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Organ motion as a result of respiratory and cardiac motion poses significant challenges for the accurate delivery of radiotherapy to both the thorax and the upper abdomen. Modern imaging techniques during radiotherapy simulation and delivery now permit better quantification of organ motion, which in turn reduces tumour and organ at risk position uncertainty. These imaging advances, coupled with respiratory correlated radiotherapy delivery techniques, have led to the development of a range of approaches to manage respiratory motion. This review summarises the key strategies of image-guided respiratory motion management with a focus on lung and liver radiotherapy., (Copyright © 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Particle therapy (PT) offers the potential for reduced normal tissue damage as well as escalation of target dose, thereby enhancing the therapeutic ratio in radiation therapy. Reflecting the building momentum of PT use worldwide, construction has recently commenced for The Australian Bragg Centre for Proton Therapy and Research in Adelaide - the first PT centre in Australia. This systematic review aims to update the clinical evidence base for PT, both proton beam and carbon ion therapy. The purpose is to inform clinical decision-making for referral of patients to PT centres in Australia as they become operational and overseas in the interim. Three major databases were searched by two independent researchers, and evidence quality was classified according to the National Health and Medical Research Council evidence hierarchy. One hundred and thirty-six studies were included, two-thirds related to proton beam therapy alone. PT at the very least provides equivalent tumour outcomes compared to photon controls with the possibility of improved control in the case of carbon ion therapy. There is suggestion of reduced morbidities in a range of tumour sites, supporting the predictions from dosimetric modelling and the wide international acceptance of PT for specific indications based on this. Though promising, this needs to be counterbalanced by the overall low quality of evidence found, with 90% of studies of level IV (case series) evidence. Prospective comparative clinical trials, supplemented by database-derived outcome information, preferably conducted within international and national networks, are strongly recommended as PT is introduced into Australasia., (© 2020 The Royal Australian and New Zealand College of Radiologists.)

Owing to its physical properties, particle therapy (PT), including proton beam therapy (PBT) and carbon ion therapy (CIT), can enhance the therapeutic ratio in radiation therapy. The major factor driving PT implementation is the reduction in exit and integral dose compared to photon plans, which is expected to translate to reduced toxicity and improved quality of life. This study extends the findings from a recent systematic review by the current authors which concentrated on tumour outcomes for PT, to now examine toxicity as a separate focus. Together, these reviews provide a comprehensive collation of the evidence relating to PT outcomes in clinical practice. Three major databases were searched by two independent researchers, and evidence quality was classified according to the National Health and Medical Research Council evidence hierarchy. One hundred and seventy-nine studies were included. Most demonstrated acceptable and favourable toxicity results. Comparative evidence reported reduced morbidities and improvement in quality of life in head and neck, paediatrics, sarcomas, adult central nervous system, gastrointestinal, ocular and prostate cancers compared to photon radiotherapy. This suggestion for reduced morbidity must be counterbalanced by the overall low quality of evidence. A concerted effort in the design of appropriate comparative clinical trials is needed which takes into account integration of PT's pace of technological advancements, including evolving delivery techniques, image guidance availability and sophistication of planning algorithms., (© 2020 The Royal Australian and New Zealand College of Radiologists.)

Introduction: We surveyed the Australian and New Zealand (ANZ) radiation oncology community to assess their perceptions, understanding and experience of the current role of proton beam therapy (PBT) and the existing referral process to access PBT overseas, ahead of the development of the first PBT centre in Australia., Methods: The survey was conducted between September and October 2019 using a 17-question instrument, which was distributed by email to all 632 radiation oncology fellows and trainees listed in the Royal Australian and New Zealand College of Radiologists database., Results: One hundred and one respondents completed the survey, with an overall response rate of 16%. Most respondents were based in Australia (93%), with the majority working in public centres only (59%); 51% were > 10 years post fellowship and 17% were trainees. Most respondents (76%) reported moderate or high levels of confidence in the role of PBT. Only 28% had previously referred a patient for PBT overseas, with the most common referral indication being chordoma. Of those who had not previously referred a patient, 48% were not convinced about the rationale of PBT over current therapies available locally, 33% were not aware of the referral process, and 24% had concerns about the timeliness of a decision for government-funded PBT abroad., Conclusion: This survey has demonstrated that, although there is reasonable confidence in the role of PBT among ANZ radiation oncologists, there are a number of important aspects of PBT awareness, education and access that need to be developed prior to commencement of PBT in Australia., (© 2020 The Royal Australian and New Zealand College of Radiologists.)

Lung cancer is the leading cause of cancer mortality worldwide and most patients are unsuitable for 'gold standard' treatment, which is concurrent chemoradiotherapy. CONCORDE is a platform study seeking to establish the toxicity profiles of multiple novel radiosensitisers targeting DNA repair proteins in patients treated with sequential chemoradiotherapy. Time-to-event continual reassessment will facilitate efficient dose-finding., Competing Interests: 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., (© 2020 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

Background: The evaluation of circulating tumour DNA (ctDNA) from clinical blood samples, liquid biopsy, offers several diagnostic advantages compared with traditional tissue biopsy, such as shorter processing time, reduced patient risk and the opportunity to assess tumour heterogeneity. The historically poor sensitivity of ctDNA testing, has restricted its integration into routine clinical practice for non-metastatic disease. The early kinetics of ctDNA during radical radiotherapy for localised NSCLC have not been described with ultra-deep next generation sequencing previously., Materials and Methods: Patients with CT/PET-staged locally advanced, NSCLC prospectively consented to undergo serial venepuncture during the first week of radical radiotherapy alone. All patients received 55Gy in 20 fractions. Plasma samples were processed using the commercially available Roche AVENIO Expanded kit (Roche Sequencing Solutions, Pleasanton, CA, US) which targets 77 genes., Results: Tumour-specific mutations were found in all patients (1 in 3 patients; 2 in 1 patient, and 3 in 1 patient). The variant allele frequency of these mutations ranged from 0.05-3.35%. In 2 patients there was a transient increase in ctDNA levels at the 72 h timepoint compared to baseline. In all patients there was a non-significant decrease in ctDNA levels at the 7-day timepoint in comparison to baseline (p = 0.4627)., Conclusion: This study demonstrates the feasibility of applying ctDNA-optimised NGS protocols through specified time-points in a small homogenous cohort of patients with localised lung cancer treated with radiotherapy. Studies are required to assess ctDNA kinetics as a predictive biomarker in radiotherapy. Priming tumours for liquid biopsy using radiation warrants further exploration.

Introduction: Radiotherapy technology and postgraduate medical training have both evolved significantly over the last 20 years. Clinical Oncology is a recognised craft specialty where the apprenticeship model of clinical training is applicable. The challenges of learning radiotherapy in the modern radiotherapy department workplace have not been comprehensively described and no optimal method has been identified., Methods and Analysis: Five Clinical Oncology trainers and five Clinical Oncology trainees at a regional cancer centre will be invited to undertake a semistructured interview regarding their personal accounts of learning radiotherapy. Both trainees and consultants will be treated as equal co-investors in the process of radiotherapy learning, with the common shared aim of passing radiotherapy skills from trainers to trainees. Interviews will last up to 40 min. After transcription, an interpretative phenomenological analysis will be performed. All trainees and trainers at the same centre (n=34) will then be invited to complete the same purpose-built questionnaire. Four trainers and three trainees have piloted the questionnaire, and input was sought from the national leads of the biennial UK Clinical Oncology training survey. Significance testing will be performed on predefined questions and thematic analysis on white space questions., Ethics and Dissemination: Medical education research is evolving in Clinical Oncology and Radiation Oncology but there are few studies comprehensively assessing this from the viewpoint of trainees and trainers. Pending the success of the proposed study, the approach detailed represents a novel method that could be used to identify the strengths and weaknesses of radiotherapy training in other centres and settings. Ethical and governance approvals have been granted by the University Research Ethics Committee and the Integrated Research Application System, respectively. This study has been funded by Friends of the Cancer Centre., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The last two decades have seen revolutionary developments in both radiotherapy technology and postgraduate medical training. Trainees are expected to attain competencies using a mix of experiential learning, formal postgraduate teaching, self-directed learning and peer education. Radiation (Clinical) Oncology is a recognised 'craft specialty' where the apprenticeship model of training is applicable. This scoping review examines the evidence in relation to how medical trainees learn radiotherapy., Methods: A systematic search of MEDINE and EMBASE was undertaken to identify studies of trainee and/or trainer experience of radiotherapy learning published 1999-2018. Results pertaining to Medical Oncology, workforce trends, undergraduate radiotherapy exposure, academic training, global health, non-medical staff, health service infrastructure and recruitment to training programmes were not included., Results: A total of 146 publications were included in the synthesis. Five themes were apparent through careful iterative analysis representing broadly inter-related issues. Most articles studied radiotherapy training from the perspective of the trainee doctor. Most literature reports results of observational, local or national surveys with a tightly defined scope. Considerable variation exists within hospitals, within countries, over time and between different curricular areas., Conclusions: Medical education has not kept pace with changes in the field of radiotherapy and large differences are demonstrated in experience between trainees in different hospitals, countries and training stages. Interpersonal relationships, departmental organisation, and national curricula impact on training quality. Qualitative and quantitative research examining modern radiotherapy learning has been uncommon and uncoordinated, until recently. To date no single study has been designed to comprehensively assess a department's training scheme.

Aims: Radiotherapy clinical trials are integral to the development of new treatments to improve the outcomes of patients with cancer. A collaborative study by the National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group and the National Institute for Health Research was carried out to understand better if and why inefficiencies occur in the set-up of radiotherapy trials in the UK., Materials and Methods: Two online surveys collected information on the time taken for UK radiotherapy trials to reach key milestones during set-up and the research support currently being provided to radiotherapy centres to enable efficient clinical trial set-up. Semi-structured interviews with project managers and chief investigators identified better ways of working to improve trial set-up in the future., Results: The timelines for the set-up of 39 UK radiotherapy trials were captured in an online survey showing that the median time from grant approval to trial opening was 600 days (range 169-1172). There were 38 responses from radiotherapy centres to a survey asking about the current support provided for radiotherapy research. Most of these centres have more than one type of staff member dedicated to supporting radiotherapy research. The most frequent barrier to radiotherapy trial set-up identified was lack of physicists' time and lack of time for clinical oncologists to carry out research activities. Four main themes around trial set-up were identified from semi-structured interviews: the importance of communication and building relationships, the previous experience of the chief investigator and clinical trials units, a lack of resources and having the time and personnel required to produce trial documentation and to process trial approval requests., Conclusions: This unique, collaborative project has provided up to date information about the current landscape of trial set-up and research support in the UK and identified several avenues on which to focus future efforts in order to support the excellent radiotherapy trial work carried out across the UK., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Patients with stage III non-small-cell lung cancer (NSCLC) treated with chemoradiotherapy (CRT) in low- and middle-income countries (LMIC) continue to have a poor prognosis. It is known that FDG PET/CT improves staging, treatment selection and target volume delineation (TVD), and although its use has grown rapidly, it is still not widely available in LMIC. CRT is often used as sequential treatment, but is known to be more effective when given concurrently. The aim of the PERTAIN study was to assess the impact of introducing FDG PET/CT-guided concurrent CRT, supported by training and quality control (QC), on the overall survival (OS) and progression-free survival (PFS) of patients with stage III NSCLC., Methods: The study included patients with stage III NSCLC from nine medical centres in seven countries. A retrospective cohort was managed according to local practices between January 2010 and July 2014, which involved only optional diagnostic FDG PET/CT for staging (not for TVD), followed by sequential or concurrent CRT. A prospective cohort between August 2015 and October 2018 was treated according to the study protocol including FDG PET/CT in treatment position for staging and multimodal TVD followed by concurrent CRT by specialists trained in protocol-specific TVD and with TVD QC. Kaplan-Meier analysis was used to assess OS and PFS in the retrospective and prospective cohorts., Results: Guidelines for FDG PET/CT image acquisition and TVD were developed and published. All specialists involved in the PERTAIN study received training between June 2014 and May 2016. The PET/CT scanners used received EARL accreditation. In November 2018 a planned interim analysis was performed including 230 patients in the retrospective cohort with a median follow-up of 14 months and 128 patients in the prospective cohort, of whom 69 had a follow-up of at least 1 year. Using the Kaplan-Meier method, OS was significantly longer in the prospective cohort than in the retrospective cohort (23 vs. 14 months, p = 0.012). In addition, median PFS was significantly longer in the prospective cohort than in the retrospective cohort (17 vs. 11 months, p = 0.012)., Conclusion: In the PERTAIN study, the preliminary results indicate that introducing FDG PET/CT-guided concurrent CRT for patients with stage III NSCLC in LMIC resulted in a significant improvement in OS and PFS. The final study results based on complete data are expected in 2020.

Aims: Curative-intent (radical) radiotherapy aims to control local disease and cure non-small cell lung cancer (NSCLC). The predominant subtypes of NSCLC are adenocarcinoma and squamous cell carcinoma (SCC). The radiotherapy paradigm offered to patients does not differ according to these two subtypes. Relapse patterns and disease control rates for adenocarcinoma and SCC treated with radical radiotherapy were determined., Materials and Methods: A radical radiotherapy database covering the period from 2004 to June 2016 was examined to determine the first sites of relapse and the actuarial local and distant control rates., Results: In total, 537 patients with known pathological subtype were treated over the period. In 39 (7%), the site of first relapse was uncertain. Of the remainder, 203 (41%) had adenocarcinoma and 295 (59%) had SCC. At a median follow-up of 16.4 months, 58% had relapsed. There was a difference in relapse patterns (chi-squared test P < 0.0005), with a higher rate of first relapse locally in SCC (42% of all patients versus 24%) and a higher rate of first relapse in the brain for adenocarcinoma (14% versus 3%). The actuarial local control rate was worse for SCC (hazard ratio 0.6, 95% confidence interval 0.5-0.9, P = 0.002). The brain metastasis-free survival was worse for adenocarcinoma (hazard ratio 4.1, 95% confidence interval 2.2-7.5, P < 0.0001)., Conclusion: There is a difference in relapse patterns between NSCLC histological subtypes, indicating that these are distinct entities. This may have implications for follow-up policy and strategies to improve disease control., (Copyright © 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

An 'abscopal' effect if often used to refer to distant tumour regression after localised irradiation. Since the first report of the abscopal effect in the 1950s, well-documented cases with radiotherapy alone are very rare. It is widely accepted that the immune response plays an important role in the abscopal effect, although the mechanism is still unclear. With the recent success of cancer immunotherapy, there is growing interest in combining immunotherapy with radiotherapy to boost abscopal response rates. Compared with conventional radiotherapy, stereotactic ablative radiotherapy (SABR) not only delivers ablative dose to the tumour, but may also induce robust immune responses. In this review we examine studies that combine SABR and immunotherapy. We review the preclinical rationale for SABR and immunotherapy combinations, the case for and against abscopal effects, and the current landscape of clinical trials., (Copyright © 2019 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Purpose: The aim of this study was to define the dose and dose-volume relationship of radiation-induced pulmonary toxicities occurring in and out-of-field in mouse models of early inflammatory and late fibrotic response., Materials and Methods: Early radiation-induced inflammation and fibrosis were investigated in C3H/NeJ and C57BL/6J mice, respectively. Animals were irradiated with 20 Gy delivered to the upper region of the right lung as a single fraction or as 3 consecutive fractions using the Small Animal Radiation Research Platform (Xstrahl Inc, Camberley, UK). Cone beam computed tomography was performed for image guidance before irradiation and to monitor late toxicity. Histologic sections were examined for neutrophil and macrophage infiltration as markers of early inflammatory response and type I collagen staining as a marker of late-occurring fibrosis. Correlation was evaluated with the dose-volume histogram parameters calculated for individual mice and changes in the observed cone beam computed tomography values., Results: Mean lung dose and the volume receiving over 10 Gy (V10) showed significant correlation with late responses for single and fractionated exposures in directly targeted volumes. Responses observed outside the target volume were attributed to nontargeted effects and showed no dependence on either mean lung dose or V10., Conclusions: Quantitative assessment of normal tissue response closely correlates early and late pulmonary response with clinical parameters, demonstrating this approach as a potential tool to facilitate clinical translation of preclinical studies. Out-of-field effects were observed but did not correlate with dosimetric parameters, suggesting that nontargeted effects may have a role in driving toxicities outside the treatment field., (Copyright © 2018 Elsevier Inc. All rights reserved.)

[This corrects the article DOI: 10.3389/fonc.2018.00433.].

Despite a major paradigm shift in radiotherapy planning and delivery over the past three decades with continuing refinements, radiation-induced lung damage (RILD) remains a major dose limiting toxicity in patients receiving thoracic irradiations. Our current understanding of the biological processes involved in RILD which includes DNA damage, inflammation, senescence and fibrosis, is based on clinical observations and experimental studies in mouse models using conventional radiation exposures. Whilst these studies have provided vital information on the pulmonary radiation response, the current implementation of small animal irradiators is enabling refinements in the precision and accuracy of dose delivery to mice which can be applied to studies of RILD. This review presents the current landscape of preclinical studies in RILD using small animal irradiators and highlights the challenges and opportunities for the further development of this emerging technology in the study of normal tissue damage in the lung.

Radical radiotherapy (RT) is a potentially curative treatment in non-small cell lung cancer (NSCLC) and is delivered in conventional 2-Gy fractions, hypofractionated and ablative stereotactic courses. No reliable, predictive biomarkers for the clinical events of local control, appearance of distant metastases and development of toxicity have been introduced in routine clinical practice. Such a test would enable the Radiotherapist to tailor the clinical management of individual patients, considering their pre-treatment characteristics, in order reduce the risk of recurrence or toxicity e.g., dose modification, accelerated fractionation, hypofractionation, or concurrent systemic therapy. The aim of this review was to map the published literature relating to investigations of the potential predictive value of patient or treatment characteristics in radical RT for NSCLC. These investigations should remain a research focus for disease control given the upward trends in lung cancer incidence, and for the avoidance of toxicity, given the survivorship afforded to the cohort of patients that do well with radical RT, or with the increasing range of systemic agents following metastatic relapse. The conclusion of the presented analysis is that there are no published, effective and validated predictive tools for estimation of risk of local/distant recurrence or toxicity after radical RT for NSCLC. The authors have identified an important space for future research in the field of lung cancer radiotherapy.

Standard of care radiotherapy in LA-NSCLC is 60-66 Gy in 30-33 fractions. However outcomes for these patients are poor with 5-year survival in the range of 10-20%. Randomised controlled trials have shown that dose escalation in a linear fashion does not improve outcomes for all patients, thus there is a need to tailor the prescription to the individual patient. This review assesses the strategies published to personalise the radiation therapy dose prescription in LA-NSCLC. A systematic and scoping search of the literature was performed to identify studies that met the inclusion criteria. 19 relevant studies were identified ranging from prospective clinical trials to mathematically modelled concept studies. Heterogeneity existed between all clinical studies. Nine heterogeneous publications proposed methodology to adapt the dose prescription to the individual patient. A number of encouraging strategies have been identified but fall short of the evidence level required to influence clinical practice., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Following growing evidence to support the safety, local control (LC) and potential improvement in overall survival (OS) in patients with oligometastatic non-small cell lung cancer (NSCLC) that have been treated with local ablative therapy such as stereotactic ablative radiotherapy (SABR) and stereotactic radiosurgery (SRS), we initiate the SARON trial to investigate the impact and feasibility of adding SABR/SRS and radical radiotherapy (RRT) following standard chemotherapy on OS., Methods and Analysis: SARON is a large, randomised controlled, multicentre, phase III trial for patients with oligometastatic EGFR, ALK and ROS1 mutation negative NSCLC (1-3 sites of synchronous metastatic disease, one of which must be extracranial). 340 patients will be recruited over 3 years from approximately 30 UK sites and randomised to receive either standard platinum-doublet chemotherapy only (control arm) or standard chemotherapy followed by RRT/SABR to their primary tumour and then SABR/SRS to all other metastatic sites (investigational arm). The primary endpoint is OS; the study is powered to detect an improvement in median survival from 9.9 months in the control arm to 14.3 months in the investigational arm with 85% power and two-sided 5% significance level. The secondary endpoints are LC, progression-free survival, new distant metastasis-free survival, toxicity and quality of life. An early feasibility review will take place after 50 randomised patients. Patients requiring both conventional thoracic RT to the primary and SABR to a thoracic metastasis will be included in a thoracic SABR safety substudy to assess toxicity and planning issues in this subgroup of patients more thoroughly., Ethics and Dissemination: All participants are given a SARON patient information sheet and required to give written informed consent. Results will be submitted for presentation at local and international conferences and expected to be published in a peer-reviewed journal., Trial Registration Number: NCT02417662., Sponsor Reference: UCL/13/0594., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

In spite of recent improvements in both the technical delivery of radiotherapy and systemic therapy in the treatment of non-small cell lung cancer, local recurrence rates after radiotherapy remain a significant challenge. In the setting of local relapse after radiotherapy, treatments such as surgical resection or radiofrequency ablation are often not appropriate owing to disease and patient factors. Re-irradiation may be a potential treatment option. This overview considers the published evidence and potential treatment strategies., (Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

A novel treatment planning framework, the Relative Biological Effective Dose (RBED), for high Z nanoparticle (NP)-enhanced photon radiotherapy is developed and tested in silico for the medical exemplar of neoadjuvant (preoperative) breast cancer MV photon radiotherapy. Two different treatment scenarios, conventional and high Z NP enhanced, were explored with a custom Geant4 application that was developed to emulate the administration of a single 2 Gy fraction as part of a 50 Gy radiotherapy treatment plan. It was illustrated that there was less than a 1% difference in the dose deposition throughout the standard and high Z NP-doped adult female phantom. Application of the RBED framework found that the extent of possible biological response with high Z NP doping was great than expected via the dose deposition alone. It is anticipated that this framework will assist the scientific community in future high Z NP-enhanced in-silico, pre-clinical and clinical trials.

Aims: The National Institute for Healthcare Excellence recommends continuous hyperfractionated, accelerated radiotherapy (CHART), concurrent chemoradiation (cCRT) and stereotactic ablative radiotherapy (SABR) for appropriate patients with non-small cell lung cancer (NSCLC), but these are not universally available in all UK radiotherapy centres. Reduced access to these treatments may be contributing to reduced survival, with the concern that elderly patients are less likely to receive guideline-recommended therapy (GRT)., Materials and Methods: We report a prospective, UK national study of patients treated with curative-intent radiotherapy for NSCLC over a 2 month period. Clinical oncologists in all UK radiotherapy centres were contacted and asked to complete a proforma on all patients treated with curative-intent radiotherapy., Results: Three hundred and seventeen records were returned from 82% of centres. Only 49% (95% confidence interval 43-55%) of patients received the GRT for their tumour type. Patients aged 70 years or over were less likely to access GRT than those under 70 years (40% compared with 60%, P = 0.001), both as a result of clinicians offering therapy less frequently (52% compared with 65%, P = 0.03) and a higher refusal of therapy (22% versus 8%, P = 0.02). A reluctance to travel to a different centre was a key component of these decisions. SABR was delivered to only 52% of suitable patients, mainly because it was not available in the local centre., Conclusions: In this study of UK curative-intent radiotherapy practice, a lack of local access seems to limit uptake of advanced radiotherapy techniques such as SABR, especially for patients aged over 70 years., (Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.)

Background and Purpose: To evaluate the impact of ATR inhibition using AZD6738 in combination with radiotherapy on the response of non-small cell lung cancer (NSCLC) tumour models and a murine model of radiation induced fibrosis., Materials and Methods: AZD6738 was evaluated as a monotherapy and in combination with radiation in vitro and in vivo using A549 and H460 NSCLC models. Radiation induced pulmonary fibrosis was evaluated by cone beam computed tomography (CBCT) and histological staining., Results: AZD6738 specifically inhibits ATR kinase and enhanced radiobiological response in NSCLC models but not in human bronchial epithelial cells (HBECs) in vitro. Significant tumour growth delay was observed in cell line derived xenografts (CDXs) of H460 cells (p<0.05) which were less significant in A549 cells. Combination of AZD6738 with radiotherapy showed no significant change in lung tissue density by CBCT (p>0.5) and histological scoring of radiation induced fibrosis (p>0.5)., Conclusion: Inhibition of ATR with AZD6738 in combination with radiotherapy increases tumour growth delay without observable augmentation of late radiation induced toxicity further underpinning translation towards clinical evaluation in NSCLC., (Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.)

Stereotactic ablative body radiotherapy (SABR) describes a radiotherapy (RT) technique where high doses of radiation are precisely delivered to an extracranial target within the body, using either a single fraction of RT or using multiple small numbers of fractions. SABR has now become the standard of care treatment for patients with early-stage non-small-cell lung cancer (NSCLC) for whom surgery is not appropriate. This systematic review considers the evidence supporting the use of SABR in early-stage NSCLC, reported toxicity rates, the use of SABR in centrally located NSCLC, the use of SABR as salvage therapy following surgery or RT, and future potential drug combinations with SABR.

More than half of those born after 1960 will develop cancer during their lifetime. Fortunately, owing to improved diagnosis and treatment, cure rates have risen steadily over the last three decades. With an increased survivorship, more will experience adverse effects of cancer therapeutics on the heart. As the oncologist's focus begins to encompass the issues of cancer survivorship, awareness of the management of cardiac toxicity would be prudent for all physicians looking after patients with cancer.

The goal of re-programming the host immune system to target malignancy with durable anti-tumour clinical responses has been speculated for decades. In the last decade such speculation has been transformed into reality with unprecedented and durable responses to immune checkpoint inhibitors seen in solid tumours. This mini-review considers the mechanism of action of immune modulating agents and the potential for combination with radiotherapy in the treatment of non-small cell lung cancer., (Copyright © 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Lung cancer is the most common cancer diagnosed in the UK. Outcomes for patients with this disease remain poor and new strategies to treat this disease require investigation. One potential option is to combine novel agents with radiotherapy in clinical studies. Here we discuss some of the important issues to consider when combining novel agents with radiotherapy, together with potential solutions as discussed at a recent Clinical Translational Radiotherapy Group (CTRad) workshop., (Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.)

Background and Purpose: To assess the impact of a standardized delineation protocol and training interventions on PET/CT-based target volume delineation (TVD) in NSCLC in a multicenter setting., Material and Methods: Over a one-year period, 11 pairs, comprised each of a radiation oncologist and nuclear medicine physician with limited experience in PET/CT-based TVD for NSCLC from nine different countries took part in a training program through an International Atomic Energy Agency (IAEA) study (NCT02247713). Teams delineated gross tumor volume of the primary tumor, during and after training interventions, according to a provided delineation protocol. In-house developed software recorded the performed delineations, to allow visual inspection of strategies and to assess delineation accuracy., Results: Following the first training, overall concordance indices for 3 repetitive cases increased from 0.57±0.07 to 0.66±0.07. The overall mean surface distance between observer and expert contours decreased from -0.40±0.03cm to -0.01±0.33cm. After further training overall concordance indices for another 3 repetitive cases further increased from 0.64±0.06 to 0.80±0.05 (p=0.01). Mean surface distances decreased from -0.34±0.16cm to -0.05±0.20cm (p=0.01)., Conclusion: Multiple training interventions improve PET/CT-based TVD delineation accuracy in NSCLC and reduce interobserver variation., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Resistance to radiotherapy due to insufficient cancer cell death is a significant cause of treatment failure in non-small cell lung cancer (NSCLC). The endogenous caspase-8 inhibitor FLIP is a critical regulator of cell death that is frequently overexpressed in NSCLC and is an established inhibitor of apoptotic cell death induced via the extrinsic death receptor pathway. Apoptosis induced by ionizing radiation (IR) has been considered to be mediated predominantly via the intrinsic apoptotic pathway; however, we found that IR-induced apoptosis was significantly attenuated in NSCLC cells when caspase-8 was depleted using RNA interference (RNAi), suggesting involvement of the extrinsic apoptosis pathway. Moreover, overexpression of wild-type FLIP, but not a mutant form that cannot bind the critical death receptor adaptor protein FADD, also attenuated IR-induced apoptosis, confirming the importance of the extrinsic apoptotic pathway as a determinant of response to IR in NSCLC. Importantly, when FLIP protein levels were downregulated by RNAi, IR-induced cell death was significantly enhanced. The clinically relevant histone deacetylase (HDAC) inhibitors vorinostat and entinostat were subsequently found to sensitize a subset of NSCLC cell lines to IR in a manner that was dependent on their ability to suppress FLIP expression and promote activation of caspase-8. Entinostat also enhanced the antitumor activity of IR in vivo Therefore, FLIP downregulation induced by HDAC inhibitors is a potential clinical strategy to radiosensitize NSCLC and thereby improve response to radiotherapy. Overall, this study provides the first evidence that pharmacological inhibition of FLIP may improve response of NCSLC to IR. Mol Cancer Ther; 15(10); 2432-41. ©2016 AACR., (©2016 American Association for Cancer Research.)

Introduction: The majority of stage III patients with non-small cell lung cancer (NSCLC) are unsuitable for concurrent chemoradiotherapy, the non-surgical gold standard of care. As the alternative treatment options of sequential chemoradiotherapy and radiotherapy alone are associated with high local failure rates, various intensification strategies have been employed. There is evidence to suggest that altered fractionation using hyperfractionation, acceleration, dose escalation, and individualisation may be of benefit. The MAASTRO group have pioneered the concept of 'isotoxic' radiotherapy allowing for individualised dose escalation using hyperfractionated accelerated radiotherapy based on predefined normal tissue constraints. This study aims to evaluate whether delivering isotoxic radiotherapy using intensity modulated radiotherapy (IMRT) is achievable., Methods and Analysis: Isotoxic IMRT is a multicentre feasibility study. From June 2014, a total of 35 patients from 7 UK centres, with a proven histological or cytological diagnosis of inoperable NSCLC, unsuitable for concurrent chemoradiotherapy will be recruited. A minimum of 2 cycles of induction chemotherapy is mandated before starting isotoxic radiotherapy. The dose of radiation will be increased until one or more of the organs at risk tolerance or the maximum dose of 79.2 Gy is reached. The primary end point is feasibility, with accrual rates, local control and overall survival our secondary end points. Patients will be followed up for 5 years., Ethics and Dissemination: The study has received ethical approval (REC reference: 13/NW/0480) from the National Research Ethics Service (NRES) Committee North West-Greater Manchester South. The trial is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (GCP). The trial results will be published in a peer-reviewed journal and presented internationally., Trial Registration Number: NCT01836692; Pre-results., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

By virtue of being a localized treatment modality, radiotherapy is unable to deliver a tumoricidal radiation dose to tissues outside of the irradiated field. Nevertheless, ionizing radiation may result in radiation damage mediated by a bystander like effect away from the irradiated field, but this response is likely to be modest when radiotherapy is the sole treatment modality. Over the last decade there has been a re-emergence of immune modulating therapies as anti-cancer treatment modalities. Clinical trials on vaccines have on the whole been largely disappointing, but greater response rates have been observed from the immune checkpoint modulators. A clinical benefit of using such agents has been shown in disease sites such as melanoma and non-small cell lung cancer. There is growing pre-clinical data and a number of case reports which suggest the presence of abscopal effects when radiotherapy is co-administered with immune checkpoint inhibitors, suggesting that this combination may lead to an enhanced tumour response outside of the primary treatment field. In this review, the mechanisms of such an enhanced out-of-field tumour response, the potential clinical utilities, the optimal radiotherapy delivery and considerations for clinical follow-up following treatment are discussed., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Aims: Modern radiotherapy uses techniques to reliably identify tumour and reduce target volume margins. However, this can potentially lead to an increased risk of geographic miss. One source of error is the accuracy of target volume delineation (TVD). Colleague peer review (CPR) of all curative-intent lung cancer plans has been mandatory in our institution since May 2013. At least two clinical oncologists review plans, checking treatment paradigm, TVD, prescription dose tumour and critical organ tolerances. We report the impact of CPR in our institution., Materials and Methods: Radiotherapy treatment plans of all patients receiving radical radiotherapy were presented at weekly CPR meetings after their target volumes were reviewed and signed off by the treating consultant. All cases and any resultant change to TVD (including organs at risk) or treatment intent were recorded in our prospective CPR database. The impact of CPR over a 13 month period from May 2013 to June 2014 is reported., Results: One hundred and twenty-two patients (63% non-small cell lung carcinoma, 17% small cell lung carcinoma and 20% 'clinical diagnosis') were analysed. On average, 3.2 cases were discussed per meeting (range 1-8). CPR resulted in a change in treatment paradigm in 3% (one patient proceeded to induction chemotherapy, two patients had high-dose palliative radiotherapy). Twenty-one (17%) had a change in TVD and one (1%) patient had a change in dose prescription. In total, 6% of patients had plan adjustment after review of dose volume histogram., Conclusion: The introduction of CPR in our centre has resulted in a change in a component of the treatment plan for 27% of patients receiving curative-intent lung radiotherapy. We recommend CPR as a mandatory quality assurance step in the planning process of all radical lung plans., (Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

This document describes best practice and evidence based recommendations for the use of FDG-PET/CT for the purposes of radiotherapy target volume delineation (TVD) for curative intent treatment of non-small cell lung cancer (NSCLC). These recommendations have been written by an expert advisory group, convened by the International Atomic Energy Agency (IAEA) to facilitate a Coordinated Research Project (CRP) aiming to improve the applications of PET based radiation treatment planning (RTP) in low and middle income countries. These guidelines can be applied in routine clinical practice of radiotherapy TVD, for NSCLC patients treated with concurrent chemoradiation or radiotherapy alone, where FDG is used, and where a calibrated PET camera system equipped for RTP patient positioning is available. Recommendations are provided for PET and CT image visualization and interpretation, and for tumor delineation using planning CT with and without breathing motion compensation., (Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Stereotactic body radiotherapy (SBRT) is now an established therapy in stage I lung cancer with comparable local control rates to surgical resection. Owing to the conformity of treatment dose delivery and with appropriate fractionation considerations, minimal side-effects to surrounding normal tissues are observed in most patients. SBRT is now being used in the treatment of oligometastatic disease, alone or alongside systemic therapy. At present there is a paucity of evidence available showing a clinical benefit, but several international studies are being set-up or have started recruitment. This overview considers the clinical entity of an oligometastatic state, discusses the role of SBRT in the management of oligometastatic disease and discusses potential novel therapy combinations with SBRT., (Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Following early results of recent studies of intraoperative radiotherapy (IORT) in the adjuvant treatment of patients with early breast cancer, the clinical utility of IORT is a subject of much recent debate within the breast oncology community. This review describes the intraoperative techniques available, the potential indications and the evidence to date pertaining to local control and toxicity. We also discuss any implications for current practice and future research.

Objective: The aim of this study was to identify sources of anatomical misrepresentation owing to the location of camera mounting, tumour motion velocity and image processing artefacts in order to optimize the four-dimensional CT (4DCT) scan protocol and improve geometrical-temporal accuracy., Methods: A phantom with an imaging insert was driven with a sinusoidal superior-inferior motion of varying amplitude and period for 4DCT scanning. The length of a high-density cube within the insert was measured using treatment planning software to determine the accuracy of its spatial representation. Scan parameters were varied, including the tube rotation period and the cine time between reconstructed images. A CT image quality phantom was used to measure various image quality signatures under the scan parameters tested., Results: No significant difference in spatial accuracy was found for 4DCT scans carried out using the wall- or couch-mounted camera for sinusoidal target motion. Greater spatial accuracy was found for 4DCT scans carried out using a tube rotation speed of 0.5 s rather than 1.0 s. The reduction in image quality when using a faster rotation speed was not enough to require an increase in patient dose., Conclusion: The 4DCT accuracy may be increased by optimizing scan parameters, including choosing faster tube rotation speeds. Peak misidentification in the recorded breathing trace may lead to spatial artefacts, and this risk can be reduced by using a couch-mounted infrared camera., Advances in Knowledge: This study explicitly shows that 4DCT scan accuracy is improved by scanning with a faster CT tube rotation speed.

Aims: To investigate the potential dosimetric and clinical benefits predicted by using four-dimensional computed tomography (4DCT) compared with 3DCT in the planning of radical radiotherapy for non-small cell lung cancer., Materials and Methods: Twenty patients were planned using free breathing 4DCT then retrospectively delineated on three-dimensional helical scan sets (3DCT). Beam arrangement and total dose (55 Gy in 20 fractions) were matched for 3D and 4D plans. Plans were compared for differences in planning target volume (PTV) geometrics and normal tissue complication probability (NTCP) for organs at risk using dose volume histograms. Tumour control probability and NTCP were modelled using the Lyman-Kutcher-Burman (LKB) model. This was compared with a predictive clinical algorithm (Maastro), which is based on patient characteristics, including: age, performance status, smoking history, lung function, tumour staging and concomitant chemotherapy, to predict survival and toxicity outcomes. Potential therapeutic gains were investigated by applying isotoxic dose escalation to both plans using constraints for mean lung dose (18 Gy), oesophageal maximum (70 Gy) and spinal cord maximum (48 Gy)., Results: 4DCT based plans had lower PTV volumes, a lower dose to organs at risk and lower predicted NTCP rates on LKB modelling (P < 0.006). The clinical algorithm showed no difference for predicted 2-year survival and dyspnoea rates between the groups, but did predict for lower oesophageal toxicity with 4DCT plans (P = 0.001). There was no correlation between LKB modelling and the clinical algorithm for lung toxicity or survival. Dose escalation was possible in 15/20 cases, with a mean increase in dose by a factor of 1.19 (10.45 Gy) using 4DCT compared with 3DCT plans., Conclusions: 4DCT can theoretically improve therapeutic ratio and dose escalation based on dosimetric parameters and mathematical modelling. However, when individual characteristics are incorporated, this gain may be less evident in terms of survival and dyspnoea rates. 4DCT allows potential for isotoxic dose escalation, which may lead to improved local control and better overall survival., (Copyright © 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Intrafraction tumour motion is an issue that is of increased interest in the era of image-guided radiotherapy. It is particularly relevant for non-small cell lung cancer, for which a number of recent developments are in use to aid with motion management in the delivery of radical radiotherapy. The ability to deliver hypofractionated ablative doses, such as in stereotactic radiotherapy, has been aided by improvements in the ability to analyse tumour motion and amend treatment delivery. In addition, accounting for tumour motion can enable dose escalation to occur by reducing the normal tissue being irradiated by virtue of a reduction in target volumes. Motion management for lung tumours incorporates five key components: imaging, breath-hold techniques, abdominal compression, respiratory tracking and respiratory gating. These will be described, together with the relevant benefits and associated complexities. Many studies have described improved dosimetric coverage and reduced normal tissue complication probability rates when using motion management techniques. Despite the widespread uptake of many of these techniques, there is a paucity of literature reporting improved outcome in overall survival and local control for patients whenever motion management techniques are used. This overview will review the extent of lung tumour motion, ways in which motion is detected and summarise the key methods used in motion management., (Copyright © 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)