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Aims: To assess in patients with 1-10 brain metastases, each of which has been treated by neurosurgery or stereotactic radiosurgery, whether hippocampal sparing whole brain radiotherapy (HS-WBRT) better spares neurocognitive function (NCF) than standard WBRT. Further, to assess whether a phase III randomised trial of HS-WBRT would be feasible in the UK., Materials and Methods: A multicentre, randomised, open label phase II trial was undertaken, randomising patients to 30Gy in 10 fractions of WBRT or HS-WBRT. The primary endpoint was decline in Total recall using Hopkins Verbal Learning Test Revised (HVLT-R) at 4 months post treatment. To assess this, we aimed to recruit 84 patients over 3 years. Secondary endpoints included further measures of NCF, quality of life, duration of functional independence, local control of treated metastases, development of new metastases, disease control within the hippocampal regions, overall survival, steroid and antiepileptic medication requirements, and toxicity., Results: The trial closed prematurely due to slower than anticipated recruitment. From April 2016 to January 2018, 23 patients were randomised. Follow up was a median of 25 months. Fifteen patients (6 WBRT, 9 HS-WBRT) were assessed for the primary endpoint; of these, 1 in each arm experienced significant decline in the 4-month HVLT-R Total recall score (p = 0.8). Patients in the HS-WBRT arm experienced less insomnia (p < 0.01) and drowsiness (p < 0.01). There were no differences in other secondary endpoints., Conclusion: A phase III randomised trial of HS-WBRT was shown not to be feasible at this time in the UK. As most randomised trials of HS-WBRT reported to date share common endpoints, including NCF, an individual patient data meta-analysis should be undertaken., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background and Purpose: A risk calculation model was presented in 2021 by Keilty et al. for determining the likelihood of severe hearing impairment (HI) for paediatric patients treated with photon radiation therapy. This study aimed to validate their risk-prediction model for our cohort of paediatric patients treated with proton therapy (PT) for malignancies of the head and neck (H&N) or central nervous system (CNS)., Materials and Methods: This was a single-institution study which extracted data on all patients aged ≤ 18 years treated with PT between Feb 2010 - Feb 2022 for malignancies of the H&N/CNS. The factors required for input into the Keilty model were extracted: age at PT, time since end of PT, mean cochlea dose, and platinum chemotherapy doses. Validation was performed using the statistical software R v 4.3.1, which analysed event discrimination and model calibration., Results: 587 patients met the criteria. Validation of the model demonstrated excellent discriminative ability, with an "optimal" cut-off value of 16% at a specificity and sensitivity of 82%. However, model calibration was less satisfactory, indicating an overestimation of risk of severe hearing loss (HI) by the model as compared to clinically observed events in our cohort, possibly linked to differences in event scoring between the model developers and this study, and short follow-up time in this study., Conclusion: The published (photon-based) model of Keilty et al. was validated in a PT context, demonstrating a high discriminative ability to determine patients at high risk versus low risk for severe HI. However the overall observed risk was lower than model predictions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Skull base chordomas and chondrosarcomas are distinct types of rare, locally aggressive mesenchymal tumors that share key principles of imaging investigation and multidisciplinary care. Maximal safe surgical resection is the treatment choice for each, often via an expanded endoscopic endonasal approach, with or without multilayer skull base repair. Postoperative adjuvant radiation therapy is frequently administered, usually with particle therapy such as proton beam therapy (PBT). Compared with photon therapy, PBT enables dose escalation while limiting damage to dose-limiting neurologic structures, particularly the brainstem and optic apparatus, due to energy deposition being delivered at a high maximum with a rapid decrease at the end of the penetration range (Bragg peak phenomenon). Essential requirements for PBT following gross total or maximal safe resection are tissue diagnosis, minimal residual tumor after resection, and adequate clearance from PBT dose-limiting structures. The radiologist should understand surgical approaches and surgical techniques, including multilayer skull base repair, and be aware of evolution of postsurgical imaging appearances over time. Accurate radiologic review of all relevant preoperative imaging examinations and of intraoperative and postoperative MRI examinations plays a key role in management. The radiology report should reflect what the skull base surgeon and radiation oncologist need to know, including distance between the tumor and PBT dose-limiting structures, tumor sites that may be difficult to access via the endoscopic endonasal route, the relationship between intradural tumor and neurovascular structures, and tumor sites with implications for postresection stability. © RSNA, 2024 Supplemental material is available for this article.

Background: Radiotherapy is key in the treatment of primary and secondary brain tumors. However, normal tissue is inevitably irradiated, causing toxicity and contributing to cognitive dysfunction. The relative importance of vascular damage to cognitive decline is poorly understood. Here, we systematically review the evidence for radiation-induced damage to the entire neurovascular unit (NVU), particularly focusing on establishing the factors that influence damage severity, and timing and duration of vascular effects relative to effects on neural tissue., Methods: Using PubMed and Web of Science, we searched preclinical and clinical literature published between January 1, 1970 and December 1, 2022 and evaluated factors influencing NVU damage severity and timing of NVU effects resulting from ionizing radiation., Results: Seventy-two rodents, 4 canines, 1 rabbit, and 5 human studies met inclusion criteria. Radiation increased blood-brain barrier (BBB) permeability, reduced endothelial cell number and extracellular matrix proteoglycans, reduced tight junction proteins, upregulated cellular adhesion molecule expression, reduced activity of glucose and BBB efflux transporters and activated glial cells. In the brain parenchyma, increased metalloproteinases 2 and 9 levels, demyelination, cell death, and inhibited differentiation were observed. Effects on the vasculature and neural compartment were observed across acute, delayed, and late timepoints, and damage extent was higher with low linear energy transfer radiation, higher doses, lower dose rates, broader beams, and in the presence of a tumor., Conclusions: Irradiation of normal brain tissue leads to widespread and varied impacts on the NVU. Data indicate that vascular damage is in most cases an early effect that does not quickly resolve. More studies are needed to confirm sequence of damages, and mechanisms that lead to cognitive dysfunction., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Background: Our neurosurgical unit adopted a model of shared decision-making (SDM) based on multidisciplinary clinics for vestibular schwannoma (VS). A unique feature of this clinic is the interdisciplinary counseling process with a surgeon presenting the option of surgery, an oncologist radiosurgery or radiotherapy, and a specialist nurse advocating for the patient., Methods: This is a retrospective cohort study. All new patients seen in the combined VS clinic and referred from the skull base multidisciplinary team (MDT) from beginning of June 2013 to end of January 2019 were included. Descriptive statistics and frequency analysis were carried out for the full cohort., Results: Three hundred and fifty-four patients presenting with new or previously untreated VS were included in the analysis. In our cohort, roughly one-third of patients fall into each of the treatment strategies with slightly smaller numbers of patients undergoing surgery than watch, wait and rescan (WWR) ,and SRS (26.6% vs. 32.8% and 37.9%, respectively)., Conclusion: In our experience, the combined surgery/oncology/specialist nurse clinic streamlines the patient experience for those with a VS suitable for either microsurgical or SRS/radiotherapy treatment. Decision-making in this population of patients is complex and when presented with all treatment options patients do not necessarily choose the least invasive option as a treatment. The unique feature of our clinic is the multidisciplinary counseling process with a specialist nurse advocating and guiding the patient. Treatment options are likely to become more rather than less complex in future years making combined clinics more valuable than ever in the SDM process., Competing Interests: The authors have no conflict of interest in this research., (© The Author(s) 2023. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)

Aims: In 2008, the UK National Health Service started the Proton Overseas Programme (POP), to provide access for proton beam therapy (PBT) abroad for selected tumour diagnoses while two national centres were being planned. The clinical outcomes for the patient group treated for central nervous system (CNS), base of skull, spinal and paraspinal malignancies are reported here., Materials and Methods: Since the start of the POP, an agreement between the National Health Service and UK referring centres ensured outcomes data collection, including overall survival, local tumour control and late toxicity data. Clinical and treatment-related data were extracted from this national patient database. Grade ≥3 late toxicities were reported following Common Terminology Criteria for Adverse Events (CTCAE) v 4.0 definition, occurring later than 90 days since the completion of treatment., Results: Between 2008 and September 2020, 830 patients were treated within the POP for the above listed malignancies. Overall survival data were available for 815 patients and local control data for 726 patients. Toxicity analysis was carried out on 702 patients, with patients excluded due to short follow-up (<90 days) and/or inadequate toxicity data available. After a median follow-up of 3.34 years (0.06-11.58), the overall survival was 91.2%. The local control rate was 85.9% after a median follow-up of 2.81 years (range 0.04-11.58). The overall grade ≥3 late toxicity incidence was 11.97%, after a median follow-up of 1.72 years (0.04-8.45). The median radiotherapy prescription dose was 54 GyRBE (34.8-79.2)., Conclusions: The results of this study indicate the safety of PBT for CNS tumours. Preliminary clinical outcomes following PBT for paediatric/teen and young adult and adult CNS tumours treated within the POP are encouraging, which reflects accurate patient selection and treatment quality. The rate of late effects compares favourably with published cohorts. Clinical outcomes from this patient cohort will be compared with those of UK-treated patients since the start of the national PBT service in 2018., (Copyright © 2023 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Purpose: Treatment-related toxicity after irradiation of brain tumours has been underreported in the literature. Furthermore, there is considerable heterogeneity on how and when toxicity is evaluated. The aim of this European Particle Network (EPTN) collaborative project is to develop recommendations for uniform follow-up and toxicity scoring of adult brain tumour patients treated with radiotherapy., Methods: A Delphi method-based consensus was reached among 24 international radiation-oncology experts in the field of neuro-oncology concerning the toxicity endpoints, evaluation methods and time points., Results: In this paper, we present a basic framework for consistent toxicity scoring and follow-up, using multiple levels of recommendation. Level I includes all recommendations that are considered minimum of care, whereas level II and III are optional evaluations in the advanced clinical or research setting, respectively. Per outcome domain, the clinical endpoints and evaluation methods per level are listed. Where relevant, the organ at risk threshold doses for recommended referral to specific organ specialists are defined., Conclusion: These consensus-based recommendations for follow-up will enable the collection of uniform toxicity data of brain tumour patients treated with radiotherapy. With adoptation of this standard, collaboration will be facilitated and we can further propel the research field of radiation-induced toxicities relevant for these patients. An online tool to implement this guideline in clinical practice is provided at www.cancerdata.org., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Clinical treatment with protons uses the concept of relative biological effectiveness (RBE) to convert the absorbed dose into an RBE-weighted dose that equals the dose for radiotherapy with photons causing the same biological effect. Currently, in proton therapy a constant RBE of 1.1 is generically used. However, empirical data indicate that the RBE is not constant, but increases at the distal edge of the proton beam. This increase in RBE is of concern, as the clinical impact is still unresolved, and clinical studies demonstrating a clinical effect of an increased RBE are emerging. Within the European Particle Therapy Network (EPTN) work package 6 on radiobiology and RBE, a workshop was held in February 2020 in Manchester with one day of discussion dedicated to the impact of proton RBE in a clinical context. Current data on RBE effects, patient outcome and modelling from experimental as well as clinical studies were presented and discussed. Furthermore, representatives from European clinical proton therapy centres, who were involved in patient treatment, laid out their current clinical practice on how to consider the risk of a variable RBE in their centres. In line with the workshop, this work considers the actual impact of RBE issues on patient care in proton therapy by reviewing preclinical data on the relation between linear energy transfer (LET) and RBE, current clinical data sets on RBE effects in patients, and applied clinical strategies to manage RBE uncertainties. A better understanding of the variability in RBE would allow development of proton treatments which are safer and more effective., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background and Purpose: To update the digital online atlas for organs at risk (OARs) delineation in neuro-oncology based on high-quality computed tomography (CT) and magnetic resonance (MR) imaging with new OARs., Materials and Methods: In this planned update of the neurological contouring atlas published in 2018, ten new clinically relevant OARs were included, after thorough discussion between experienced neuro-radiation oncologists (RTOs) representing 30 European radiotherapy-oncology institutes. Inclusion was based on daily practice and research requirements. Consensus was reached for the delineation after critical review. Contouring was performed on registered CT with intravenous (IV) contrast (soft tissue & bone window setting) and 3 Tesla (T) MRI (T1 with gadolinium & T2 FLAIR) images of one patient (1 mm slices). For illustration purposes, delineation on a 7 T MRI without IV contrast from a healthy volunteer was added. OARs were delineated by three experienced RTOs and a neuroradiologist based on the relevant literature., Results: The presented update of the neurological contouring atlas was reviewed and approved by 28 experts in the field. The atlas is available online and includes in total 25 OARs relevant to neuro-oncology, contoured on CT and MRI T1 and FLAIR (3 T & 7 T). Three-dimensional (3D) rendered films are also available online., Conclusion: In order to further decrease inter- and intra-observer OAR delineation variability in the field of neuro-oncology, we propose the use of this contouring atlas in photon and particle therapy, in clinical practice and in the research setting. The updated atlas is freely available on www.cancerdata.org., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

The UK has an important role in the evaluation of proton beam therapy (PBT) and takes its place on the world stage with the opening of the first National Health Service (NHS) PBT centre in Manchester in 2018, and the second in London coming in 2020. Systematic evaluation of the role of PBT is a key objective. By September 2019, 108 patients had started treatment, 60 paediatric, 19 teenagers and young adults and 29 adults. Obtaining robust outcome data is vital, if we are to understand the strengths and weaknesses of current treatment approaches. This is important in demonstrating when PBT will provide an advantage and when it will not, and in quantifying the magnitude of benefit.The UK also has an important part to play in translational PBT research, and building a research capability has always been the vision. We are perfectly placed to perform translational pre-clinical biological and physical experiments in the dedicated research room in Manchester. The nature of DNA damage from proton irradiation is considerably different from X-rays and this needs to be more fully explored. A better understanding is needed of the relative biological effectiveness (RBE) of protons, especially at the end of the Bragg peak, and of the effects on tumour and normal tissue of PBT combined with conventional chemotherapy, targeted drugs and immunomodulatory agents. These experiments can be enhanced by deterministic mathematical models of the molecular and cellular processes of DNA damage response. The fashion of ultra-high dose rate FLASH irradiation also needs to be explored.

Inhomogeneities in radiotherapy dose distributions covering the vertebrae in children can produce long-term spinal problems, including kyphosis, lordosis, scoliosis, and hypoplasia. In the published literature, many often interrelated variables have been reported to affect the extent of potential radiotherapy damage to the spine. Articles published in the 2D and 3D radiotherapy era instructed radiation oncologists to avoid dose inhomogeneity over growing vertebrae. However, in the present era of highly conformal radiotherapy, steep dose gradients over at-risk structures can be generated and thus less harm is caused to patients. In this report, paediatric radiation oncologists from leading centres in 11 European countries have produced recommendations on how to approach dose coverage for target volumes that are adjacent to vertebrae to minimise the risk of long-term spinal problems. Based on available information, it is advised that homogeneous vertebral radiotherapy doses should be delivered in children who have not yet finished the pubertal growth spurt. If dose fall-off within vertebrae cannot be avoided, acceptable dose gradients for different age groups are detailed here. Vertebral delineation should include all primary ossification centres and growth plates, and therefore include at least the vertebral body and arch. For partial spinal radiotherapy, the number of irradiated vertebrae should be restricted as much as achievable, particularly at the thoracic level in young children (<6 years old). There is a need for multicentre research on vertebral radiotherapy dose distributions for children, but until more valid data become available, these recommendations can provide a basis for daily practice for radiation oncologists who have patients that require vertebral radiotherapy., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Clinical Issue: Successful radiotherapy requires precise localization of the tumor and requires high-quality imaging for developing a treatment plan., Standard Treatment: Irradiation of the tumor region, including a safety margin., Treatment Innovations: The target volume consists of the gross tumor volume (GTV) containing visible parts of the tumor, the clinical target volume (CTV) covering the GTV plus invisible tumor extensions, and the planning target volume (PTV) to account for uncertainties. The non-GTV parts of the CTV are based on historical patient data. The PTV margins are based on a calculation of possible uncertainties during planning, setup, or treatment. Normal tissue deserves the identical care in contouring, since its tolerance may limit the tumor dose, taking into account the contours of organs at risk. Serial risk organs benefit from defining a planning organ of risk volume (PRV) to better limit the dose delivered to them., Diagnostic Work-Up: The better the imaging, the more reliable the definition of the GTV and treatment success will be. Multiple imaging sequences are desirable to support the delineation of the tumor. They may result in different CTVs that, depending on their tumor burden, may require different doses., Performance: The definition of standardized target volumes according to the ICRU reports 50, 62, and 83 forms the basis for an individualized radiation treatment planning according to unified criteria on a high-quality level., Achievements: Radio-oncology is by nature interdisciplinary, the diagnostic radiologist being an indispensable team partner. A regular dialogue between the disciplines is pivotal for target volume definition and treatment success., Practical Recommendations: Imaging for target volume definition requires highest quality imaging, the use of functional imaging methods and close cooperation with a diagnostic radiologist experienced in this field.

Purpose: For unbiased comparison of different radiation modalities and techniques, consensus on delineation of radiation sensitive organs at risk (OARs) and on their dose constraints is warranted. Following the publication of a digital, online atlas for OAR delineation in neuro-oncology by the same group, we assessed the brain OAR-dose constraints in a follow-up study., Methods: We performed a comprehensive search to identify the current papers on OAR dose constraints for normofractionated photon and particle therapy in PubMed, Ovid Medline, Cochrane Library, Embase and Web of Science. Moreover, the included articles' reference lists were cross-checked for potential studies that met the inclusion criteria. Consensus was reached among 20 radiation oncology experts in the field of neuro-oncology., Results: For the OARs published in the neuro-oncology literature, we summarized the available literature and recommended dose constraints associated with certain levels of normal tissue complication probability (NTCP) according to the recent ICRU recommendations. For those OARs with lacking or insufficient NTCP data, a proposal for effective and efficient data collection is given., Conclusion: The use of the European Particle Therapy Network-consensus OAR dose constraints summarized in this article is recommended for the model-based approach comparing photon and proton beam irradiation as well as for prospective clinical trials including novel radiation techniques and/or modalities., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: To create a digital, online atlas for organs at risk (OAR) delineation in neuro-oncology based on high-quality computed tomography (CT) and magnetic resonance (MR) imaging., Methods: CT and 3 Tesla (3T) MR images (slice thickness 1 mm with intravenous contrast agent) were obtained from the same patient and subsequently fused. In addition, a 7T MR without intravenous contrast agent was obtained from a healthy volunteer. Based on discussion between experienced radiation oncologists, the clinically relevant organs at risk (OARs) to be included in the atlas for neuro-oncology were determined, excluding typical head and neck OARs previously published. The draft atlas was delineated by a senior radiation oncologist, 2 residents in radiation oncology, and a senior neuro-radiologist incorporating relevant available literature. The proposed atlas was then critically reviewed and discussed by European radiation oncologists until consensus was reached., Results: The online atlas includes one CT-scan at two different window settings and one MR scan (3T) showing the OARs in axial, coronal and sagittal view. This manuscript presents the three-dimensional descriptions of the fifteen consensus OARs for neuro-oncology. Among these is a new OAR relevant for neuro-cognition, the posterior cerebellum (illustrated on 7T MR images)., Conclusion: In order to decrease inter- and intra-observer variability in delineating OARs relevant for neuro-oncology and thus derive consistent dosimetric data, we propose this atlas to be used in photon and particle therapy. The atlas is available online at www.cancerdata.org and will be updated whenever required., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

About 90% of patients with brain metastases have impaired neurocognitive function at diagnosis and up to two-thirds will show further declines within 2-6 months of whole brain radiotherapy. Distinguishing treatment effects from progressive disease can be challenging because the prognosis remains poor in many patients. Omitting whole brain radiotherapy after local therapy in good prognosis patients improves verbal memory at 4 months, but the effect of higher intracranial recurrence and salvage therapy rates on neurocognitive function beyond this time point is unknown. Hippocampal-sparing whole brain radiotherapy and postoperative stereotactic radiosurgery are investigational techniques intended to reduce toxicity. Here we describe the changes that can occur and review technological, pharmacological and practical approaches used to mitigate their effect in clinical practice., (Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: Neurofibromatosis Type 2 (NF2) is a dominantly inherited tumour syndrome with a phenotype which includes bilateral vestibular (eighth cranial nerve) schwannomas. Conventional thinking suggests that these tumours originate at a single point along the superior division of the eighth nerve., Methods: High resolution MRI was performed in children genetically proven to have NF2. The superior vestibular nerve (SVN) and inferior vestibular nerve (IVN) were visualised along their course with points of tumour origin calculated as a percentage relative to the length of the nerve., Results: Out of 41 patients assessed, 7 patients had no identifiable eighth cranial nerve disease. In 16 patients there was complete filling of the internal auditory meatus by a tumour mass such that its specific neural origin could not be determined. In the remaining 18 cases, 86 discrete separate foci of tumour origin on the SVN or IVN could be identified including 23 tumours on the right SVN, 26 tumours on the right IVN, 18 tumours on the left SVN and 19 tumours on the left IVN., Discussion: This study, examining the origins of vestibular schwannomas in NF2, refutes their origin as being from a single site on the transition zone of the superior division of the vestibular nerve. We hypothesise a relationship between the number of tumour foci, tumour biology and aggressiveness of disease. The development of targeted drug therapies in addition to bevacizumab are therefore essential to improve prognosis and quality of life in patients with NF2 given the shortcomings of surgery and radiation treatments when dealing with the multifocality of the disease., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

1p19q co-deletion is a chromosomal alteration associated with primary brain tumours of oligodendroglial histology. It is an established predictive and prognostic biomarker that informs whether patients are offered radiotherapy, chemotherapy or both. In the near future, 1p19q co-deletion status may also be incorporated into the reclassification of gliomas. Analysis is commonly carried out using fluorescence in situ hybridisation (FISH) because it is a reliable and validated laboratory technique. The result is generally considered to be dichotomous (1p19q co-deletion present or absent), but there are subtleties in interpretation that are of clinical relevance. Separate centres may interpret certain chromosome deletion patterns differently. Pivotal trials in mixed and pure anaplastic oligodendrogliomas have used slightly different FISH probe ratios as the cut-off for chromosome deletion. Here we review the clinical implications of this variability and review the process of 1p19q co-deletion assessment using FISH in gliomas from a clinician's perspective. We also consider common alternative methods of analysis., (Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Brain metastases are common and the prognosis for patients with multiple brain metastases treated with whole brain radiotherapy is limited. As systemic disease control continues to improve, the expectations of radiotherapy for brain metastases are growing. Stereotactic radiosurgery (SRS) as a high precision localised irradiation given in a single fraction prolongs survival in patients with a single brain metastasis and functional independence in those with up to three brain metastases. SRS technology has become commonplace and is available in many radiation oncology and neurosurgery departments. With increasing use there is a need for appropriate patient selection, refinement of dose-fractionation and safe integration of SRS with other treatment modalities. We review the evidence for current practice and new developments in the field, with a specific focus on patient-relevant outcomes., (Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Here we review current practices in target volume delineation for radical radiotherapy planning for gliomas. Current radiotherapy planning margins for glioma are informed by historic data of recurrence patterns using radiological imaging or post-mortem studies. Radiotherapy planning for World Health Organization grade II-IV gliomas currently relies predominantly on T1-weighted contrast-enhanced magnetic resonance imaging (MRI) and T2/fluid-attenuated inversion recovery sequences to identify the gross tumour volume (GTV). Isotropic margins are added empirically for each tumour type, usually without any patient-specific individualisation. We discuss novel imaging techniques that have the potential to influence radiotherapy planning, by improving definition of the tumour extent and its routes of invasion, thus modifying the GTV and allowing anisotropic expansion to a clinical target volume better reflecting areas at risk of recurrence. Identifying the relationships of tumour boundaries to important white matter pathways and eloquent areas of cerebral cortex could lead to reduced normal tissue complications. Novel magnetic resonance approaches to identify tumour extent and invasion include: (i) diffusion-weighted magnetic resonance metrics; (ii) diffusion tensor imaging; and (iii) positron emission tomography, using radiolabelled amino acids methyl-11C-L-methionine and 18F-fluoroethyltyrosine. Novel imaging techniques may also have a role together with clinical characteristics and molecular genetic markers in predicting response to therapy. Most significant among these techniques is dynamic contrast-enhanced MRI, which uses dynamic acquisition of images after injection of intravenous contrast. A number of studies have identified changes in diffusion and microvascular characteristics occurring during the early stages of radiotherapy as powerful predictive biomarkers of outcome., (Copyright © 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: Preclinical data have indicated the anti-epidermal growth factor receptor (EGFR) agent cetuximab (Erbitux) as a radiosensitizer in pancreatic cancer, but this has not been specifically addressed in a clinical study. We report the results of an original study initiated in 2007, where cetuximab was tested with radiotherapy (RT) alone in locally advanced pancreatic cancer in a phase II trial (PACER)., Methods: Patients (n = 21) received cetuximab loading dose (400 mg/m(2)) and weekly dose (250 mg/m(2)) during RT (50.4 Gy in 28 fractions). Toxicity and disease response end point data were prospectively assessed. A feasibility study of on-trial patient blood and skin sampling was incorporated., Results: Treatment was well tolerated, and toxicity was low; most patients (71%) experienced acute toxicities of grade 2 or less. Six months posttreatment, stable local disease was achieved in 90% of evaluable patients, but only 33% were free from metastatic progression. Median overall survival was 7.5 months, and actuarial survival was 33% at 1 year and 11% at 3 years, reflecting swift metastatic progression in some patients but good long-term control of localized disease in others. High-grade acneiform rash (P = .0027), posttreatment stable disease (P = .0059), and pretreatment cancer antigen 19.9 (CA19.9) level (P = .0042) associated with extended survival. Patient skin and blood samples yielded sufficient RNA and good quality protein, respectively., Conclusions: The results indicate that cetuximab inhibits EGFR-mediated radioresistance to achieve excellent local control with minimal toxicity but does not sufficiently control metastatic progression in all patients. Translational studies of patient tissue samples may yield molecular information that may enable individual treatment response prediction.

Rapid and accurate delineation of target volumes and multiple organs at risk, within the enduring International Commission on Radiation Units and Measurement framework, is now hugely important in radiotherapy, owing to the rapid proliferation of intensity-modulated radiotherapy and the advent of four-dimensional image-guided adaption. Nevertheless, delineation is still generally clinically performed with little if any machine assistance, even though it is both time-consuming and prone to interobserver variation. Currently available segmentation tools include those based on image greyscale interrogation, statistical shape modelling and body atlas-based methods. However, all too often these are not able to match the accuracy of the expert clinician, which remains the universally acknowledged gold standard. In this article we suggest that current methods are fundamentally limited by their lack of ability to incorporate essential human clinical decision-making into the underlying models. Hybrid techniques that utilise prior knowledge, make sophisticated use of greyscale information and allow clinical expertise to be integrated are needed. This may require a change in focus from automated segmentation to machine-assisted delineation. Similarly, new metrics of image quality reflecting fitness for purpose would be extremely valuable. We conclude that methods need to be developed to take account of the clinician's expertise and honed visual processing capabilities as much as the underlying, clinically meaningful information content of the image data being interrogated. We illustrate our observations and suggestions through our own experiences with two software tools developed as part of research council-funded projects.

Objective: A study of interobserver variation in the segmentation of the post-operative clinical target volume (CTV) and organs at risk (OARs) for parotid tumours was undertaken. The segmentation exercise was performed as a baseline, and repeated after 3 months using a segmentation protocol to assess whether CTV conformity improved., Methods: Four head and neck oncologists independently segmented CTVs and OARs (contralateral parotid, spinal cord and brain stem) on CT data sets of five patients post parotidectomy. For each CTV or OAR delineation, total volume was calculated. The conformity level (CL) between different clinicians' outlines was measured using a validated outline analysis tool. The data for CTVs were re-analysed after using the cochlear sparing therapy and conventional radiation segmentation protocol., Results: Significant differences in CTV morphology were observed at baseline, yielding a mean CL of 30% (range 25-39%). The CL improved after using the segmentation protocol with a mean CL of 54% (range 50-65%). For OARs, the mean CL was 60% (range 53-68%) for the contralateral parotid gland, 23% (range 13-27%) for the brain stem and 25% (range 22-31%) for the spinal cord., Conclusions: There was low conformity for CTVs and OARs between different clinicians. The CL for CTVs improved with use of a segmentation protocol, but the CLs remained lower than expected. This study supports the need for clear guidelines for segmentation of target and OARs to compare and interpret the results of head and neck cancer radiation studies.

Background: The aim was to evaluate the accuracy of Cockcroft-Gault, Jelliffe, Wright and Modification of Diet in Renal Disease (MDRD) formulae as a substitute for the gold standard measure of glomerular filtration rate (GFR) using chromium 51 EDTA., Patients and Methods: Retrospective analysis of GFR measurements in oncology patients from a University Teaching Hospital over 3 years was carried out. Bias and precision of estimates of GFR were compared with measured GFR., Results: Six hundred and sixty patients with measured GFR (median 90 ml/min, range 23-179 ml/min) were identified. Cockcroft-Gault produced the smallest bias (median percentage error -1.4%) and highest precision (median absolute percentage error 14.0%) and was the most accurate for carboplatin dosing. For patients>30% over their ideal body weight (IBW), using IBW+30% in the Cockcroft-Gault formula was more precise than using actual body weight or IBW. The Wright formula was most accurate for patients aged 70+years and patients with a body mass index (BMI)≥30 but overestimated GFR when GFR<50 ml/min., Conclusions: When measured GFR is unavailable, we advise estimating GFR using the Cockcroft-Gault formula and using IBW+30% for patients weighing>30% over their IBW. If the GFR is ≥50 ml/min and the patient is >70 years and/or BMI≥30, the Wright formula gives the best estimate of GFR.

Aims: Patients with locally advanced pancreatic cancer (LAPC) are most commonly managed with chemotherapy or concurrent chemoradiotherapy (CRT), which may or may not include non-involved regional lymph nodes in the clinical target volume. We present our results of CRT for LAPC using capecitabine and delivering radiotherapy to a limited radiation field that excluded non-involved regional lymph nodes from the clinical target volume., Materials and Methods: Thirty patients were studied. Patients received 50.4 Gy external beam radiotherapy in 28 fractions, delivered to a planning target volume expanded from the primary tumour and involved nodes only. Capecitabine (500-600 mg/m2) was given twice daily continuously during radiotherapy. Toxicity and efficacy data were prospectively collected., Results: Nausea, vomiting and tumour pain were the most common grade 2 toxicities. One patient developed grade 3 nausea. The median time to progression was 8.8 months, with 20% remaining progression free at 1 year. The median overall survival was 9.7 months with a 1 year survival of 30%. Of 21 patients with imaged progression, 13 (62%) progressed systemically, three (14%) had local progression, two (10%) had locoregional progression and three (14%) progressed with both local/locoregional and systemic disease., Conclusion: CRT using capecitabine and limited field radiotherapy is a well-tolerated, relatively efficacious treatment for LAPC. The low toxicity and low regional progression rates support the use of limited field radiotherapy, allowing evaluation of this regimen with other anti-cancer agents., (Copyright (c) 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Purpose: To determine the incidence of capsular contracture (CC) requiring revisional surgery in patients receiving postoperative radiotherapy (RT) or no RT following mastectomy and immediate breast reconstruction., Material and Methods: One hundred and seventy-eight immediate breast reconstructions performed at the Cambridge Breast Unit between 1.1.2001 and 31.12.2005 were identified. RT was delivered using a standard UK scheme of 40 Gray in 15 fractions over 3 weeks. The influence of hormones and chemotherapy as well as postoperative RT on time to development of severe CC after implant-based reconstruction was explored in univariate and multivariate analysis., Results: One hundred and ten patients had implant-based reconstructions with a median follow-up of 51 months. In the RT group (41 patients), there were 8 patients with severe CC requiring revisional surgery, a crude rate of 19.5%, with actuarial rates of 0%, 5%, 5%, 21%, 30% and 30% at 1, 2, 3, 4, 5 and 6 years follow-up. In the unirradiated group, there were no cases of severe CC. This difference is highly significant (p<0.001). Hormones and chemotherapy were not significantly associated with severe CC., Conclusions: This series showed a significantly higher rate of severe CC with postoperative RT. This finding has important clinical implications, when counselling patients for immediate breast reconstruction.

Distal oesophageal and Type I-II oesophagogastric junctional adenocarcinomas have a poor prognosis. In radical chemoradiotherapy, consensus is lacking on radiotherapy margins. Here, we review the effect of common imaging modalities on the extent of the gross tumour volume (GTV) and the evidence for margins. To do this, papers were identified from PubMed, and geometric uncertainties were combined using the British Institute of Radiology formula. CT and endoscopic ultrasound were best for GTV delineation, but the role of positron emission tomography is uncertain. Evidence suggests 3 cm proximal and 5 cm distal GTV-CTV (clinical target volume) margins (along the mucosa) for advanced tumours, but is lacking for early tumours and radial margins. Nodal spread, present in most pT2 tumours, is strongly prognostic and is initially to regional nodes (not wholly covered by typical radiotherapy). Calculated CTV-PTV (planning target volume) margins for three-dimensional conformal radiotherapy using literature estimates of tumour motion and set-up errors with bony online set-up correction, ignoring delineation errors, are 2.2 cm superiorly (sup) and inferiorly (inf) and 1.2-1.3 cm radially (1.3 cm sup-inf; 0.8 cm radially if the tumour's mid-position is known). As these margins may risk excessive toxicity, we propose treating microscopic disease for potentially curable tumours (cT2N0, some cT3N0), but gross disease only for advanced tumours. Recommended GTV-CTV margins are a maximum of 3 cm proximally and 5 cm distally up to cT2N0; 3 cm proximally and 5 cm distally for cT3N0 if anticipated toxicity allows; and 0 cm for cT4 and most node-positive tumours. The CTV-PTV margins above must be added to this for all stages. Methods of including elective nodal areas close to the GTV should be researched, e.g. nodal maps and intensity-modulated radiotherapy.

Aims: To assess the local control and cranial nerve toxicity in vestibular schwannoma patients treated with fractionated conformal radiotherapy delivered using a linear accelerator., Materials and Methods: Ninety-five patients were referred for consultation to the Oncology Department in Addenbrookes Hospital between 1996 and 2005. The 42 cases who received fractionated conformal radiotherapy are the subject of this analysis. All patients had radiological or symptomatic progression. Conformal radiotherapy was prescribed at 50Gy in 30 fractions over 6 weeks, delivered using a linear accelerator. Patients were immobilised using either a beam direction shell or a Gill Thomas Cosman relocatable stereotactic head frame., Results: The median age was 63 years (range 28-81) with 57% men. The average tumour size was 21.5mm on magnetic resonance imaging. Before treatment, 20 (48%) patients were deemed to have useful hearing on the affected side. The median follow-up was 18.6 months (range 0.3-6.5 years) and the actuarial local control rate at 2.5 years was 96.9% (one patient progressed after treatment). In previously hearing patients, the actuarial rate of useful hearing preservation was 100%, and the rate of mild hearing loss was 20% at 1 year and 26.7% at 2.5 years of follow-up. There were five neurofibromatosis type 2 patients treated, two of whom had useful hearing before radiotherapy. In one patient this was affected, with a 20dB loss, although he still has useful hearing. In those with normal facial nerve function before radiotherapy (n=40), this was preserved in 96.8% at 2.5 years. Trigeminal nerve function was preserved in all patients (n=38) who had normal nerve function before radiotherapy., Conclusion: Although follow-up was relatively short in this single institution series, fractionated linear accelerator radiotherapy gave excellent local control, useful hearing preservation and retained cranial nerve function in vestibular schwannoma.