Background Central nervous system (CNS) tumours account for around 25% of childhood neoplasms. With multi-modal therapy, 5-year survival is at around 75% in the UK. Conventional photon radiotherapy has made significant contributions to survival, but can be associated with long-term side effects. Proton beam radiotherapy (PBT) reduces the volume of irradiated tissue outside the tumour target volume which may potentially reduce toxicity. Our aim was to assess the effectiveness and safety of PBT and make recommendations for future research for this evolving treatment. Methods A systematic review assessing the effects of PBT for treating CNS tumours in children/young adults was undertaken using methods recommended by Cochrane and reported using PRISMA guidelines. Any study design was included where clinical and toxicity outcomes were reported. Searches were to May 2021, with a narrative synthesis employed. Results Thirty-one case series studies involving 1731 patients from 10 PBT centres were included. Eleven studies involved children with medulloblastoma / primitive neuroectodermal tumours (n = 712), five ependymoma (n = 398), four atypical teratoid/rhabdoid tumour (n = 72), six craniopharyngioma (n = 272), three low-grade gliomas (n = 233), one germ cell tumours (n = 22) and one pineoblastoma (n = 22). Clinical outcomes were the most frequently reported with overall survival values ranging from 100 to 28% depending on the tumour type. Endocrine outcomes were the most frequently reported toxicity outcomes with quality of life the least reported. Conclusions This review highlights areas of uncertainty in this research area. A well-defined, well-funded research agenda is needed to best maximise the potential of PBT. Systematic review registration. PROSPERO-CRD42016036802.

Abstract Introduction We assessed the feasibility of hippocampal sparing in adults with primary brain tumours using Intensity Modulated Proton Therapy (IMPT) and compared this with Intensity Modulated Radiotherapy (IMRT) and 3D-Conformal Radiotherapy (3DCRT). Methods and Materials 20 patients were identified, and each patient underwent a radiotherapy planning CT scan and 2 MRI scans. A pre-operative diagnostic MRI scan was fused with the planning CT and used for target delineation and a dedicated 3T MRI scan at the time of planning was fused with the CT for hippocampus delineation. 3 hippocampal sparing plans were generated for each patient with specific prescriptions (54Gy/30 fractions, 60Gy/30 fractions and 59.4Gy/33 fractions) using IMPT, IMRT and 3DCRT. Hippocampal sparing was defined as median dose to contralateral hippocampus ≤25Gy without compromising target coverage and organ at risk dose constraints. Results Hippocampal sparing was achieved in 19 patients (95%) with IMPT, 16 patients (80%) with IMRT and 13 patients (65%) with 3DCRT. The largest median hippocampal dose reduction was seen with IMPT, with a mean median hippocampal dose of 4.8Gy (range: 0.0Gy-24.9Gy), 14.6Gy (range: 1.9Gy-21.7Gy), and 16.2Gy (range: 2.3Gy-25.0Gy) for IMPT, IMRT and 3DCRT respectively. Hippocampal sparing IMPT failed in one case with the largest tumour volume (650cc) where 2/3 of the hippocampus overlapped the target volume. Conclusion IMPT as compared to IMRT and 3DCRT plans showed a trend towards significant and effective hippocampal sparing in adult patients with primary brain tumours. We are currently evaluating this in a larger patient cohort and comparing IMPT with VMAT.

Limb reports that the potential benefits from expanding the indications for proton therapy should be evaluated in randomised clinical trials.1 In proton therapy, in which advantages in radiation dose distribution are usually used to reduce the severity of long term morbidity, randomised clinical trials with an endpoint decades later may be problematic. An example is when the aim is to reduce the risk of late …

1 on the challenges and future approaches to curing patients with primary brain tumours.We congratulate Cancer Research UK (CRUK) on convening this group of expert clinicians and scientists, and we applaud the authors' elegant synthesis of multiple complex issues.However, we note that among the disciplines represented by the 26 authors of this article, expertise in radiation oncology is conspicuously absent.The authors assert that CRUK "convened an international panel of brain cancer researchers with interests in neurobiology, preclinical tumour modelling, genomics, pharmaco logy, drug discovery and/or development, neuropathology, neurosurgery, imaging, radiotherapy and medical oncology, with the task of identifying the most important challenges that must be overcome if we are to eventually be in the position to cure all patients with a brain tumour" 1 .Aside from radiation oncology, all of the neurooncological subspecialties listed above were represented.Beyond issues of author representation, radiotherapy is only discussed in the context of efforts to reduce the dose of radiation or to eliminate radiotherapy entirely from the treatment of patients with certain disease characteristics.Even in clinical situations in which attempts to reduce the radiation dose have failed (such as medulloblastoma) 2,3 , the authors contend that this is a function of and novel systemic therapies are ongoing; these collaborative undertakings might translate into more meaningful improvements in survival outcomes 14 .Current and future studies also aim to tailor the delivery of radiotherapy by molecular profile and couple this with high-precision technologies designed to individualize both target volume and dose 15 .In this sense, the authors of the CRUK position paper 1 are absolutely correct: the neurooncology community must meet the challenges of treating primary brain tumours with robust research efforts across all boundaries: across disciplines; across geographical borders; across the academia-industry divide; and across the bench-to-bedside spectrum of research.Ensuring that all neuro-oncology disciplines, including radiation oncology, are given a voice as we rise to meet these challenges is imperative to engage in truly collaborative research.

Background and purpose: To describe the outcome of patients with stage III Wilms tumours (WT) treated in the UKW3 trial. Material and methods: Patients with a pathologically confirmed stage III non-anaplastic WT at nephrectomy (Group A) or with an 'inoperable' tumour at diagnosis managed by biopsy and pre-operative chemotherapy (Actinomycin D-Vincristine-Doxorubicin) but stage I or II at subsequent nephrectomy (Group B) were included. Results: The 4-year overall (OS)/event free survival (EFS) for Group A (n = 117) patients was 90%(95% CI: 83-94)/81%(CI: 73-87) and for Group B (n = 32) 94%(CI: 77-98)/88%(CI: 70-95). The 4-year OS/EFS of patients with pathological stage III WT according to whether they received flank/abdominal radiotherapy (95 patients) or not (37 patients, 22 from UKW3 pooled with 17 patients from UKW2) were 91%(CI: 8395)/ 82%(CI: 73-89), and 84%(CI: 67-92)/78%(CI: 61-89), respectively. The 4-year OS/EFS for patients having one reason to be stage III versus two or three was 92%(CI: 84-96)/83%(CI: 73-90) and 85%(CI: 70-93)/78%(CI: 61-88), respectively. Conclusion: Our findings question the inclusion of biopsy or pre-operative chemotherapy as sole criterion for assigning a tumour stage III. Selected patients with pathological stage III WT can survive without radiotherapy. Whilst cautious interpretation is needed due to the post hoc nature of these analyses, further biological studies may better characterise those who could benefit from reduced therapy. (C) 2018 Published by Elsevier B.V.

OBJECTIVES: To assess the clinical effects of PBT for the treatment of children with malignant CNS tumours.METHODS: Eleven electronic databases were searched from 1985 onwards.Comparative and non-comparative studies were included.Outcomes included overall survival (OS), local/distant relapse rates (LRR and DRR), toxicities, neurocognitive outcomes and quality of survival.Standard systematic review methods were used to minimise bias in study identification, selection and data extraction.RESULTS: Seventeen studies with 492 patients (pts) were included.Mean sample size was 29 (range: 6-109) with mean follow-up of 3.1 years (range: 0.1-11.7).Studies were in: low grade glioma [n ¼ 3, pts ¼ 65; OS: 83%-100% (follow-up: 2.0-7.6 years); 3-year LRR: 0%]; ependymoma [n ¼ 3 pts ¼ 91; OS: 79%-100% (follow-up: 2.2-3.0 years); LRR: 0%-46% (follow-up: 2.2-5.0 years); DRR: 17%-33% (follow-up: 3.0-5.0years)]; medulloblastoma/primitive neuroectodermal tumours (PNET's) (n ¼ 5, pts ¼ 211; OS: 81%-86% (follow-up: 3.0-7.0years); LRR: 0%-15% (follow-up: 3.2-7.0years); DRR: 24% at 7.0-years]; atypical teratoid rhabdoid tumours (AT/RT) [n ¼ 5, pts ¼ 76; OS: 53%-90% (follow-up: 2.0-3.2years); LRR: 0%-20% and DRR: 20%-40% (follow-up: 2.3-3.2years)]; germ cell tumour [n ¼ 1, pts ¼ 22; OS: 100%; LRR: 0%; DRR: 4.5% (follow-up: 2.3 years)]; pineoblastoma [n ¼ 1, pts ¼ 11; LRR and DRR both 9% at 1.7-years].Adverse late effects reported were ototoxicity (9%-21%), neuro-endocrinopathies (3%-63%), growth problems and neurocognitive deficits.CONCLUSIONS: The limited quantity and quality of evidence suggests PBT probably achieves similar OS and LRR as historic photon cohorts, whilst having a similar or reduced mid-late toxicity profile.However, this is subject to substantial uncertainty due to limited longterm outcome data and no controlled evidence.

According to the American Society for Radiation Oncology's Model Policy published in 2014 (1), solid tumors in children are considered among the highest priority for proton therapy. Worldwide, there are currently 54 facilities offering proton therapy and 61 more under construction (2). As the number of institutions proliferates, expert opinion is important in guiding safe and rational adoption and use of this technology in young patients. In June 2015, 24 international leaders in pediatric radiation oncology, pediatric oncology, medical physics, and radiobiology convened in Stockholm to exchange ideas and perspectives on treating children with proton therapy.

Most radiotherapy (RT) involves the use of high doses (>50 Gy) to treat malignant disease. However, low to intermediate doses (approximately 3-50 Gy) can provide effective control of a number of benign conditions, ranging from inflammatory/proliferative disorders (e.g. Dupuytren's disease, heterotopic ossification, keloid scarring, pigmented villonodular synovitis) to benign tumours (e.g. glomus tumours or juvenile nasopharyngeal angiofibromas). Current use in UK RT departments is very variable. This review identifies those benign diseases for which RT provides good control of symptoms with, for the most part, minimal side effects. However, exposure to radiation has the potential to cause a radiation-induced cancer (RIC) many years after treatment. The evidence for the magnitude of this risk comes from many disparate sources and is constrained by the small number of long-term studies in relevant clinical cohorts. This review considers the types of evidence available, i.e. theoretical models, phantom studies, epidemiological studies, long-term follow-up of cancer patients and those treated for benign disease, although many of the latter data pertain to treatments that are no longer used. Informative studies are summarized and considered in relation to the potential for development of a RIC in a range of key tissues (skin, brain etc.). Overall, the evidence suggests that the risks of cancer following RT for benign disease for currently advised protocols are small, especially in older patients. However, the balance of risk vs benefit needs to be considered in younger adults and especially if RT is being considered in adolescents or children.

1STEPHANIE R MCKEOWN, MA, PhD, 2PAUL HATFIELD, FRCR, PhD, 2ROBIN JD PRESTWICH, FRCR, PhD, 3RICHARD E SHAFFER, MRCP, FRCR and 4ROGER E TAYLOR, FRCP, FRCR School of Biomedical Sciences, University of Ulster, Coleraine, UK Leeds Cancer Centre, St James’s University Hospital, Leeds, UK St Luke’s Cancer Centre, Royal Surrey County Hospital, Guildford, UK College of Medicine, Swansea University, South West Cancer Centre, Swansea, UK

Most patients treated by external beam radiotherapy are being treated for cancer. However, historically, many patients have been treated with radiotherapy for a variety of benign (i.e. non-neoplastic) conditions. Furthermore, radiotherapy is also used for the treatment of a wide range of benign tumours [[1]Seegenschmiedt M.H. Makoski H.-B. Trott K.-R. Radiotherapy for non-malignant disorders. Contemporary concepts and clinical results. Springer, Berlin2008Crossref Google Scholar]. In recent years, the Faculty of Clinical Oncology of the Royal College of Radiologists has become aware that, within the UK, the use of radiotherapy for benign conditions has declined, with varying and often small patient numbers being treated. This editorial aims to highlight this issue and to summarise a recent report by a Royal College of Radiologists working group [[2]The Royal College of Radiologists. A review of the use of radiotherapy in the UK for the treatment of benign clinical conditions and benign tumours. London: The Royal College of Radiologists, 2015.Google Scholar]. The report is designed to inform the development of a more evidence-based and equitable strategy for the use of radiotherapy, where it has proven efficacy, across all parts of the UK. Furthermore, the document will serve as a 'handbook' for clinicians to consult when referred a patient with a benign condition. It was agreed that the review should include the use of radiotherapy for most benign conditions historically treated by external beam radiotherapy and selected conditions treated by stereotactic (brain) radiotherapy. The review also includes selected benign tumours, generally those that are rarely treated by radiotherapy and where the literature is not well known (see Table 1).Table 1Individual diseases reviewedDisease groupDiseases reviewed with the number of centres out of 25 respondents reporting treatmentHead and neckParagangliomas (11)Juvenile nasopharyngeal angiofibroma(4) Pleomorphic adenoma (N)Sialorrhea (2)EyeThyroid eye disease (19)Orbital pseudotumour (4)Pterygium (0)Age-related macular degeneration (0)Choroidal haemangioma (0)Central nervous systemGrade 1 meningioma (N)Cerebral arterio-venous malformations (N)Trigeminal neuralgia (1)Vestibular schwannoma (8)Orthopaedic/musculoskeletalDupuytren's disease of the hand (4)Plantar fibromatosis of the foot (Ledderhose disease) (N)Plantar fasciitis (1)Peyronie's disease (0)Heterotopic ossification of the hip (14)Pigmented villonodular synovitis (PVNS) (4)Vertebral haemangioma (1)Aneurbysmal bone cyst (1)Skin/soft tissuesKeloid scarring (15)Lentigo maligna (N)Hidradenitis suppurativa (1)Psoriasis (N)Chronic eczema (1)Prevention and treatment of gynaecomastia due to endocrine therapy for prostate cancer (N)N – not included in the original questionnaire survey, but reviewed in the main document. Open table in a new tab N – not included in the original questionnaire survey, but reviewed in the main document. In order to provide an estimate of the current use of radiotherapy for benign disease, a questionnaire survey of radiotherapy departments throughout the UK was undertaken in 2012. This requested the numbers of patients treated per annum for a range of benign tumours and non-malignant conditions. Responses were received from 25/61 departments (41%). This showed a core of activity in many centres, particularly for some benign tumours. When radiotherapy was used for non-malignant conditions, those most commonly treated were heterotopic ossification, keloid scarring, thyroid eye disease and Dupuytren's contracture. The large activity for treatment of trigeminal neuralgia (in one centre) and vestibular schwannoma were related to treatment with stereotactic radiosurgery. One important feature was the wide variation in practice across the UK. For example, one centre annually treated about 64 patients with keloid scarring, whereas most others treated none. As the degree of variation was not clear before the survey, potential reasons that might explain the inter-departmental variation were not asked for. Details of numbers treated for individual conditions are provided in the main document. There are conditions that are considered to be more appropriate for treatment than others, for example most departments (19/25; 76%) reported treating patients with thyroid eye disease, but no department reported treating patients with pterygium, although this was often treated up to the 1980s. The review includes discussion of the radiobiological principles of radiotherapy for benign conditions, including the potential influence of a wide range of radiotherapy-related and patient-specific factors. The exposure of normal tissues to ionising radiation in the intermediate dose range (about 20–40 Gy) is discussed, including the vascular, stromal and anti-inflammatory sequelae. Broadly, there are two basic mechanisms that can be exploited. First, the anti-proliferative effect of radiotherapy [3Rodemann H.P. Blaese M.A. Responses of normal cells to ionizing radiation.Semin Radiat Oncol. 2007; 2: 81-88Abstract Full Text Full Text PDF Scopus (153) Google Scholar, 4Westbury C.B. Yarnold J.R. Radiation fibrosis - current clinical and therapeutic perspectives.Clin Oncol. 2012; 10: 657-672Abstract Full Text Full Text PDF Scopus (71) Google Scholar, 5Yarnold J. Brotons M.C. Pathogenetic mechanisms in radiation fibrosis.Radiother Oncol. 2010; 1: 149-161Abstract Full Text Full Text PDF Scopus (440) Google Scholar], which, for example, can be exploited to reduce the risk of heterotopic ossification after hip replacement. Second, the anti-inflammatory effect [[6]Arenas M. Sabater S. Hernández V. et al.Anti-inflammatory effects of low-dose radiotherapy. Indications, dose, and radiobiological mechanisms involved.Strahlenther Onkol. 2012; 11: 975-981Crossref Scopus (103) Google Scholar] can be used for the treatment of a number of soft tissue inflammatory conditions, such as thyroid eye disease. The radiotherapy doses used for the treatment of benign conditions are often well below the range used to treat cancer. For example, a so-called 'anti-inflammatory dose' of radiotherapy is often around 20 Gy in 10 fractions or its equivalent. The highest doses used are for the treatment of benign tumours (40–50 Gy in 2 Gy fractions) and, consequently, for most patients acute toxicity is rarely a problem. The most important age-dependent side-effect for these radiation doses is the potential increased risk of radiation-induced cancer (RIC). This is considered for a range of tissues and is further detailed in the discussion of the individual indications. Interpretation of the literature on radiotherapy for benign conditions is problematic. Much of the evidence is based on case reports and single institution case series, although randomised studies and systematic reviews do exist. Many of the more substantial studies using radiation in the dose range applicable to treating benign disease relate to regimens no longer in use and delivered with obsolete equipment, e.g. ankylosing spondylitis [7Court-Brown W.M. Doll R. Mortality from cancer and other causes after radiotherapy for ankylosing spondylitis.Br Med J. 1965; : 1327-1332Crossref Scopus (370) Google Scholar, 8Darby W.C. Doll R. Gill S.K. et al.Long term mortality after a single treatment course with X-rays in patients treated for ankylosing spondylitis.Br J Cancer. 1987; 55: 179-190Crossref PubMed Scopus (279) Google Scholar, 9Weiss H.A. Darby S.C. Doll R. Cancer mortality following X-ray treatment for ankylosing spondylitis.Int J Cancer. 1994; 9: 327-338Crossref Scopus (190) Google Scholar]. Consequently, extrapolation to current treatment indications with modern techniques is problematic. Although these groups have been followed-up for many years, many other studies tend to have relatively short-term follow-up. This may be a problem for younger individuals and especially children in terms of balancing the long-term benefits and risks. For some conditions evidence is more complete; for example, there have been randomised trials into the benefits of radiotherapy for treating pterygium [10Jurgenliemk-Schulz I.M. Hartman L.J. Roesink J.M. et al.Prevention of pterygium recurrence by postoperative single-dose beta-irradiation: a prospective randomized clinical double-blind trial.Int J Radiat Oncol Biol Phys. 2004; 59: 1138-1147Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar, 11Simsek T. Gunalp I. Atilla H. Comparative efficacy of beta-irradiation and mitomycin-C in primary and recurrent pterygium.Eur J Ophthalmol. 2001; 11: 126-132PubMed Google Scholar] and there is ongoing clinical research in the field of radiotherapy for macular degeneration. The decline in the use of radiotherapy for benign conditions is probably multifactorial, but important factors would be increased availability of alternative medical therapies, advances in surgery and also concerns as to the potential risk, if very small, of RIC. This is exemplified by the increased incidence of leukaemia after radiotherapy for ankylosing spondylitis [7Court-Brown W.M. Doll R. Mortality from cancer and other causes after radiotherapy for ankylosing spondylitis.Br Med J. 1965; : 1327-1332Crossref Scopus (370) Google Scholar, 8Darby W.C. Doll R. Gill S.K. et al.Long term mortality after a single treatment course with X-rays in patients treated for ankylosing spondylitis.Br J Cancer. 1987; 55: 179-190Crossref PubMed Scopus (279) Google Scholar, 9Weiss H.A. Darby S.C. Doll R. Cancer mortality following X-ray treatment for ankylosing spondylitis.Int J Cancer. 1994; 9: 327-338Crossref Scopus (190) Google Scholar]. However, bearing in mind the age range of most patients and the relatively low radiotherapy doses used, often to peripheral areas of the body, the risks of radiotherapy may be lower than the risks of alternative therapies such as anti-inflammatory drugs or other interventions. Clearly, the risk of RIC is an issue that needs to be discussed with patients. Indeed, it is also a factor that may influence the judgement of referring clinicians, for example ophthalmologists, dermatologists and orthopaedic surgeons. As the factors governing the risk of RIC are complex, hard to estimate and often very patient specific (e.g. age, site of irradiation, dose, etc.), guidance is provided as to the most important factors that should be used to advise patients and referers [12Berrington de Gonzalez A. Curtis R.E. Kry S.F. et al.Proportion of second cancers attributable to radiotherapy treatment in adults: a cohort study in the US SEER cancer registries.Lancet Oncol. 2011; 12: 353-360Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar, 13Berrington de Gonzalez A. Gilbert E. Curtis R. et al.Second solid cancers after radiation therapy: a systematic review of the epidemiologic studies of the radiation dose-response relationship.Int J Radiat Oncol Biol Phys. 2013; 86: 224-233Abstract Full Text Full Text PDF PubMed Scopus (210) Google Scholar, 14Trott K.R. Kamprad F. Estimation of cancer risks from radiotherapy of benign diseases.Strahlenther Onkol. 2006; 182: 431-443Crossref PubMed Scopus (89) Google Scholar]. Unfortunately, only in a few instances is there any substantive quantitative evidence of RIC risk, as the numbers required to estimate risk are very large and the numbers who currently receive radiotherapy for many of these conditions is relatively small; additionally they would require very long follow-up to detect RIC. With these provisos, an attempt has been made to identify the risk to inform discussion with patients considered for radiotherapy for a wide range of benign conditions (Table 1). The limited use of radiotherapy for benign conditions in the UK is in contrast to practice in Germany. This has been informed by the reports of the German Working Group on Radiotherapy of Benign Diseases, which has extensively reviewed the use of radiotherapy for benign disease in a series of Patterns of Care Study reports. The conclusions were that radiotherapy was a well-accepted modality that was relatively often used for a wide range of benign diseases; however, significant departmental and geographical variations in its use were evident. At that time (2000–2002) they provided consensus guidelines on the use of radiotherapy [15Seegenschmiedt M.H. Katalinic A. Makoski H.-B. et al.Radiation therapy for benign diseases: patterns of care study in Germany.Int J Radiat Oncol Biol Phys. 2000; 47: 195-201Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 16Micke O. Seegenschmiedt MH for the German Working Group of Radiotherapy of Benign Diseases. Consensus guidelines for radiation therapy of benign diseases: a multicentre approach in Germany.Int J Radiat Oncol Biol Phys. 2002; 52: 496-513Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar], informed consent, treatment documentation and follow-up, including late toxicity scoring. A European Society for Radiotherapy and Oncology workshop in 2004 also reviewed the use of radiotherapy for benign disease and a consensus summary was published [[17]Leer J.W. van Houtte P. Seegenschmiedt H. Radiotherapy of non-malignant disorders: where do we stand?.Radiother Oncol. 2007; 83: 175-177Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar]. As with treating cancer, an overarching principle that also applies when treating benign disease is to minimise the volume of irradiated normal tissue. Current radiotherapy techniques can help to achieve this. For instance, modern imaging can allow more accurate target definition and other developments in immobilisation and image guidance can allow reduced margins. Techniques such as intensity-modulated radiotherapy, can achieve better conformality to complex target volumes, although this may increase the volume of tissue receiving lower doses. In some sites, particularly the skull base, dose distributions achievable with proton therapy may have advantages. It is important to note that there are currently only limited data regarding the application of modern radiotherapy techniques to the treatment of benign conditions, including the implications for RIC risks from treatments such as intensity-modulated radiotherapy. Much of the evidence reviewed is derived from radiotherapeutic literature, and it is frequently difficult to be certain as to how the use of radiotherapy would fit into the overall multimodality management of these conditions. It is hoped that this new review will lead to a reappraisal of the role of radiotherapy for benign conditions. It is recommended that there should be discussion at national and local levels between clinical oncologists and representatives of other professional bodies that often provide the primary consultants for these disparate conditions, e.g. ophthalmologists, orthopaedic surgeons, neurologists, dermatologists and urologists. It is recommended that radiotherapy departments should review their protocols for the treatment of benign diseases, including, where appropriate, the use of modern techniques. In view of the ageing population it is possible that radiotherapy could provide a useful treatment modality, with low toxicity, for patients with a range of benign conditions in an age group where the risk of RIC is not clinically relevant. Even in younger patients the benefits versus risk may be acceptable. It is hoped that the disease-specific information contained in the document will assist clinicians in the consent process, in particular advising patients on the balance between risks and benefits. In England there should be discussion within the Radiotherapy and Stereotactic Radiotherapy Clinical Reference Groups and the relevant commissioning organisations in Scotland, Wales and Northern Ireland regarding potential national approaches. We would like to thank Mrs Gillian Dollamore for co-ordinating the project, members of the Faculty Board of the Royal College of Radiologists Clinical Oncology Faculty for reviewing the manuscript and for helpful suggestions and the production team of the Royal College of Radiologists for production of the document to which this editorial refers.

Background and purpose To evaluate feasibility and toxicity of Hyperfractionated Accelerated Radiotherapy (HART) 1.24Gy b.i.d. followed by chemotherapy for M1–3 Medulloblastoma (MB). The aim of HART was to use hyperfractionation to improve therapeutic ratio combined with acceleration to minimise tumour cell repopulation during radiotherapy (RT). Materials and methods Between February 2002 and May 2008, 34 eligible patients (22 male, 12 female) aged 3–15years (median 7) with metastatic MB (M1–9; M2–3, M3–22) received HART with a craniospinal radiotherapy (CSRT) dose of 39.68Gy followed by 22.32Gy boost to the whole posterior fossa and 9.92Gy metastatic boosts. The 8th and subsequent patients received vincristine (VCR) 1.5mg/m2 weekly×8 doses over 8weeks starting during the 1st week of RT. Maintenance chemotherapy comprised 8 six-weekly cycles of VCR 1.5mg/m2 weekly×3, CCNU 75mg/m2 and cisplatin 70mg/m2. Results Median duration of HART was 34days (range 31–38). Grade 3–4 toxicities included mucositis (8), nausea (10), anaemia (5), thrombocytopaenia (2), leucopaenia (24). With 4.5-year median follow-up, 3-year EFS and OS were 59% and 71%, respectively. Of 10 relapses, 1 was outside the central nervous system (CNS), 1 posterior fossa alone and 8 leptomeningeal with 3 also associated with posterior fossa. Conclusion HART with or without VCR was well tolerated and may have a place in the multi-modality management of high-risk MB.

Brain tumours in the elderly show differences from the general population in their spectrum of incidence, their molecular profile and their response to treatment. Furthermore, this population also finds it more difficult to tolerate the treatments applied to younger patients. For these reasons it is justified to investigate older patients separately and to devise treatments applicable specifically to this population. In recent years important information has come from the research literature that allows us to make specific recommendations for the management of elderly patients with brain tumours. Here we review the important publications and document these recommendations.

Promising new treatments need a strong evidence base Survival of UK children with cancer is showing sustained improvement, with the proportion of under 15s living five years after diagnosis now at 82%.1 With more young people facing the prospect of long term cure, focus has moved from “cure at all cost” to “the cost of cure.” This is particularly important in brain tumours, as they account for nearly a quarter of all cancers in this age group. Although cure rates have improved, these cancers are the commonest cause of deaths from cancer in children, and 60% of survivors are moderately or severely disabled.2 Novel therapeutic strategies are being introduced in the hope of increasing survival rates while maximising the quality of resultant long term survival. Proton beam therapy, the focus of much recent discussion, is one such strategy. The case of Ashya King has highlighted the immense pressure that develops for children, their parents, and their treating teams when dealing with the complex clinical management of brain tumours.3 Working closely and effectively with parents in the best interests of the ill child is an overwhelming priority for clinical teams. When communication breaks down, the consequences can be profound, as noted by the medical director of Southampton General Hospital.4 This underlines the importance …

Molecular subclassification is rapidly informing the clinical management of medulloblastoma. However, the disease remains associated with poor outcomes and therapy-associated late effects, and the majority of patients are not characterized by a validated prognostic biomarker. Here, we investigated the potential of epigenetic DNA methylation for disease subclassification, particularly in formalin-fixed biopsies, and to identify biomarkers for improved therapeutic individualization. Tumor DNA methylation profiles were assessed, alongside molecular and clinical disease features, in 230 patients primarily from the SIOP-UKCCSG PNET3 clinical trial. We demonstrate by cross-validation in frozen training and formalin-fixed test sets that medulloblastoma comprises four robust DNA methylation subgroups (termed WNT, SHH, G3 and G4), highly related to their transcriptomic counterparts, and which display distinct molecular, clinical and pathological disease characteristics. WNT patients displayed an expected favorable prognosis, while outcomes for SHH, G3 and G4 were equivalent in our cohort. MXI1 and IL8 methylation were identified as novel independent high-risk biomarkers in cross-validated survival models of non-WNT patients, and were validated using non-array methods. Incorporation of MXI1 and IL8 into current survival models significantly improved the assignment of disease risk; 46 % of patients could be classified as ‘favorable risk’ (>90 % survival) compared to 13 % using current models, while the high-risk group was reduced from 30 to 16 %. DNA methylation profiling enables the robust subclassification of four disease subgroups in frozen and routinely collected/archival formalin-fixed biopsy material, and the incorporation of DNA methylation biomarkers can significantly improve disease-risk stratification. These findings have important implications for future risk-adapted clinical disease management.

The MYC oncogenes are the most commonly amplified loci in medulloblastoma, and have previously been proposed as biomarkers of adverse disease prognosis by us and others. Here, we report focussed and comprehensive investigations of MYCC, MYCN and MYCL in an extensive medulloblastoma cohort (n = 292), aimed to define more precisely their biological significance and optimal clinical application to direct improved disease risk-stratification and individualisation of therapy. MYCC and MYCN expression elevations were multifactorial, associated with high-risk (gene amplification, large-cell/anaplastic pathology (LCA)) and favourable-risk (WNT/SHH molecular subgroups) disease features. Highly variable cellular gene amplification patterns underlay overall MYC copy number elevations observed in tumour biopsies; we used these alternative measures together to define quantitative methodologies and thresholds for amplification detection in routinely collected tumour material. MYCC and MYCN amplification, but not gain, each had independent prognostic significance in non-infants (≥3.0–16.0 years), but MYCC conferred a greater hazard to survival than MYCN when considered across this treatment group. MYCN’s weaker group-wide survival relationship may be explained by its pleiotropic behaviour between clinical disease-risk groups; MYCN predicted poor prognosis in clinical high-risk (metastatic (M+) or LCA), but not standard-risk, patients. Extending these findings, survival decreased in proportion to the total number of independently significant high-risk features present (LCA, M+ or MYCC/MYCN amplification). This cumulative-risk model defines a patient group characterised by ≥2 independent risk-factors and an extremely poor prognosis (<15% survival), which can be identified straightforwardly using the reported MYC amplification detection methodologies alongside clinical assessments, enabling targeting for novel/intensified therapies in future clinical studies.

PURPOSE:To compare event-free survival (EFS), overall survival (OS), pattern of relapse, and hearing loss in children with standard-risk medulloblastoma treated by postoperative hyperfractionated or conventionally fractionated radiotherapy followed by maintenance chemotherapy. PATIENTS AND METHODS:In all, 340 children age 4 to 21 years from 122 European centers were postoperatively staged and randomly assigned to treatment with hyperfractionated radiotherapy (HFRT) or standard (conventional) fractionated radiotherapy (STRT) followed by a common chemotherapy regimen consisting of eight cycles of cisplatin, lomustine, and vincristine. RESULTS:After a median follow-up of 4.8 years (range, 0.1 to 8.3 years), survival rates were not significantly different between the two treatment arms: 5-year EFS was 77% ± 4% in the STRT group and 78% ± 4% in the HFRT group; corresponding 5-year OS was 87% ± 3% and 85% ± 3%, respectively. A postoperative residual tumor of more than 1.5 cm(2) was the strongest negative prognostic factor. EFS of children with all reference assessments and no large residual tumor was 82% ± 2% at 5 years. Patients with a delay of more than 7 weeks to the start of RT had a worse prognosis. Severe hearing loss was not significantly different for the two treatment arms at follow-up. CONCLUSION:In this large randomized European study, which enrolled patients with standard-risk medulloblastoma from more than 100 centers, excellent survival rates were achieved in patients without a large postoperative residual tumor and without RT treatment delays. EFS and OS for HFRT was not superior to STRT, which therefore remains standard of care in this disease.

In the last two decades, paediatric radiation oncology has evolved as an important sub-speciality, supported by national and international working groups such as the Children's Cancer and Leukaemia Group and the International Society of Paediatric Oncology, which have established common radiotherapy protocols across a range of malignancies. Although chemotherapy has contributed considerably to improved survival rates, radiotherapy plays a major role for about 40% of children with cancer. The principles of paediatric radiation oncology have been described by Dr Thorp [[1]Thorp N. Basic principles of paediatric radiotherapy.J Clin Oncol. 2013; 25: 3-10Scopus (16) Google Scholar]. Because of the importance of accurate immobilisation, planning and delivery of radiotherapy, it is essential to incorporate modern developments, including cone beam computed tomography, intensity-modulated radiotherapy and, more recently, proton therapy, for which many UK children are now travelling abroad. Pivotal in achieving all this has been the establishment of paediatric radiotherapy multiprofessional teams. An essential component of any review article on paediatric radiotherapy is a description of late effects. Aiming for the maximum probability of cure while minimising late effects is one of the central principles of paediatric radiotherapy, applied from day-to-day practice through to international trial development. The focus on late effects parallels the emphasis on quality of survival inherent in the UK national survivorship initiative. In view of their links with adult and paediatric oncology, clinical oncologists will be well suited to provide specialist advice that covers the teenage and young adult age ranges. Children with brain tumours comprise one of the most important groups for whom radiotherapy is employed. One of the most important of these is medulloblastoma, a highly radiosensitive and chemosensitive tumour for which craniospinal radiotherapy is an essential component of treatment. However, this is one of the most complex techniques used in radiotherapy departments and needs to incorporate modern technological developments. An important inclusion within this article by Drs Saran, Bartlett and Kortmann [[2]Bartlett F. Kortmann R. Saran F. Medulloblastoma.J Clin Oncol. 2013; 25: 36-45Scopus (58) Google Scholar] is a summary of the burgeoning data on genetic and biological aspects of medulloblastoma. Biological parameters that influence prognosis are now being incorporated into decision-making around stratification for intensity of treatment and the design of and entry into clinical trials. For several decades, patients with neuroblastoma and leukaemia have had molecular analyses carried out before decision making about therapy and in light of recent knowledge this is becoming standard practice for medulloblastoma. Medulloblastoma is sufficiently common in order to undertake randomised clinical trials. However, these have to be either on a national basis in North America, or in Europe based on international multicentre collaboration. Medulloblastoma trials have been carried out since the 1970s and more recently with the increasing interest in paediatric neuro-oncology clinical trial methodology is now being applied for other brain tumours. Hodgkin lymphoma spans the paediatric, adolescent and young adult age groups. Children with Hodgkin lymphoma have a better than 90% probability of long-term survival and therefore minimising long-term side-effects has been an important area for clinical practice and research, as described by Drs Frew, Lewis and Lucraft [[3]Frew J.A. Lewis J. Lucraft H.H. Management of children with lymphomas.J Clin Oncol. 2013; 25: 11-18Scopus (4) Google Scholar]. The two main areas for attention have been second malignancy induction and cardiac late effects, involving a successive reduction in radiation dose and volume while ensuring that disease control outcomes are not compromised. The current European protocol includes a central review of radiotherapy planning, underlining the importance of quality assurance, which can be a model for other areas of radiation oncology practice. The emphasis on minimising and managing late effects led to the UK national recall of female children and adults who had been treated with mediastinal radiotherapy and the initiation of a comprehensive breast cancer screening programme. Although modern radiotherapy protocols with reduced doses and target volumes will probably result in significantly reduced late effects compared with treatment given in previous eras, late effects will probably remain an issue for some years to come. There is still uncertainty about the precise cardiac risk and how this might be mitigated by attention to other lifestyle issues, such as smoking, hypercholesterolaemia, hypertension, diet and exercise, etc. Drs Boelling, Hardes and Dirksen [[4]Bölling T. Hardes J. Dirksen U. Management of bone tumours in paediatric oncology.J Clin Oncol. 2013; 25: 19-26Scopus (27) Google Scholar] describe the current management of bone tumours. In recent years the proportion of patients with Ewing's sarcoma being treated by radical radiotherapy alone for local control has fallen significantly with the realisation that improved local tumour control is achieved by surgery or a combination of surgery and radiotherapy compared with radiotherapy alone. However, comparisons between these modalities have not been randomised and it is difficult to be sure to what extent the selection of patients has influenced outcomes. Of course, patients who are cured by surgery alone in combination with adjuvant chemotherapy do not have the added risk of radiation-induced malignancy. Effective management of Ewing's sarcoma requires considerable attention to detail, including the co-ordination of chemotherapy and local primary tumour management, including surgery, radiotherapy or a combination of both. There is current interest in the use of preoperative radiation for selected patients. Furthermore, there is also a fairly well-established role for the radical irradiation of individual metastases as long-term survival is possible even for patients with multiple metastases. Drs Terezakis and Wharam [[5]Terezakis S.A. Wharam M.D. Radiotherapy for rhabdomyosarcoma: indications and outcome.J Clin Oncol. 2013; 25: 27-35Scopus (25) Google Scholar] describe the current management of rhabdomyosarcoma. Despite improved survival rates, local tumour control remains an important issue for most patients. Largely because of the concern about the long-term side-effects of radiation, in Europe in the 1990s the pendulum swung away from the use of radiotherapy. However, in the last decade there has been a reinstatement of its role for many categories of patients, in recognition of the fact that the treatment of local relapse can lead to even more severe late effects. In designing clinical trials, attention has been paid to the effect of disease parameters on outcome, leading to clinical risk stratification with an appropriate radiotherapy dose based on local recurrence risk. Nowhere is the effect of late effects more relevant than in the treatment of rhabdomyosarcoma arising in the head and neck regions. Modern radiotherapy technologies have been used to try to minimise these late effects, including proton therapy.