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Most children requiring radiotherapy receive external beam treatment and few have tumours suitable for brachytherapy. No paediatric radiotherapy centre will treat enough patients from its own normal catchment population for expertise in brachytherapy to be developed and sustained. Following discussion and agreement in the national paediatric radiotherapy group, a service for paediatric brachytherapy in the UK has been developed. We report the process that has evolved over more than 10 years, with survival and functional outcome results. Since 2009, potential patients have been referred to the central paediatric oncology multidisciplinary team meeting, where imaging, pathology and treatment options are discussed. Since 2013, the National Soft Tissue Sarcoma Advisory Panel has also reviewed most patients, with the principal aim of advising on the most suitable primary tumour management for complex patients. Clinical assessment and examination under anaesthetic with biopsies may be undertaken to confirm the appropriateness of brachytherapy, either alone or following conservative surgery. Fractionated high dose rate brachytherapy was delivered to a computed tomography planned volume after implantation of catheters under ultrasound imaging guidance. Since 2019, follow-up has been in a dedicated multidisciplinary clinic. From 2009 to 2021 inclusive, 35 patients (16 female, 19 male, aged 8 months to 17 years 6 months) have been treated. Histology was soft-tissue sarcoma in 33 patients and carcinoma in two. The treated site was pelvic in 31 patients and head and neck in four. With a median follow-up of 5 years, the local control and overall survival rates are 100%. Complications have been few, and functional outcome is good. Brachytherapy is effective for selected paediatric patients, resulting in excellent tumour control and good functional results. It is feasible to deliver paediatric brachytherapy at a single centre within a national referral service. • A national referral service for paediatric brachytherapy has been established in the UK. • Potential patients are carefully selected for suitability through a national multidisciplinary expert panel discussion and clinical evaluation. • Over 13 years, 35 patients have been treated with a median follow-up of 5 years. • All patients have achieved local control and the 5-year survival probability is 100% with good functional outcomes. [ABSTRACT FROM AUTHOR]

Abstract: Aims: To determine whether palliation of chest symptoms from a 10Gy single fraction (regimen 1) was equivalent to that from 30Gy in 10 fractions (regimen 2). Materials and methods: Patients with cytologically proven, symptomatic lung cancer not amenable to curative therapy, with performance status 0–3, were randomised to receive either 30Gy in 10 fractions or a 10Gy single fraction. Local symptoms were scored on a physician-assessed, five-point categorical scale and summed to produce a total symptom score (TSS). This, performance status, Hospital Anxiety and Depression (HAD) score and Spitzer''s quality-of-life index were noted before treatment, at 1 month after treatment and every 2 months thereafter. Palliation was defined as an improvement of one point or more in the categorical scale. Equivalence was defined as less than 20% difference in the number achieving an improvement in the TSS. Results: We randomised 149 patients and analysed 74 in each arm. According to the design criteria, palliation was equivalent between the two arms. TSS improved in 49 patients (77%) on regimen 1, and in 57 (92%) patients on regimen 2, a difference of 15% (95% confidence interval [CI] 3–28) in the proportion improving between the two regimens. A complete resolution of all symptoms was achieved in three (5%) on regimen 1, and in 14 (23%) patients on regimen 2 (P<0.001), a difference in the proportion between the two regimens of 21% (95% CI 10–33). A significantly higher proportion of patients experienced palliation and complete resolution of chest pain and dyspnoea with regimen 2. No differences were observed in toxicity. The median survival was 22.7 weeks for regimen 1 and 28.3 weeks for regimen 2 (P=0.197). Conclusions: Although this trial met the pre-determined criteria for equivalence between the two palliative regimens, significantly more patients achieved complete resolution of symptoms and palliation of chest pain and dyspnoea with the fractionated regimen. [Copyright &y& Elsevier]

For high-risk neuroblastoma, planning target volume coverage is often compromised to respect adjacent kidney tolerance. This trial investigated whether intensity-modulated arc radiotherapy techniques (IMAT) could facilitate dose escalation better than conventional techniques. Children with high-risk abdominal neuroblastoma referred for radiotherapy to the primary tumour site and involved regional lymph nodes were randomised to receive either standard dose (21 Gy in 14 fractions) or escalated dose (36 Gy in 24 fractions) radiotherapy. Dual planning with both a conventional anterior-posterior parallel opposed pair radiotherapy technique and an IMAT technique was performed. The quality of target volume and organ-at-risk delineation, and dosimetric plans, were externally reviewed. Dosimetric parameters were used to judge the superior technique for treatment. This feasibility trial was not powered to detect improvement in outcome with dose escalation. Between 2017 and 2020, 50 patients were randomised and dual-planned. The IMAT technique was judged more favourable in 48 patients. In all patients randomised to receive 36 Gy, IMAT would have permitted delivery of the full dose (median D50% 36.0 Gy, inter-quartile range 36.0–36.1 Gy) to the target volume, whereas dose compromise would have been required with conventional planning (median D50% 35.6 Gy, inter-quartile range 28.7–35.9 Gy). IMAT facilitates safe dose escalation to 36 Gy in patients receiving radiotherapy for neuroblastoma. The value of dose escalation is now being evaluated in a current prospective phase III randomised trial. • The standard tumour bed radiotherapy dose used for neuroblastoma is 21 Gy. • The optimal dose is uncertain, and a higher dose may lead to better local control. • Organ-at-risk tolerance may limit the desired dose to the target volume. • Intensity-modulated arc therapy facilitates better delivery of higher doses. [ABSTRACT FROM AUTHOR]

This is a retrospective review of 131I-MIBG therapy for metastatic neuroendocrine tumours in 25 adult patients. The tumours comprised 17 carcinoids, six paragangliomas, one somatostatinoma and one intestinal smooth muscle sarcoma. All patients (age range 28–84 years) had stage IV disease and a positive diagnostic 123I-MIBG scan. Patients received 11.1 GBq (300 mCi) of 131I-MIBG given in three cycles at 3-monthly intervals. The mean cumulative dose was 27.7 GBq (751 mCi). Symptomatic response was observed in 80%, hormonal response in 55% and tumour response in 48% (WHO criteria). Of the 25 patients, 40% are still under follow-up. Death was due to disease progression in all except one. The median survival time was 48 months from diagnosis of metastatic disease, and 17 months from the last 131I-MIBG therapy. The 5-year survival rate was 59% (95% confidence interval, 34%–78%). There was no statistical difference in survival between previously treated (chemo/radiotherapy) and treatment-naı¨ve patients. Side-effects were minimal and commonly include nausea (in the first 24 h) and a transient fall in platelet count. 131I-MIBG provides a good therapeutic response in patients with metastatic neuro-endocrine tumours. [Copyright &y& Elsevier]

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. 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 (V18 Gy). 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 V18 Gy tolerance doses. 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 V18 Gy 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 (r 2 = 0.97, P < 0.0001) and of %ILF with ipsilateral lung V18 Gy (r 2 = 0.99, P < 0.0001). For the validation cohort, the median %HIF and MHD were 3.9 (0.6–8) and 2.5 (1.4–4.7) Gy. The median %ILF and ipsilateral lung V18 Gy were 20.1 (12.4–32.0) and 20.9 (12.4–34.4) %. The validation cohort confirmed that %HIF and %ILF continue to be predictive surrogates for heart and ipsilateral lung dose during VSim of left- and right-sided cases when including the SCF ± internal mammary nodes with a three-field photon technique. 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. • Virtual simulation of breast radiotherapy (±nodes) in the absence of dose surrogates may lead to unnecessary compromise to target coverage or the heart and/or ipsilateral lung dose being exceeded on the optimised plan. • Predicting heart and lung dose during virtual simulation will improve efficiency. • Percentage of heart-in-field is an accurate surrogate for mean heart dose during virtual simulation. • Percentage of lung-in-field is an accurate surrogate for ipsilateral lung V18 Gy during virtual simulation. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. • Some neuroblastomas may benefit from pencil beam scanning (PBS) proton therapy. • PBS may dosimetrically disadvantage select cases compared with advanced photon plans. • Unilateral tumours show the most consistent benefit with PBS. • Tumour location, planning target volume (PTV) and PTV anterior extension can assist case selection. • Larger bowel gas variation observed with general anaesthesia can impact PBS dosimetry. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. • Paediatric thyroid cancer patients are treated in a small number of UK centres. • Despite presentation with advanced disease, good long-term outcomes are expected. • National prospective data collection is recommended. [ABSTRACT FROM AUTHOR]

Abstract Aims External beam radiotherapy is widely used in various ways in the management of neuroblastoma. Despite extensive clinical experience, the precise role of radiotherapy in neuroblastoma remains unclear. The purpose of this systematic review was to survey the published literature to identify, without bias, the evidence for the clinical effectiveness of external beam radiotherapy as part of the initial multimodality treatment of high-risk neuroblastoma. We considered four areas: treatment of the tumour bed and residual primary tumour, identification of any dose–response relationship, treatment of metastatic sites, identification of any technical advances that may be beneficial. We also aimed to define uncertainties, which may be clarified in future clinical trials. Materials and methods Bibliographic databases were searched for neuroblastoma and radiotherapy. Reviewers assessed 1283 papers for inclusion by title and abstract, with consensus achieved through discussion. Data extraction on 57 included papers was carried out by one reviewer and checked by another. Studies were assessed for their level of evidence and risk of bias, and a descriptive analysis of data was carried out. Results Fifteen papers provided some evidence that radiotherapy to the tumour bed and residual tumour may possibly be of value. However, there is a significant risk of bias and no evidence that all subgroups will benefit. There is some suggestion from six papers that dose may be important, but no hard evidence. It remains unclear whether irradiation of metastatic sites is helpful. Technical advances may be of value in radiotherapy of high-risk neuroblastoma. Conclusions There are data that show that radiotherapy is of some efficacy in the management of high-risk neuroblastoma, but there is no level one evidence that shows that it is being used in the best possible way. Prospective randomised trials are necessary to provide more evidence to guide development of optimal radiotherapy treatment schedules. Highlights • A systematic review of radiotherapy for high-risk neuroblastoma. • Explored the need for radiotherapy, the dose and metastatic site irradiation. • All evidence identified was low quality, with a significant risk of bias. • Radiotherapy may be of value, but the evidence is unclear and conflicting. • Prospective randomised trials are essential to strengthen the evidence base. [ABSTRACT FROM AUTHOR]

Local control in high-risk neuroblastoma relies on effective multi-modality treatment, including radiotherapy. We evaluated the quality of radiotherapy delivered in the SIOPEN High-Risk Neuroblastoma trial (HR-NBL1/SIOPEN, EUDRACT 2006-001489-17) and investigated whether this correlated with survival. The protocol treatment was 21 Gy in 1.5 Gy fractions to the pre-operative primary tumour volume. Radiotherapy data were submitted via the trial data centre website, SIOPEN-R-NET, or QUARTET platform. At least two members of the radiotherapy committee retrospectively performed a Radiotherapy Quality Assurance (RTQA) review which evaluated plan parameters including prescription and fractionation, delineations and dosimetry for target and normal tissue structures, as well as treatment technique and overall dosimetry against protocol requirements. Plans were rated as per protocol, justified, or unjustified deviation with no harm likely or potential for harm. Potential for harm indicates possible impact on local control or morbidity. A statistical analysis for correlation between the RTQA outcome and survival was performed. 2034 patients received radiotherapy, of which 236 (11.6%) had sufficient data for RTQA evaluation and statistical analysis. 112 (47%) cases were per protocol while 62 (26%) had justified and 62 (26%) had unjustified deviations. Cases scored with any potential for harm (n=63, 27%) fared significantly worse in terms of 5-year overall survival (OS) compared with per protocol cases; 0.34±0.08, 0.63±0.05 respectively (p=0.029). The RTQA cohort is representative of all patients who received radiotherapy. Despite recommendations for RTQA review within the HR-NBL1/SIOPEN protocol, complete radiotherapy data submission rates were poor. Protocol deviations were demonstrated in the majority of cases. Cases with an RTQA outcome including potential for harm demonstrate significantly worse overall survival. Prospective RTQA is therefore recommended to improve both data completeness and protocol compliance and is being implemented in the SIOPEN High-risk Neuroblastoma Trial 2 using the QUARTET platform. [ABSTRACT FROM AUTHOR]

Objectives To determine the hearing status of survivors treated for head and neck rhabdomyosarcoma (HNRMS) at long-term follow-up. Design Cross-sectional long-term follow-up study. Setting Tertiary comprehensive cancer centre. Participants Survivors treated for HNRMS during childhood in two concurrent cohorts; survivors in London had been treated with external beam radiotherapy (EBRT-based local therapy); survivors in Amsterdam were treated with AMORE (Ablative surgery, MOuld technique afterloading brachytherapy and surgical REconstruction) if feasible, otherwise EBRT (AMORE-based local therapy). Main outcome measures We assessed hearing status of HNRMS survivors at long-term follow-up. Hearing thresholds were obtained by pure-tone audiometry. Methods We assessed the hearing thresholds, the number of patients with clinically relevant hearing loss and hearing impairment graded according to the Common Terminology Criteria for Adverse Events version 4.0 (CTCAEv4) and Boston criteria. Furthermore, we compared hearing loss between survivors treated with EBRT-based local therapy (London) and AMORE-based local therapy (Amsterdam). Results Seventy-three survivors were included (median follow-up 11 years). We found clinically relevant hearing loss at speech frequencies in 19% of survivors. Multivariable analysis showed that survivors treated with EBRT-based treatment and those with parameningeal tumours had significantly more hearing impairment, compared to survivors treated with AMORE-based treatment and non-parameningeal tumours. Conclusions One in five survivors of HNRMS developed clinically relevant hearing loss. AMORE-based treatment resulted in less hearing loss compared to EBRT-based treatment. As hearing loss was highly prevalent and also occurred in survivors with orbital primaries, we recommend systematic audiological follow-up in all HNRMS survivors. [ABSTRACT FROM AUTHOR]

Purpose Head and neck rhabdomyosarcoma (HNRMS) survivors are at increased risk of developing pituitary dysfunction as an adverse event of radiotherapy. Our aim was to investigate the frequency and risk factors for pituitary dysfunction in these survivors. Secondly, we aimed to compare the prevalence of pituitary dysfunction between survivors treated with external beam radiation therapy (EBRT) and survivors treated with the ablative surgery, moulage technique after loading brachytherapy, and surgical reconstruction (AMORE) procedure. Methods Eighty HNRMS survivors treated in London (EBRT based) and Amsterdam (AMORE based: AMORE if feasible, otherwise EBRT) in the period 1990–2010 and alive ≥2 years post-treatment were evaluated. Survivors were evaluated in multidisciplinary late-effects clinics, with measurement of linear growth, determination of thyroid function, and growth hormone parameters. Additional data, such as baseline characteristics, anthropometrics, pubertal stage, and the results of additional laboratory investigations, were retrieved from patient charts. Results Pituitary dysfunction was diagnosed in 24 in 80 (30%) survivors, after a median follow-up time of 11 years. Median time to develop pituitary dysfunction after HNRMS diagnosis was 3.0 years. Risk factors were EBRT-based therapy (odds ratio [OR] 2.06; 95% confidence interval [CI] 1.79–2.46), parameningeal tumour site (OR 1.83; 95% CI 1.60–2.17) and embryonal RMS histology (OR 1.49; 95% CI 1.19–1.90). Conclusions Radiotherapy used for the treatment of HNRMS confers a significant risk of the development of pituitary dysfunction. AMORE-based treatment in children with HNRMS resulted in less pituitary dysfunction than treatment with conventional EBRT. Our findings underscore the importance of routine early endocrine follow-up in this specific population. [ABSTRACT FROM AUTHOR]