this study is not recommended for the treatment of neuroblastoma. There are several reasons why this treatment schedule may not have resulted in objective responses, and as other studies do show benefit, the treatment should not be regarded as being of no value. Further trials designed to overcome this schedule’s limitations are required. ISRCTN98918118; URL: https://www.isrctn.com/search?q=98918118

Conservative surgery (CS) brachytherapy (BT) techniques for local therapy in bladder-prostate rhabdomyosarcoma (BP-RMS) seek to retain organ function. We report bladder function after high-dose rate (HDR) BT combined with targeted CS for any vesical component of BP-RMS.Prospective cohort of all BP-RMS patients between 2014 and 2019 receiving HDR-BT (iridium-192, 27.5 Gy in five fractions) with/without percutaneous endoscopic polypectomy (PEP) or partial cystectomy (PC). Functional assessment included frequency-volume chart, voided volumes, post-void residual, flow studies, continence status and ultrasound scanning; abnormalities triggered video urodynamics.Thirteen patients (10 male), aged 9 months to 4 years (median 23 months), presented with localised fusion-negative embryonal BP-RMS measuring 23-140 mm (median 43 mm) in cranio-caudal extent. After induction chemotherapy, local treatment consisted of PC+BT in three, PEP+BT in four and BT alone in six. At a median 3.5 years (range 21 months to 7 years) follow-up, all were alive without relapse. At a median age of 6 years (4-9 years), the median bladder capacity was 86% (47%-144%) of that expected for age, including 75% (74%-114%) after PC. Radiation dose to the bladder was associated with urinary urgency, but not bladder capacity or nocturnal enuresis. Complications occurred in two: one urethral stricture and one vesical decompensation in a patient with pre-existing high-grade vesico-ureteric reflux (VUR). The remaining patients were dry by day; five with anticholinergic medication for urinary urgency. Three patients are enuretic.Day-time dryness at a median 3.5 years after CS-HDR-BT was achieved in 92%, with 85% voiding urethrally, and 62% attaining day-and-night continence aged 4-9 years. We report reduced open surgery with minimally invasive percutaneous surgery, with HDR-BT or BT alone being suitable for many.

Infants (12 months) with rhabdomyosarcoma have historically had poorer outcome than the older age groups. We present outcomes for infants and young children aged 12-36 months with localised rhabdomyosarcoma with a particular emphasis on infants.All children less than 36 months of age enrolled on the EpSSG RMS 2005 study for localised disease are included. Treatment comprised chemotherapy, local surgery and/or radiation therapy adapted to risk group and age. Main outcome measures were event free survival (EFS) and overall survival (OS).Outcome data were available for 485/490 patients aged less than 36 months, 110 were infants. Infants received chemotherapy according to the risk group with no toxic deaths. Radiotherapy was delivered to 33.6% of infants and 63.5% of 12-36 months old, with respectively 41.7% and 22.2% receiving brachytherapy. Radical surgery was performed in 62% of infants and 57.1% of 12-36 months old. Median follow up for patients who are alive (n = 393) was 72.7 months (range 6.9-158.2). Five-year OS for infants was 88.4% (95%CI 80.3-93.2), which is significantly better than the OS in 12-36 months old patients of 78.0% (95%CI 73.2-82.0; p = 0.0204). Five-year EFS for infants was 72.5% (95%CI 62.8-80.0) compared with 66.1% (95%CI 61.0-70.7; p = 0.2663) for 12-36 months old.Infants treated on RMS 2005 achieved excellent EFS and OS. The EpSSG RMS 2005 chemotherapy regimen, combined with an increase in the application of adequate local therapy, improvements in imaging and supportive care and potentially favourable patients' characteristics may have contributed to these results.

PurposeNeuroendocrine tumors (NET) are rare cancers with variable behavior. A better understanding of prognosis would aid individualized management. The aim of this hypothesis-generating pilot study was to investigate the prognostic potential of tumor heterogeneity and tracer avidity in NET using texture analysis (TA) of 68Ga-DOTATATE positron emission tomography (PET) and non-enhanced computed tomography (CT) performed at baseline in patients treated with 177Lu-DOTATATE. It aims to justify a larger-scale study to evaluate its clinical value.MethodsThe pretherapy 68Ga-DOTATATE PET-CT scans of 44 patients with metastatic NET (carcinoid, pancreatic, thyroid, head and neck, catecholamine-secreting, and unknown primary NET) treated with 177Lu-DOTATATE were analyzed retrospectively using commercially available texture analysis research software. Image filtration extracted and enhanced objects of different sizes (fine, medium, coarse), then quantified heterogeneity by statistical and histogram-based parameters (mean intensity, standard deviation, entropy, mean of positive pixels, skewness, and kurtosis). Regions of interest were manually drawn around up to five of the most 68Ga-DOTATATE avid lesions for each patient. 68Gallium uptake on PET was quantified as SUVmax and SUVmean. Associations between imaging and clinical markers with progression-free (PFS) and overall survival (OS) were assessed using univariate Kaplan-Meier analysis. Independence of the significant univariate markers of survival was tested using multivariate Cox regression analysis.ResultsMeasures of heterogeneity (higher kurtosis, higher entropy, and lower skewness) on coarse-texture scale CT and unfiltered PET images predicted shorter PFS (CT coarse kurtosis: p=0.05, PET entropy: p=0.01, PET skewness: p=0.03) and shorter OS (CT coarse kurtosis: p=0.05, PET entropy: p=0.01, PET skewness p=0.02). Conventional PET parameters such as SUVmax and SUVmean showed trends towards predicting outcome but were not statistically significant. Multivariate analysis identified that CT-TA (coarse kurtosis: HR=2.57, 95% CI=1.22–5.38, p=0.013) independently predicted PFS, and PET-TA (unfiltered skewness: HR=9.05, 95% CI=1.19–68.91, p=0.033) independently predicted OS.ConclusionThese preliminary data generate a hypothesis that radiomic analysis of neuroendocrine cancer on 68Ga-DOTATATE PET-CT may be of prognostic value and a valuable addition to the assessment of patients.

Aims To obtain an overview of the management and outcomes of children aged 18 years or younger diagnosed with differentiated thyroid carcinoma of follicular cell origin across the UK, by collecting and analysing data from the limited number of centres treating these patients. This multicentre data might provide a more realistic perspective than single-institution series. Materials and methods Six centres submitted data extracted from historical records on patients aged 18 years or younger, diagnosed between 1964 and 2017. The univariate and multivariable Cox proportional hazard model was used to identify potential predictors of progression-free survival, using national data as a control. Results Data on 166 patients were available for analysis. Females (74%) were predominant, and the age ranged from 3 to 19 years at diagnosis, mean 14.1 years. Nodal metastases were present in 51%; 12% had distant metastases. After surgery, 95% received radioactive iodine (39% on more than one occasion) and 4% received external beam radiotherapy. With a median follow-up duration of 5 years, 69% are alive with no evidence of disease; 20% are alive with a raised thyroglobulin level as the only evidence of residual disease; 6% have residual structural disease detectable on imaging; 2% have died, from cerebral metastases. Conclusion Despite most patients having advanced disease at presentation, outcomes are very good. A national prospective registry should allow systematic collection of good-quality data and may facilitate research to further improve outcomes.

Imaging has an essential role in the planning and delivery of radiotherapy. Recent advances in imaging have led to the development of advanced radiotherapy techniques—including image-guided radiotherapy, intensity-modulated radiotherapy, stereotactic body radiotherapy and proton beam therapy. The optimal use of imaging might enable higher doses of radiation to be delivered to the tumour, while sparing normal surrounding tissues. In this article, we review how the integration of existing and novel forms of computed tomography, magnetic resonance imaging and positron emission tomography have transformed tumour delineation in the radiotherapy planning process, and how these advances have the potential to allow a more individualised approach to the cancer therapy. Recent data suggest that imaging biomarkers that assess underlying tumour heterogeneity can identify areas within a tumour that are at higher risk of radio-resistance, and therefore potentially allow for biologically focussed dose escalation. The rapidly evolving concept of adaptive radiotherapy, including artificial intelligence, requires imaging during treatment to be used to modify radiotherapy on a daily basis. These advances have the potential to improve clinical outcomes and reduce radiation-related long-term toxicities. We outline how recent technological advances in both imaging and radiotherapy delivery can be combined to shape the future of precision radiation oncology.

Recent reports personalizing the administered activity (AA) of each cycle of peptide receptor radionuclide therapy based on the predicted absorbed dose (AD) to the kidneys (dose-limiting organ) have been promising. Assuming identical renal pharmacokinetics for each cycle is pragmatic, however it may lead to over- or under-estimation of the optimal AA. Here, we investigate the influence that earlier cycles of [A simulation study, based on dosimetry data from six children with NBL who received four-cycles of [The median tumour AD per cycle was found to decrease from 15.6 Gy (range 8.12-26.4) in cycle 1 to 11.4 Gy (range 9.67-28.8), 11.3 Gy (range 2.73-32.9) and 4.3 Gy (range 0.72-20.1) in cycles 2, 3 and 4, respectively. By the fourth cycle, the median of the ratios of the delivered AD (ADThis study demonstrates variability in Gy/GBq and tumour AD per cycle in children receiving four administrations of [

Reducing radiation-induced side effects is one of the most important challenges in paediatric cancer treatment. Recently, there has been growing interest in using spatial normalisation to enable voxel-based analysis of radiation-induced toxicities in a variety of patient groups. The need to consider three-dimensional distribution of doses, rather than dose-volume histograms, is desirable but not yet explored in paediatric populations. In this paper, we investigate the feasibility of atlas construction and spatial normalisation in paediatric radiotherapy. We used planning computed tomography (CT) scans from twenty paediatric patients historically treated with craniospinal irradiation to generate a template CT that is suitable for spatial normalisation. This childhood cancer population representative template was constructed using groupwise image registration. An independent set of 53 subjects from a variety of childhood malignancies was then used to assess the quality of the propagation of new subjects to this common reference space using deformable image registration (i.e. spatial normalisation). The method was evaluated in terms of overall image similarity metrics, contour similarity and preservation of dose-volume properties. After spatial normalisation, we report a dice similarity coefficient of 0.95 ± 0.05, 0.85 ± 0.04, 0.96 ± 0.01, 0.91 ± 0.03, 0.83 ± 0.06 and 0.65 ± 0.16 for brain and spinal canal, ocular globes, lungs, liver, kidneys and bladder. We then demonstrated the potential advantages of an atlas-based approach to study the risk of second malignant neoplasms after radiotherapy. Our findings indicate satisfactory mapping between a heterogeneous group of patients and the template CT. The poorest performance was for organs in the abdominal and pelvic region, likely due to respiratory and physiological motion and to the highly deformable nature of abdominal organs. More specialised algorithms should be explored in the future to improve mapping in these regions. This study is the first step toward voxel-based analysis in radiation-induced toxicities following paediatric radiotherapy.

Background/objectives The primary aim of this study was to analyse and evaluate the impact of different local treatments on the pattern of relapse in children with primary head and neck non-parameningeal (HNnPM) rhabdomyosarcoma (RMS), treated in the European paediatric Soft tissue sarcoma Study Group (EpSSG) RMS2005 study. The secondary aim was to assess whether current risk stratification is valid for this specific site. Design/methods This study includes all patients with localised HNnPM RMS enrolled in the RMS2005 study between 2005 and 2016. Treatment comprised chemotherapy adapted to risk group, with local surgery and/or radiation therapy. The main outcome measures were event-free survival (EFS) and overall survival (OS). Results A total of 165 patients were identified; the median age was 6.4 years (range, 0.1–25). The most common tumour sites were cheek/chin (22%) and nasal ala/nasolabial fold (20%). Histology was unfavourable for 40%, and regional nodal involvement present in 26%. Local therapy included surgery (58%) and/or radiotherapy (72%) to primary tumour and/or regional lymph nodes. After a median follow-up of 66 months (range, 6–158), 42 patients experienced an event, and 17 are still alive. Tumour events were frequent in oral primary (36%), parotid site (26%), cheek/chin (24%), and nasal ala/nasolabial fold (24%) and included locoregional failure in 84% of cases. The 5-year EFS and OS were 75% (95% confidence interval [CI]: 67.3–81.2) and 84.9% (95% CI: 77.5–89.7), respectively. Favourable histology was associated with a better EFS (82.3% versus 64.6%; p = 0.02) and nodal spread with a worse OS (88.6% versus 76.1%; p = 0.04). Different sublocations within the HNnPM primary did not have significant impact on outcome. Conclusion Locoregional relapse/progression is the main tumour failure event in this site. Despite frequent unfavourable risk factors, HNnPM RMS remains a favourable location in the context of a risk-adapted strategy.

Purpose There is limited evidence to define the role of radiation therapy in children with metastatic rhabdomyosarcoma (mRMS). In the international BERNIE study, children with mRMS or non-RMS soft tissue sarcoma were randomized to receive standard chemotherapy with or without bevacizumab, with radiation therapy to all disease sites recommended after chemotherapy cycle 6. We retrospectively evaluated the impact of radiation therapy on survival in the mRMS cohort. Methods and Materials Patients were grouped according to the radiation therapy they received: radical, partial, or none. Radical irradiation was defined as radiation therapy delivered to all disease sites, unless a site was completely surgically resected. Partial irradiation was defined as radiation therapy to ≥1, but not all, disease sites. Landmark analysis excluded patients with an event before day 221. Overall survival (OS) and event-free survival (EFS) were modeled using Cox proportional hazards models. Results Of 102 patients with mRMS, 97 were included in the analysis for OS and 85 for EFS. Overall, 27 patients received radical irradiation, 46 partial irradiation, and 24 no irradiation. EFS was not significantly different among patient groups after adjustment for prognostic factors (hazard ratio [HR] = 0.520; P = .054 for any vs no irradiation). Radiation therapy was associated with improved OS compared with no radiation therapy (adjusted HR = 0.249; P = .00025), with OS being greater for radical versus partial irradiation (HR = 0.245; P = .039). The 3-year OS rate was 84%, 54%, and 23% for patients receiving radical, partial, and no irradiation, respectively. Radical treatment (surgery, irradiation, or both) of the primary site improved EFS and OS compared with no treatment. Conclusions These findings demonstrate variability in the application of radiation therapy for mRMS and support the routine use of radical treatment to the primary site. Radical irradiation to metastatic sites may further improve OS. The burden of such treatment should be balanced against prognosis; further studies are needed.

Background Previous studies have found that parents of children with cancer desire more prognostic information than is often given even when prognosis is poor. We explored in audio-recorded consultations the kinds of information they seek. Methods Ethnographic study including observation and audio recording of consultations at diagnosis. Consultations were transcribed and analyzed using an interactionist perspective including tools drawn from conversation and discourse analysis. Results Enrolled 21 parents and 12 clinicians in 13 cases of children diagnosed with a high-risk brain tumor (HRBT) over 20 months at a tertiary pediatric oncology center. Clinicians presented prognostic information in all cases. Through their questions, parents revealed what further information they desired. Clinicians made clear that no one could be absolutely certain what the future held for an individual child. Explicit communication about prognosis did not satisfy parents' desire for information about their own child. Parents tried to personalize prognostic information and to apply it to their own situation. Parents moved beyond prognostic information presented and drew conclusions, which could change over time. Parents who were present in the same consultations could form different views of their child's prognosis. Conclusion Population level prognostic information left parents uncertain about their child's future. The need parents revealed was not for more such information but rather how to use the information given and how to apply it to their child in the face of such uncertainty. Further research is needed on how best to help parents deal with uncertainty and make prognostic information actionable.

Chapter 1 introduces the topic of cancer in children, teenagers, and young adults. Cancer in children and young people is rare: less than 1% of total cancer incidence. There is a wide variety of tumour types, and these are often different from the common adult cancers. Leukaemia, brain tumours, and malignancies of embryonal origin are most common in younger children. Genetic predisposition is important. Environmental causes are less common than in adults. Treatments have improved significantly and, currently, about three out of four children and young people are cured of their cancer. Multimodality protocols including chemotherapy, surgery, and, more frequently now, biological treatment, in addition to selective use of more sophisticated radiotherapy techniques, is the norm. Increasing personalization of treatment based on risk stratification has allowed for improved cure rates with a reduction in treatment-related morbidity.

Chapter 2 discusses cancer services for children, teenagers, and young adults. Paediatric and teenage and young adult practice covers an age range from babies through adolescence to maturity. Oncological services should be age and developmentally appropriate. As cancers in this age group are rare and different from common adult malignancies, specialist treatment should be limited to regional centres with the required expertise. Multidisciplinary teams with diagnostic, therapeutic, and supportive-care expertise are needed. As decision-making can be challenging, wider discussions are sometimes required to select the best treatment option. The aim is to maximize the chance of cure with the fewest late effects. Radiotherapy for children and young people is complex and requires a team approach including specialist radiographers and radiation oncologists, as well as support from paediatric medical, nursing, and anaesthetic staff. Enrolment into clinical trials is the standard of care. Paediatric radiation oncologists should be involved in these trials.

Chapter 8 discusses lymphoid and haematological malignancy and related conditions in children and young people. Radiotherapy is less frequently used in haematological malignancy and allied disorders than it once was. In Hodgkin lymphoma, better risk stratification, more effective systemic therapy and the use of 18F-fluoro-deoxyglucose positron emission tomography (18F-FDG-PET) imaging to assess response to chemotherapy have facilitated a safe reduction in the indications for radiotherapy. Nonetheless, radiotherapy remains an important component of multimodality therapy in patients with advanced or poorly responding disease. In acute leukaemia, radiotherapy is no longer used as part of first-line treatment schedules. Instead, it is reserved for refractory and relapsed disease. Total body irradiation remains valuable as part of conditioning prior to haemopoietic stem cell transplantation. Cranial and testicular radiotherapy is helpful for selected patients who relapse in these sanctuary sites. Radiotherapy is also indicated infrequently in some unusual and benign haematological conditions.

Chapter 6 discusses brain tumours, the commonest solid neoplasms of children and young people, which account for about one-quarter of all malignancies in this age group. There are many different varieties: medulloblastomas and other embryonal tumours, and low- and high-grade gliomas, form the commonest categories. Craniopharyngiomas, ependymomas, intracranial germ cell tumours, and other rare types are less frequently encountered. Most brain and spinal tumours are treated with a multimodality schedule comprising surgery, chemotherapy, and radiotherapy. The place of radiotherapy in the management of central nervous system tumours is described in detail.

Chapter 4 discusses radiotherapy preparation and treatment. There are many ways of delivering radiotherapy, and the best technique should be chosen for each child, teenager, or young adult for whom irradiation is indicated. Image-guided, intensity-modulated radiotherapy techniques are gradually replacing three-dimensional conformal approaches. Proton beam radiotherapy offers the advantage of lower normal tissue radiation doses in many circumstances, and its availability and use is growing. Highly specialized techniques including hypofractionated stereotactic radiotherapy, molecular radiotherapy, and brachytherapy offer important advantages in a small number of cases. Anaesthetic teams are essential for the immobilization of infants and most younger children requiring radiotherapy. Play specialists may reduce the need for anaesthesia in some cases, and greatly facilitate treatment of older children. Good imaging is essential for accurate target volume delineation, and careful prospective quality assurance of this process will help to improve outcomes.

Chapter 3 discusses cancer diagnosis, risk stratification, and therapeutic choices in children and young people. Radiological investigations support the diagnosis and provide staging information for accurate risk stratification. Interventional radiology is useful for obtaining tissue for pathological examination. Histopathology and molecular studies define the precise tumour type and subtype and are used to confirm or rule out the presence of metastatic disease. Post-operative histopathology defines the extent of spread and is important for the staging of some tumours. Together, these findings inform multidisciplinary team discussion and help to identify the best treatment schedule. A significant proportion of cancers have a genetic basis, and it is important to identify these from the family history, predisposing syndromes, or tumour type. Modern molecular genomic techniques have made definitive diagnosis easier. Some genetic conditions lead to increased radiosensitivity and may predispose the patient to excessive radiation-related morbidity and a high risk of second primary tumours.

Chapter 7 discusses paediatric extracranial solid tumours. Paediatric extracranial solid tumours are very diverse. They include soft tissue and bone sarcomas, embryonal tumours such as neuroblastoma and Wilms tumour, and carcinomas. The prognosis of each type varies considerably depending on stage, tumour biology, and other factors. Careful risk stratification is necessary to determine the best approach to treatment. This is often multimodal, usually including chemotherapy and surgery, and sometimes radiotherapy. It is often possible to avoid radiotherapy in the better-prognosis risk groups, reserving this treatment, and the associated late effects, for those with the worst outlook. A strong evidence base has developed for the most common tumour types, but further clinical trials are required to optimize the role of radiotherapy.

Molecular radiotherapy, or targeted radionuclide therapy, uses systemically administered drugs bearing a suitable radioactive isotope, typically a beta emitter. These are delivered via metabolic or other physiological pathways to cancer cells in greater concentrations than to normal tissues. The absorbed radiation dose in tumour deposits causes chromosomal damage and cell death. A partner radiopharmaceutical, most commonly the same vector labelled with a different radioactive atom, with emissions suitable for gamma camera or positron emission tomography imaging, is used to select patients for treatment and to assess response. The use of these pairs of radio-labelled drugs, one optimised for therapy, the other for diagnostic purposes, is referred to as theragnostics. Theragnostics is increasingly moving away from a fixed number of defined activity administrations, to a much more individualised or personalised approach, with the aim of improving treatment outcomes, and minimising toxicity. There is, however, still significant scope for further progress in that direction. The main tools for personalisation are the following: imaging biomarkers for better patient selection; predictive and post-therapy dosimetry to maximise the radiation dose to the tumour while keeping organs at risk within tolerance limits; imaging for assessment of treatment response; individualised decision making and communication about radiation protection, adjustments for toxicity, inpatient and outpatient care.

Purpose Iodine-131-labelled meta-iodobenzylguanidine (I-mIBG) and lutetium-177-labelled DOTATATE (Lu-DOTATATE) are used for molecular radiotherapy of metastatic neuroblastoma. These are taken up by the noradrenaline transporter (NAT) and the somatostatin receptor subtype 2 (SSTR-2), respectively. Scintigraphy of iodine-123-labelled meta-iodobenzylguanidine (I-mIBG) and gallium-68 DOTATATE (Ga-DOTATATE) PET are used to select patients for therapy. These demonstrate the extent and location of tumour, and avidity of uptake by cells expressing NAT and SSTR-2, respectively. This study compared the similarities and differences in the anatomical distribution of these two imaging biomarkers in an unselected series of patients with metastatic neuroblastoma undergoing assessment for molecular radiotherapy. Methods Paired whole-body planar I-mIBG views and Ga-DOTATATE maximum intensity projection PET scans of metastatic neuroblastoma patients were visually compared. The disease extent was assessed by a semiquantitative scoring method. Results Paired scans from 42 patients were reviewed. Ga-DOTATATE scans were positive in all patients, I-mIBG scans were negative in two. In two patients, there was a mismatch, with some lesions identified only on the I-mIBG scan, and others visible only on the Ga-DOTATATE scan. Conclusion Ga-DOTATATE and I-mIBG scans yield complementary information. For a more comprehensive assessment, consideration could be given to the use of both I-mIBG and Ga-DOTATATE imaging scans. Because of the heterogeneity of distribution of molecular targets revealed by these techniques, a combination of both I-mIBG and Lu-DOTATATE molecular radiotherapy may possibly be more effective than either alone.

The common contemporary indications for paediatric molecular radiotherapy (pMRT) are differentiated thyroid cancer and neuroblastoma. It may also have value in neuroendocrine cancers, and it is being investigated in clinical trials for other diseases. pMRT is the prototypical biomarker-driven, precision therapy, with a unique mode of delivery and mechanism of action. It is safe and well tolerated, compared with other treatments. However, its full potential has not yet been achieved, and its wider use faces a number of challenges and obstacles. Paradoxically, the success of radioactive iodine as a curative treatment for metastatic thyroid cancer has led to a 'one size fits all' approach and limited academic enquiry into optimisation of the conventional treatment regimen, until very recently. Second, the specialised requirements for the delivery of pMRT are available in only a very limited number of centres. This limited capacity and geographical coverage results in reduced accessibility. With few enthusiastic advocates for this treatment modality, investment in research to improve treatments and broaden indications from both industry and national and charitable research funders has historically been suboptimal. Nonetheless, there is now an increasing interest in the opportunities offered by pMRT. Increased research funding has been allocated, and technical developments that will permit innovative approaches in pMRT are available for exploration. A new portfolio of clinical trials is being assembled. These studies should help to move at least some paediatric treatments from simply palliative use into potentially curative protocols. Therapeutic strategies require modification and optimisation to achieve this. The delivery should be personalised and tailored appropriately, with a comprehensive evaluation of tumour and organ-at-risk dosimetry, in alignment with the external beam model of radiotherapy. This article gives an overview of the current status of pMRT, indicating the barriers to progress and identifying ways in which these may be overcome.

PURPOSE To evaluate the impact of surgeon-assessed extent of primary tumor resection on local progression and survival in patients in the International Society of Pediatric Oncology Europe Neuroblastoma Group High-Risk Neuroblastoma 1 trial. PATIENTS AND METHODS Patients recruited between 2002 and 2015 with stage 4 disease > 1 year or stage 4/4S with MYCN amplification < 1 year who had completed induction without progression, achieved response criteria for high-dose therapy (HDT), and had no resection before induction were included. Data were collected on the extent of primary tumor excision, severe operative complications, and outcome. RESULTS A total of 1,531 patients were included (median observation time, 6.1 years). Surgeon-assessed extent of resection included complete macroscopic excision (CME) in 1,172 patients (77%) and incomplete macroscopic resection (IME) in 359 (23%). Surgical mortality was 7 (0.46%) of 1,531. Severe operative complications occurred in 142 patients (9.7%), and nephrectomy was performed in 124 (8.8%). Five-year event-free survival (EFS) ± SE (0.40 ± 0.01) and overall survival (OS; 0.45 ± 0.02) were significantly higher with CME compared with IME (5-year EFS, 0.33 ± 0.03; 5-year OS, 0.37 ± 0.03; P < .001 and P = .004). The cumulative incidence of local progression (CILP) was significantly lower after CME (0.17 ± 0.01) compared with IME (0.30 ± 0.02; P < .001). With immunotherapy, outcomes were still superior with CME versus IME (5-year EFS, 0.47 ± 0.02 v 0.39 ± 0.04; P = .038); CILP was 0.14 ± 0.01 after CME and 0.27 ± 0.03 after IME ( P < .002). A hazard ratio of 1.3 for EFS associated with IME compared with CME was observed before and after the introduction of immunotherapy ( P = .030 and P = .038). CONCLUSION In patients with stage 4 high-risk neuroblastoma who have responded to induction therapy, CME of the primary tumor is associated with improved survival and local control after HDT, local radiotherapy (21 Gy), and immunotherapy.

Metàstasis; Pediatria; Radioteràpia Metástasis; Pediatría; Radioterapia Metastases; Paediatrics; Radiotherapy Purpose/objective About 20% of children with solid tumours (ST) present with distant metastases (DM). Evidence regarding the use of radical radiotherapy of these DM is sparse and open for personal interpretation. The aim of this survey was to review European protocols and to map current practice regarding the irradiation of DM across SIOPE-affiliated countries. Materials/methods Radiotherapy guidelines for metastatic sites (bone, brain, distant lymph nodes, lung and liver) in eight European protocols for rhabdomyosarcoma, non-rhabdomyosarcoma soft-tissue sarcoma, Ewing sarcoma, neuroblastoma and renal tumours were reviewed. SIOPE centres irradiating ≥50 children annually were invited to participate in an online survey. Results Radiotherapy to at least one metastatic site was recommended in all protocols, except for high-risk neuroblastoma. Per protocol, dose prescription varied per site, and information on delineation and treatment planning/delivery was generally missing. Between July and September 2019, 20/27 centres completed the survey. Around 14% of patients were deemed to have DM from ST at diagnosis, of which half were treated with curative intent. A clear cut-off for a maximum number of DM was not used in half of the centres. Regardless of the tumour type and site, conventional radiotherapy regimens were most commonly used to treat DM. When stereotactic radiotherapy was used, a wide range of fractionation regimens were applied. Conclusion Current radiotherapy guidelines for DM do not allow a consistent approach in a multicentre setting. Prospective (randomised) trials are needed to define the role of radical irradiation of DM from paediatric ST. Stichting Kinderen Kankervrij [project no. 343]. KiKa (Children Cancer Free) foundation, grant number 343 and title: Towards optimization of radiotherapy techniques for metastatic lesions in children stage IV disease. The funding source had no role in the study design, collection, analysis and interpretation of data, writing of this manuscript or the decision to submit the article for publication.

Aims Pencil beam scanning (PBS) proton therapy is an increasingly used radiation modality for childhood malignancies due to its ability to minimise dose to surrounding organs. However, the dosimetry is extremely sensitive to anatomical and density changes. The aims of this study were to investigate if there is a dosimetric benefit or detriment with PBS for paediatric abdominal neuroblastoma, assess gastrointestinal air variability and its dosimetric consequences, plus identify if there are factors that could assist case selection for PBS referral. Materials and methods Twenty neuroblastoma cases were double-planned with PBS and intensity-modulated arc therapy (IMAT). Cases were divided into unilateral, midline unilateral and midline bilateral locations in relation to the kidneys. Plans were recalculated after the gastrointestinal volume was simulated as air (Hounsfield Units –700) and water (Hounsfield Units 0), then compared with nominal plans (recalculated – nominal, ΔD). Forty-three weekly cone beam computed tomography scans were analysed to quantify gastrointestinal air variability during treatment. Results PBS reduced the mean dose to normal tissues at all tumour locations, particularly unilateral tumours. However, 15% had better dosimetry with IMAT, all of which were midline tumours. Increased gastrointestinal air caused significant compromises to PBS versus IMAT plans for midline tumours [median/maximum ΔD95% clinical target volume (CTV) –2.4%/–15.7% PBS versus 1.4%/0% IMAT, P = 0.003], whereas minimal impact was observed for unilateral tumours (ΔD95% CTV –0.5%/–1.9% PBS versus 0.5%/–0.5% IMAT, P = 0.008). D95% CTV was significantly decreased in PBS plans if planning target volume (PTV) ≥400 cm3 (median –4.1%, P = 0.001) or PTV extension ≥60% anterior to vertebral body (–2.1%, P = 0.002). A larger variation in gastrointestinal air was observed in patients treated under general anaesthesia (median 38.4%) versus awake (11.5%); P = 0.004. Conclusion In this planning study, tumours at the unilateral location consistently showed improved dose reductions to normal tissue with minimal dose degradation from increased gastrointestinal air with PBS plans. Tumour location, PTV volume and anterior extension of PTV are useful characteristics in facilitating patient selection for PBS.

To explore the effects of immunotherapy in the International Society of Paediatric Oncology Europe Neuroblastoma Group SIOPEN high-risk neuroblastoma 1 trial (HR-NBL1 trial), two cohorts were studied: one prior to and one after the introduction of dinutuximab beta. All patients received standard induction and high-dose therapy (HDT) with autologous stem cell rescue (ASCR), the local control comprised surgery and radiotherapy to the primary tumour site, followed by isotretinoin. A landmark timepoint of 109 days, resulting from the median time between ASCR and initiation of immunotherapy, was used to define patients&rsquo, eligibility in the pre-immunotherapy analysis cohort. Median follow-up was 5.8 years (inter-quartile range (IQR): 4.2&ndash, 8.2 years) for 844 eligible patients balanced for risk factors, such as age, sex, stage 4, MYCN amplification and response prior to HDT. The five-year event-free and overall survival (95% confidence interval (CI) of 466 patients not receiving immunotherapy was 42% (38&ndash, 47%) and 50% (46&ndash, 55%) but was 57% (51&ndash, 62%) and 64% (59&ndash, 69%) for 378 patients receiving immunotherapy (p &lt, 0.001). A multivariate analysis identified absence of immunotherapy (p = 0.0002, hazard ratio (HR) 1.573), type of HDT (p = 0.0029, HR 1.431), less than complete response prior to maintenance therapy (p = 0.0043, HR 1.494) and &gt, 1 metastatic compartment at diagnosis (p &lt, 0.001, HR 2.665) as risk factors for relapse or progression. Results suggest an important role for dinutuximab beta-based immunotherapy within the treatment concepts applied in HR-NBL1/SIOPEN.

Targeted radiotherapy of metastatic neuroblastoma using the somatostatin receptor (SSTR)-targeted octreotide analogue DOTATATE radiolabelled with lutetium-177 (177Lu-DOTATATE) is a promising strategy. This study evaluates whether its effectiveness may be enhanced by combination with radiosensitising drugs. The growth rate of multicellular tumour spheroids, derived from the neuroblastoma cell lines SK-N-BE(2c), CHLA-15 and CHLA-20, was evaluated following treatment with 177Lu-DOTATATE, nutlin-3 and topotecan alone or in combination. Immunoblotting, immunostaining and flow cytometric analyses were used to determine activation of p53 signalling and cell death. Exposure to 177Lu-DOTATATE resulted in a significant growth delay in CHLA-15 and CHLA-20 spheroids, but not in SK-N-BE(2c) spheroids. Nutlin-3 enhanced the spheroid growth delay induced by topotecan in CHLA-15 and CHLA-20 spheroids, but not in SK-N-BE(2c) spheroids. Importantly, the combination of nutlin-3 with topotecan enhanced the spheroid growth delay induced by X-irradiation or by exposure to 177Lu-DOTATATE. The efficacy of the combination treatments was p53-dependent. These results indicate that targeted radiotherapy of high risk neuroblastoma with 177Lu-DOTATATE may be improved by combination with the radiosensitising drugs nutlin-3 and topotecan.