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Objective: Determine whether the ACSM walking equations, which calculate caloric expenditure, were accurate for college-aged males and females., Participants: Between 2011 and 2016, 100 college-aged males, 20.24 ± 2.0 years old, and 100 college-aged females, 20.8 ± 1.3 years old, volunteered to participate., Methods: Participants walked on a treadmill at 80.4 m⋅min -1 at grades of 2, 4, and 6%. Oxygen uptake was measured with an oxygen analyzer (Medgraphics VO2000, Minneapolis, MN). Measurements were converted to caloric expenditure., Results: The mean metabolically derived (MD) VO ̇ 2 values, in ml·kg -1 ·min -1 for males walking at grades of 2.0, 4.0 and 6.0% were: 15.4 ± 2.7, 17.3 ± 2.6, 19.6 ± 2.8, respectively, and for females were: 15.2 ± 1.1, 16.0 ± 2.0, 17.4 ± 4.2, respectively. ACSM prediction equation values for VO ̇ 2 at the described parameters are 14.4, 17.3 and 20.8, respectively., Conclusions: ACSM prediction equations are not a good predictor of overall caloric expenditure, in college-aged males and females.

Introduction: In 'IDEAL-6' patients (N = 78) treated for locally-advanced non-small-cell lung cancer using isotoxically dose-escalated radiotherapy, overall survival (OS) was associated more strongly with V LAwall-64-73-EQD2 , the left atrial (LA) wall volume receiving 64-73 Gy equivalent dose in 2 Gy fractions (EQD2), than with whole-heart irradiation measures. Here we test this in an independent cohort 'OX-RT' (N = 64) treated routinely., Methods: Using Cox regression analysis we assessed how strongly OS was associated with V LAwall-64-73-EQD2 , with whole-heart volumes receiving 64-73 Gy EQD2 or doses above 10-to-70 Gy thresholds, and with principal components of whole-heart dose-distributions. Additionally, we tested associations between OS and volumes of cardiac substructures receiving dose-ranges described by whole-heart principal components significantly associated with OS., Results: In univariable analyses of OX-RT, OS was associated more strongly with V LAwall-64-73-EQD2 than with whole-heart irradiation measures, but more strongly still with V AortV-29-38-EQD2 , the volume of the aortic valve region receiving 29-38 Gy EQD2. The best multivariable OS model included LA wall and aortic valve region mean doses, and the aortic valve volume receiving ≥38 Gy EQD2, V AortV-38-EQD2 . In a subsidiary analysis of IDEAL-6, the best multivariable model included V LAwall-64-73-EQD2 , V AortV-29-38-EQD2 , V AortV-38-EQD2 and mean aortic valve dose., Conclusion: We propose reducing heart mean doses to the lowest levels possible while meeting protocol dose-limits for lung, oesophagus, proximal bronchial tree, cord and brachial plexus. This in turn achieves large reductions in V AortV-29-38-EQD2 and V LAwall-64-73-EQD2 , and we plan to closely monitor patients with values of these measures still >0% (their median value in OX-RT) following reduction., 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 © 2021 Elsevier B.V. All rights reserved.)

Introduction: Stereotactic Ablative Radiotherapy (SABR) is increasingly used to treat metastatic oligorecurrence and locoregional recurrences but limited evidence/guidance exists in the setting of pelvic re-irradiation. An international Delphi study was performed to develop statements to guide practice regarding patient selection, pre-treatment investigations, treatment planning, delivery and cumulative organs at risk (OARs) constraints., Materials and Methods: Forty-one radiation oncologists were invited to participate in three online surveys. In Round 1, information and opinion was sought regarding participants' practice. Guidance statements were developed using this information and in Round 2 participants were asked to indicate their level of agreement with each statement. Consensus was defined as ≥75% agreement. In Round 3, any statements without consensus were re-presented unmodified, alongside a summary of comments from Round 2., Results: Twenty-three radiation oncologists participated in Round 1 and, of these, 21 (91%) and 22 (96%) completed Rounds 2 and 3 respectively. Twenty-nine of 44 statements (66%) achieved consensus in Round 2. The remaining 15 statements (34%) did not achieve further consensus in Round 3. Consensus was achieved for 10 of 17 statements (59%) regarding patient selection/pre-treatment investigations; 12 of 13 statements (92%) concerning treatment planning and delivery; and 7 of 14 statements (50%) relating to OARs. Lack of agreement remained regarding the minimum time interval between irradiation courses, the number/size of pelvic lesions that can be treated and the most appropriate cumulative OAR constraints., Conclusions: This study has established consensus, where possible, in areas of patient selection, pre-treatment investigations, treatment planning and delivery for pelvic SABR re-irradiation for metastatic oligorecurrence and locoregional recurrences. Further research into this technique is required, especially regarding aspects of practice where consensus was not achieved., Competing Interests: Declarations/conflicts of interest statement FS is a Clinical Research Fellow supported by a Cancer Research UK Centres Network Accelerator Award to the ART-NET consortium (grant number A21993). FA reports speaker honoraria and consultancy for Varian and Elekta. BAJF reports institutional research funding grants from Italian Association for Cancer Research (AIRC), FIEO-CCM & FUV and Accuray, outside of the submitted work. BAJF reports travel expenses/speaker fees from Janssen, Ferring, Bayer, Roche, Astellas, Elekta, Carl Zeiss, Ipsen, Accuray and IBA, outside of the submitted work. MAH is supported by funding from the NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust. AMH is supported by grants from Cancer Research UK (award number 108036), National Institute for Health Research (NIHR) (award number 111218), Medical Research Council (MRC) (award number 107154) and Sir John Fisher Foundation (charity, no award number). LJM is an associate professor supported by a Yorkshire Cancer Research funded by Yorkshire Cancer Research (award number L389LM)., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aims: Anal squamous cell carcinomas (ASCC) are strongly associated with human papillomaviruses. Standard of care is chemoradiotherapy at uniform doses with no treatment stratification. Immunohistochemical staining for p16INK4A (p16), a surrogate for human papillomaviruses, is prognostic for outcomes. We investigated this alongside clinical-pathological factors, including tumour infiltrating lymphocyte (TIL) scores., Materials and Methods: Using an independent, multicentre cohort of 257 ASCC treated with chemoradiotherapy, pretreatment biopsies were stained and scored for p16 and TIL. Kaplan-Meier curves were derived for outcomes (disease-free survival [DFS], overall survival and cancer-specific survival), by stage, p16 and TIL scores and Log-rank tests were carried out to investigate prognostic effect. A multivariate analysis was carried out using Cox regression., Results: Stage, sex, p16 and TILs were independently prognostic. Hazard ratios for death (overall survival) were 2.51 (95% confidence interval 1.36-4.63) for p16 negative versus p16 positive, 2.17 (1.34-3.5) for T3/4 versus T1/2, 2.42 (1.52-3.8) for males versus females and 3.30 (1.52-7.14) for TIL1 versus TIL3 (all P < 0.05)., Conclusions: We have refined prognostic factors in ASCC. p16 adds to stratification by stage with respect to DFS in early disease and overall survival/DFS in locally advanced cancers. Our data support the role of the host immune response in mediating outcomes. These factors will be prospectively evaluated in PLATO (ISRCTN88455282)., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Neoadjuvant chemoradiotherapy for oesophageal cancer significantly improves overall survival but is associated with severe post-operative complications. Proton beam therapy may reduce these toxicities by sparing normal tissues compared with standard radiotherapy. ProtOeus is a proposed randomised phase II study of neoadjuvant chemoradiotherapy in oesophageal cancer that compares proton beam therapy to standard radiotherapy techniques. As proton beam therapy services are often centralised in academic centres in major cities, proton beam therapy trials raise distinct challenges including patient acceptance of travelling for proton beam therapy, coordination of treatments with local centres and ensuring equity of access for patients., Methods: Focus groups were held early in the trial development process to establish patients' views on the trial proposal. Topics discussed include perception of proton beam therapy, patient acceptability of the trial pathway and design, patient-facing materials, and common clinical scenarios. Focus groups were led by the investigators and facilitated by patient involvement teams from the institutions who are involved in this research. Responses for each topic were analysed, and fed back to the trial's development group., Results: Three focus groups were held in separate locations in the UK (Manchester, Cardiff, Wigan). Proton beam therapy was perceived as superior to standard radiotherapy making the trial attractive. Patients felt strongly that travel costs should be reimbursed to ensure equity of access to proton beam therapy. They were very supportive of a shorter treatment schedule and felt that toxicity reduction was the most important endpoint., Discussion and Conclusions: Incorporating patient views early in the trial development process resulted in significant trial design refinements including travel/accommodation provisions, choice of primary endpoint, randomisation ratio and fractionation schedule. Focus groups are a reproducible and efficient method of incorporating the patient and public voice into research., (© 2020. Springer Nature Switzerland AG.)

Radiation resistance is a significant clinical problem in rectal cancer treatment, the mechanisms of which are poorly understood. NRF2 signalling is known to contribute to chemo/radioresistance in some cancers, but its role in therapeutic resistance in colorectal cancer (CRC) is unexplored. Using siRNA and CRiSPR/Cas9 isogenic CRC cell lines, we investigated the effect of the knockdown and upregulation of the NRF2 pathway on chemo-radiosensitivity. Poly (A) enriched RNA sequencing and geneset enrichment analysis (GSEA) were carried out on both sensitive and resistant cell models for mechanistic insights. Finally, a cohort of rectal patient samples was profiled to understand the clinical relevance of NRF2 signalling. Radioresistant cell lines were significantly radiosensitised by siRNA knockdown (SW1463, SER10 1.22, ANOVA p < 0.0001; HT55, SER10 1.17, ANOVA p < 0.01), but not the (already) radiosensitive HCT116. The constitutive activation of NRF2 via a CRISPR Cas9 NFE2L2 mutation, E79K, induced radioresistance in HCT116 (SER10 0.71, ANOVA, p < 0.0001). GSEA demonstrated significant opposing metabolic dependencies in NRF2 signalling, specifically, the downregulation of amino acid and protein synthesis with low levels of NRF2 and upregulation with over expression. In a clinical cohort of 127 rectal patients, using a validated mRNA signature, higher baseline NRF2 signalling was associated with incomplete responses to radiation higher final neoadjuvant rectal (NAR) score (OR 1.34, 95% C.I. 1.01-1.80, LRT p -value = 0.023), where high NAR indicates poor radiation response and poor long-term prognosis. This is the first demonstration of NRF2-mediated radiation resistance in colorectal cancer. NRF2 appears to regulate crucial metabolic pathways, which could be exploited for therapeutic interventions.

Aim: This is the first randomised study to evaluate toxicity and survival outcomes of two neoadjuvant chemoradiotherapy (CRT) regimens for patients with localised oesophageal adenocarcinoma (OAC) or gastro-oesophageal junction (GOJ) adenocarcinoma. The initial results showed comparable toxicity between regimens and pathological complete response (pCR) rate favouring CarPacRT. Herein, we report survival, progression patterns, and long-term toxicity after a median follow-up of 40.7 months., Methods: NeoSCOPE was an open-label, UK multicentre, randomised, phase II trial. Eighty-five patients with resectable OAC or GOJ adenocarcinoma, ≥cT3 and/or ≥cN1 (TNM v7), suitable for neoadjuvant CRT, were recruited between October 2013 and February 2015. Patients were randomised to OxCapRT (oxaliplatin 85 mg/m 2 on Days 1, 15, and 29; capecitabine 625 mg/m 2 orally twice daily on days of radiotherapy [RT]) or CarPacRT (carboplatin AUC2; paclitaxel 50 mg/m 2 on Days 1, 8, 15, 22, and 29). RT dose was 45 Gy/25 fractions/5 weeks. Both arms received induction chemotherapy (two cycles oxaliplatin 130 mg/m 2 on Day 1, capecitabine 625 mg/m 2 orally twice daily on Days 1-21) before CRT. Surgery was performed 6-8 weeks after CRT. The primary end-point was pCR. Secondary end-points were toxicity, progression-free survival (PFS), overall survival (OS), and patterns of progression., Results: Eighty-five patients were recruited from 17 UK centres. The median OS was 41.7 months (95% confidence interval [CI] 19.6 to not reached) in the OxCapRT arm and was not reached in the CarPacRT arm (multivariable hazard ratio [HR] = 0.48, 95% CIs: 0.24-0.95, P = 0.035). The median PFS was 32.6 months (95% CIs: 17.1 to not reached) in the OxCapRT arm and was not reached in the CarPacRT arm (multivariable HR = 0.54, 95% CIs: 0.29-1.01, P = 0.053). In both arms, the distant progression was twice as common as locoregional progression., Conclusions: OS and PFS favoured neoadjuvant CarPacRT over OxCapRT. Distant was more common than locoregional progression; therefore, priority should be given to optimising the systemic treatment component., Clinical Trial Information: EudraCT Number: 2012-000640-10; ClinicalTrials.gov: NCT01843829., Competing Interests: Conflicts of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: RAS is an employee of and holds stock in Varian Medical Systems. All other authors have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Aims: Due to its physical advantages over photon radiotherapy, proton beam therapy (PBT) has the potential to improve outcomes from oesophageal cancer. However, for many tumour sites, high-quality evidence supporting PBT use is limited. We carried out a systematic review of published literature of PBT in oesophageal cancer to ascertain potential benefits of this technology and to gauge the current state-of-the-art. We considered if further evaluation of this technology in oesophageal cancer is desirable., Materials and Methods: A systematic literature search of Medline, Embase, Cochrane Library and Web of Science using structured search terms was carried out. Inclusion criteria included non-metastatic cancer, full articles and English language studies only. Articles deliberating technical aspects of PBT planning or delivery were excluded to maintain a clinical focus. Studies were divided into two sections: dosimetric and clinical studies; qualitatively synthesised., Results: In total, 467 records were screened, with 32 included for final qualitative synthesis. This included two prospective studies with the rest based on retrospective data. There was heterogeneity in treatment protocols, including treatment intent (neoadjuvant or definitive), dose, fractionation and chemotherapy used. Compared with photon radiotherapy, PBT seemed to reduce dose to organs at risk, especially lung and heart, although not for all reported parameters. Toxicity outcomes, including postoperative complications, were reduced compared with photon radiotherapy. Survival outcomes were reported to be at least comparable with photon radiotherapy., Conclusion: There is a paucity of high-quality evidence supporting PBT use in oesophageal cancer. Wide variation in intent and treatment protocols means that the role and 'gold-standard' treatment protocol are yet to be defined. Current literature suggests significant benefit in terms of toxicity reduction, especially in the postoperative period, with comparable survival outcomes. PBT in oesophageal cancer holds significant promise for improving patient outcomes but requires robust systematic evaluation in prospective studies., (Copyright © 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: We have carried out a study to determine the scope for reducing heart doses in photon beam radiotherapy of locally advanced non-small cell lung cancer (LA-NSCLC)., Materials and Methods: Baseline VMAT plans were created for 20 LA-NSCLC patients following the IDEAL-CRT isotoxic protocol, and were re-optimized after adding an objective limiting heart mean dose (MD Heart ). Reductions in MD Heart achievable without breaching limits on target coverage or normal tissue irradiation were determined. The process was repeated for objectives limiting the heart volume receiving ≥ 50 Gy (V Heart-50-Gy ) and left atrial wall volume receiving ≥ 63 Gy (V LAwall-63-Gy )., Results: Following re-optimization, mean MD Heart , V Heart-50-Gy and V LAwall-63-Gy values fell by 4.8 Gy and 2.2% and 2.4% absolute respectively. On the basis of associations observed between survival and cardiac irradiation in an independent dataset, the purposefully-achieved reduction in MD Heart is expected to lead to the largest improvement in overall survival. It also led to useful knock-on reductions in many measures of cardiac irradiation including V Heart-50-Gy and V LAwall-63-Gy , providing some insurance against survival being more strongly related to these measures than to MD Heart . The predicted hazard ratio (HR) for death corresponding to the purposefully-achieved mean reduction in MD Heart was 0.806, according to which a randomized trial would require 1140 patients to test improved survival with 0.05 significance and 80% power. In patients whose baseline MD Heart values exceeded the median value in a published series, the average MD Heart reduction was particularly large, 8.8 Gy. The corresponding predicted HR is potentially testable in trials recruiting 359 patients enriched for greater MD Heart values., Conclusions: Cardiac irradiation in RT of LA-NSCLC can be reduced substantially. Of the measures studied, reduction of MD Heart led to the greatest predicted increase in survival, and to useful knock-on reductions in other cardiac irradiation measures reported to be associated with survival. Potential improvements in survival can be trialled more efficiently in a population enriched for patients with greater baseline MD Heart levels, for whom larger reductions in heart doses can be achieved.

Aims: Preoperative (chemo)radiotherapy followed by total mesorectal excision is the current standard of care for patients with locally advanced rectal cancer. The use of intensity-modulated radiotherapy (IMRT) for rectal cancer is increasing in the UK. However, the extent of IMRT implementation and current practice was not previously known. A national survey was commissioned to investigate the landscape of IMRT use for rectal cancer and to inform the development of national rectal cancer IMRT guidance., Materials and Methods: A web-based survey was developed by the National Rectal Cancer IMRT Guidance working group in collaboration with the Royal College of Radiologists and disseminated to all UK radiotherapy centres. The survey enquired about the implementation of IMRT with a focus on the following aspects of the workflow: dose fractionation schedules and use of a boost; pre-treatment preparation and simulation; target volume/organ at risk definition; treatment planning and treatment verification. A descriptive statistical analysis was carried out., Results: In total, 44 of 63 centres (70%) responded to the survey; 30/44 (68%) and 36/44 (82%) centres currently use IMRT to treat all patients and selected patients with rectal cancer, respectively. There was general agreement concerning several aspects of the IMRT workflow, including patient positioning, use of intravenous contrast and bladder protocols. Greater variation in practice was identified regarding rectal protocols; use of a boost to primary/nodal disease; target volume delineation; organ at risk delineation and dose constraints and treatment verification. Delineation of individual small bowel loops and daily volumetric treatment verification were considered potentially feasible by most centres., Conclusion: This survey identified that IMRT is already used to treat rectal cancer in many UK radiotherapy centres, but there is heterogeneity between centres in its implementation and practice. These results have been a valuable aid in framing the recommendations within the new National Rectal Cancer IMRT Guidance., (Copyright © 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background and Purpose: Following resection of pancreatic cancer, risk of positive margins and local recurrence remain high, especially for borderline-resectable pancreatic cancer (BRPC). We aimed to establish the maximum tolerated dose of a margin-intensified five-fraction stereotactic body radiotherapy (SBRT) regimen designed to treat the region at risk., Materials and Methods: We conducted a prospective multicentre phase-1 rolling-six dose-escalation study. BRPC patients received pre-operative SBRT, with one dose to the primary tumour and an integrated boost to the region where tumour was in contact with vasculature. Four dose-levels were proposed, with starting dose 30 Gy to primary PTV and 45 Gy to boost volume (PTV&#95;R), in five daily fractions. Primary endpoint was maximum tolerated dose (MTD), defined as highest dose where zero of three or one of six patients experienced dose-limiting toxicity (DLT)., Results: Twelve patients were registered, eleven received SBRT. Radiotherapy was well tolerated with all treatment completed as scheduled. Dose was escalated one level up from starting dose without encountering any DLT (prescribed 32.5 Gy PTV, 47.5 Gy PTV&#95;R). Nine serious adverse reactions or events occurred (seven CTCAE Grade 3, two Grade 4). Two patients went on to have surgical resection. Median overall survival for SBRT patients was 8.1 months. The study closed early when it was unable to recruit to schedule., Conclusion: Toxicity of SBRT was low for the two dose-levels that were tested, but MTD was not established. Few patients subsequently underwent resection of pancreatic tumour after SBRT, and it is difficult to draw conclusions regarding the safety or toxicity of these therapies in combination., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Stereotactic ablative body radiotherapy (SABR) is increasingly being used to treat oligometastatic cancers, but high-level evidence to provide a basis for policy making is scarce. Additional evidence from a real-world setting is required. We present the results of a national study of patients with extracranial oligometastases undergoing SABR, representing the largest dataset, to our knowledge, on outcomes in this population so far., Methods: In 2015, National Health Service (NHS) England launched a Commissioning through Evaluation scheme that funded a prospective, registry-based, single-arm, observational, evaluation study of patients with solid cancer and extracranial oligometastases treated with SABR. Prescribed doses ranged from 24-60 Gy administered in three to eight fractions. The study was done at 17 NHS radiotherapy centres in England. Patients were eligible for the scheme if aged 18 years or older with confirmed primary carcinoma (excluding haematological malignancies), one to three extracranial metastatic lesions, a disease-free interval from primary tumour development to metastases of longer than 6 months (with the exception of synchronous colorectal liver metastases), a WHO performance status of 2 or lower, and a life expectancy of at least 6 months. The primary outcome was overall survival at 1 year and 2 years from the start of SABR treatment. The study is now completed., Findings: Between June 15, 2015, and Jan 30, 2019, 1422 patients were recruited from 17 hospitals in England. The median age of the patients was 69 years (IQR 62-76), and the most common primary tumour was prostate cancer (406 [28·6%] patients). Median follow-up was 13 months (IQR 6-23). Overall survival was 92·3% (95% CI 90·5-93·9) at 1 year and 79·2% (76·0-82·1) at 2 years. The most common grade 3 adverse event was fatigue (28 [2·0%] of 1422 patients) and the most common serious (grade 4) event was increased liver enzymes (nine [0·6%]). Notreatment-related deaths were reported., Interpretation: In patients with extracranial oligometastatic cancer, use of SABR was associated with high overall survival and low toxicity. 'The study findings complement existing evidence from a randomised, phase 2 trial, and represent high-level, real-world evidence supporting the use of SABR in this patient cohort, with a phase 3 randomised, controlled trial to confirm these findings underway. Based on the selection criteria in this study, SABR was commissioned by NHS England in March, 2020, as a treatment option for patients with oligometastatic disease., Funding: NHS England Commissioning through Evaluation scheme., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Despite of the predominant role of chemotherapy and surgery in pancreatic ductal adenocarcinoma (PDAC), radiotherapy (RT) still has a place in multimodal management of this disease where local tumour sequelae are fatal in about 40% of the patients. RT (chemoradiotherapy and stereotactic body radiotherapy) is used and investigated in the non-metastatic setting as part of definitive treatment strategies, in (neo)adjuvant settings and for locally recurrent disease. The ACROP committee was delegated by ESTRO to recommend target volume delineation for these clinical situations. The guidelines of this document are a result of a structured evaluation of the best available evidence by a panel of international experts in the field. Guidance for treatment planning including diagnostic imaging is provided. Recommendations are given for GTV delineation. The role and the definition of CTV volumes are critically discussed. Aspects of motion management and patient positioning are taken into account for PTV definition. Furthermore, aspects of delineation of organs at risk and of dose constraints are described in both, standard and hypofractionated, settings. This guideline has the purpose to support standardised and optimised processes of RT treatment planning for both, clinical practice and prospective studies., 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 © 2021. Published by Elsevier B.V.)

Biliary tract cancers (BTC) are a disease entity comprising diverse epithelial tumors, which are categorized according to their anatomical location as intrahepatic (iCCA), perihilar (pCCA), distal (dCCA) cholangiocarcinomas, and gallbladder carcinomas (GBC), with distinct epidemiology, biology, and prognosis. Complete surgical resection is the mainstay in operable BTC as it is the only potentially curative treatment option. Nevertheless, even after curative (R0) resection, the 5-year survival rate ranges between 20 and 40% and the disease free survival rates (DFS) is approximately 48-65% after one year and 23-35% after three years without adjuvant treatment. Improvements in adjuvant chemotherapy have improved the DFS, but the role of adjuvant radiotherapy is unclear. On the other hand, more than 50% of the patients present with unresectable disease at the time of diagnosis, which limits the prognosis to a few months without treatment. Herein, we review the role of radiotherapy in the treatment of cholangiocarcinoma in the curative and palliative setting., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Gkika, Hawkins, Grosu and Brunner.)

Aims: The use of diffusion-weighted magnetic resonance imaging (DW-MRI) as a prognostic marker of treatment response would enable early individualisation of treatment. We aimed to quantify the changes in mean apparent diffusion coefficient (ΔADC mean ) between a DW-MRI at diagnosis and on fraction 8-10 of chemoradiotherapy (CRT) as a biomarker for cellularity, and correlate these with anal squamous cell carcinoma recurrence., Materials and Methods: This prospective study recruited patients with localised anal cancer between October 2014 and November 2017. DW-MRI was carried out at diagnosis and after fraction 8-10 of radical CRT. A region of interest was delineated for all primary tumours and any lymph nodes >2 cm on high-resolution T 2 -weighted images and propagated to the ADC map. Routine clinical follow-up was collected from Nation Health Service electronic systems., Results: Twenty-three of 29 recruited patients underwent paired DW-MRI scans. Twenty-six regions of interest were delineated among the 23 evaluable patients. The median (range) tumour volume was 13.6 cm 3 (2.8-84.9 cm 3 ). Ten of 23 patients had lesions with ΔADC mean ≤ 20%. With a median follow-up of 41.2 months, four patients either failed to have a complete response to CRT or subsequently relapsed. Three of four patients with disease relapse had lesions demonstrating ΔADC mean <20%, the other patient with persistent disease had ΔADC mean of 20.3%., Conclusions: We demonstrated a potential correlation between patients with ΔADC mean <20% and disease relapse. Further investigation of the prognostic merit of DW-MRI change is needed in larger, prospective cohorts., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

We hypothesise that the NRF2 transcription factor would act a biomarker of poor prognosis in colorectal cancer. We derived and validated an mRNA based metagene signature of NRF2 signalling and validated it in 1360 patients from 4 different datasets as an independent biomarker of poor prognosis. This is a novel insight into the molecular signalling of colorectal cancer., Background: NRF2 over activity confers poor prognosis in some cancers but its prognostic role in colorectal cancer (CRC) is unknown. As a transcription factor, we hypothesise a signature of NRF2 regulated genes could act as a prognostic biomarker in CRC and reveal novel biological insights., Methods: Using known NRF2 regulated genes, differentially expressed in CRC, we defined a signature of NRF2 pathway activity using principal component analysis and Cox proportional hazard models and tested it in four independent mRNA datasets, profiled on three different mRNA platforms., Results: 36 genes comprised the final NRF2 signature. 1360 patients were included in the validation. High NRF2 was associated with worse disease free survival (DFS) and/or overall survival (OS) in all datasets: (GSE14333 HR=1.55, 95% C.I 1.2-2.004, p = 0.0008; GSE39582 HR=1.24, 95% C.I 1.086-1.416, p = 0.001; GSE87211 HR=1.431, 95% C.I 1.06-1.93, p = 0.056; MRC FOCUS trial HR=1.14, 95% C.I 1.04-1.26, p = 0.008). In multivariate analyses, NRF2 remained significant when adjusted for stage and adjuvant chemotherapy in stage I-III disease, and BRAF V600E mutation and sidedness in stage IV disease. NRF2 activity was particularly enriched in Consensus Molecular Subtype (CMS) 4., Conclusion: For the first time, NRF2 is shown to be a consistent, robust prognostic biomarker across all stages of colorectal cancer with additional clinical value to current known prognostic biomarkers. High NRF2 signalling in CMS 4 further refines the molecular taxonomy of CRC, a new biological insight, suggesting avenues of further study., Competing Interests: Declaration of Competing Interest Dr. Maughan reports grants from Medical Research Council, grants from Cancer Research UK, during the conduct of the study; non-financial support and other from Astra Zeneca, personal fees from Pierre Fabre, outside the submitted work. Dr Holmes reports funding from Novartis for research collaboration outside the submitted work., (Copyright © 2020. Published by Elsevier Inc.)

Background: Stereotactic ablative radiotherapy (SBRT) is a radical option for oligometastatic colorectal cancer (CRC) patients, but most data relate to visceral metastases., Methods: A prospective, multi-centre database of CRC patients treated with SBRT was interrogated. Inclusion criteria were ECOG PS 0-2, ≤3 sites of disease, a disease free interval of >6 months unless synchronous liver metastases. Primary endpoints were local control (LC), progression free survival (PFS) and overall survival (OS)., Results: 163 patients (172 metastases) were analysed. The median FU was 16 months (IQR 12.2-22.85). The LC at 1 year was 83.8% (CI 76.4%-91.9%) with a PFS of 55% (CI 47%-64.7%) respectively. LC at 1 year was 90% (CI 83%-99%) for nodal metastases (NM), 75% (63%-90%) for visceral metastases (VM). NM had improved median PFS (9 vs 19 months) [HR 0.6, CI 0.38-0.94, p = 0.032] and median OS (32 months vs not reached) [HR 0.28, CI 0.18-0.7, p = 0.0062] than VM, regardless of whether the NM were located inside or outside the pelvis. On multivariate analysis, NM and ECOG PS 0 were significant good prognostic factors. An exploratory analysis suggests KRAS WT is also a good prognostic factor., Conclusion: Nodal site is an important prognostic determinant of SBRT that should incorporated into patient selection. We hypothesise this may have an immunoediting basis., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

The coronavirus disease 2019 (COVID-19) pandemic epicentre has moved to the USA and Europe, where it is placing unprecedented demands on healthcare resources and staff availability. These service constraints, coupled with concerns relating to an increased incidence and severity of COVID-19 among patients with cancer, should lead to re-consideration of the risk-benefit balance for standard treatment pathways. This is of particular importance to pancreatic cancer, given that standard diagnostic modalities such as endoscopy may be restricted, and that disease biology precludes significant delays in treatment. In light of this, we sought consensus from UK clinicians with an interest in pancreatic cancer for management approaches that would minimise patient risk and accommodate for healthcare service restrictions. The outcomes are described here and include recommendations for treatment prioritisation, strategies to bridge to later surgical resection in resectable disease and factors that modify the risk-benefit balance for treatment in the resectable through to the metastatic settings. Priority is given to strategies that limit hospital visits, including through the use of hypofractionated precision radiotherapy and chemoradiotherapy treatment approaches.

Purpose: Stereotactic body radiation therapy (SBRT) has emerged as a potential therapeutic option for locally recurrent rectal cancer (LRRC) but contemporaneous clinical data are limited. We aimed to evaluate the local control, toxicity, and survival outcomes in a cohort of patients previously treated with neoadjuvant pelvic radiation therapy for nonmetastatic locally recurrent rectal cancer, now treated with SBRT., Methods and Materials: Inoperable rectal cancer patients with ≤3 sites of pelvic recurrence and >6 months since prior pelvic radiation therapy were identified from a prospective registry over 4 years. SBRT dose was 30 Gy in 5 fractions, daily or alternate days, using cumulative organ at risk dose constraints. Primary outcome was local control (LC). Secondary outcomes were progression free survival, overall survival, toxicity, and patient reported quality of life scores using the EQ visual analog scale (EQ-VAS) tool., Results: Thirty patients (35 targets) were included. Median gross tumor volume size was 14.3 cm 3 . In addition, 27 of 30 (90%) previously received 45 to 50.4 Gy in 25 of 28 fractions, with 10% receiving an alternative prescription. All patients received the planned reirradiation SBRT dose. The median follow-up was 24.5 months (interquartile range, 17.8-28.8). The 1-year LC was 84.9% (95% confidence interval [CI], 70.6-99) and a 2-year LC was 69% (95% CI, 51.8-91.9). The median progression free survival was 12.1 months (95% CI, 8.6-17.66), and median overall survival was 28.3 months (95% CI, 17.88-39.5 months). No patient experienced >G2 acute toxicity and only 1 patient experienced late G3 toxicity. Patient-reported QoL outcomes were improved at 3 months after SBRT (Δ EQ-VAS, +10 points, Wilcoxon signed-rank, P = .009)., Conclusions: Our study demonstrates that, for small volume pelvic disease relapses from rectal cancer, reirradiation with 30 Gy in 5 fractions is well tolerated and achieves an excellent balance between high local control rates with limited toxicity., (© 2020 The Authors.)

Around the world, recommendations for cancer treatment are being adapted in real time in response to the pandemic of COVID-19. We, as a multidisciplinary team, reviewed the standard management options, according to the Barcelona Clinic Liver Cancer classification system, for hepatocellular carcinoma. We propose treatment recommendations related to COVID-19 for the different stages of hepatocellular carcinoma (ie, 0, A, B, and C), specifically in relation to surgery, locoregional therapies, and systemic therapy. We suggest potential strategies to modify risk during the pandemic and aid multidisciplinary treatment decision making. We also review the multidisciplinary management of intrahepatic cholangiocarcinoma as a potentially curable and incurable diagnosis in the setting of COVID-19., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

As of April 6, 2020, there are over 1,200,000 reported cases and 70,000 deaths worldwide due to COVID-19, the disease caused by the SARS-CoV-2 virus, and these numbers rise exponentially by the day [1]. According to the Centers for Disease Control (CDC), the most effective means of minimizing the spread of the virus is through reducing interactions between individuals [2]. We performed a review of the literature, as well as national and international treatment guidelines, seeking data in support of the RADS principle (Remote visits, Avoid radiation, Defer radiation, Shorten radiation) [3] as it applies to gastrointestinal cancers. The purpose of the present work is to guide radiation oncologists managing patients with gastrointestinal cancers during the COVID-19 crisis in order to maintain the safety of our patients, while minimizing the impact of the pandemic on cancer outcomes., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Chemoradiotherapy remains the standard of care for locally advanced rectal cancer. Efforts to intensify treatment and increase response rates have yet to yield practice changing results due to increased toxicity and/or absence of increased radiosensitization. Enadenotucirev (EnAd) is a tumour selective, oncolytic adenovirus which can be given intravenously. Pre-clinical evidence of synergy with radiation warrants further clinical testing and assessment of safety with radiation., Methods: Eligibility include histology confirmed locally advanced rectal cancer that require chemoradiation. The trial will use a Time-to-Event Continual Reassessment Model-based (TiTE-CRM) approach using toxicity and efficacy as co-primary endpoints to recommend the optimal dose and treatment schedule 30 patients will be recruited. Secondary endpoints include pathological complete response the neoadjuvant rectal score. A translational program will be based on a mandatory biopsy during the second week of treatment for 'proof-of-concept' and exploration of mechanism. The trial opened to recruitment in July 2019, at an expected rate of 1 per month for up to 4 years., Discussion: Chemoradiation with Enadenotucirev as a radiosensitiser in locally Advanced Rectal cancer (CEDAR) is a prospective multicentre study testing a new paradigm in radiosensitization in rectal cancer. The unique ability of EnAd to selectively infect tumour cells following intravenous delivery is an exciting opportunity with a clear translational goal. The novel statistical design will make efficient use of both toxicity and efficacy data to inform subsequent studies., Trial Registration: ClinicalTrial.gov, NCT03916510. Registered 16th April 2019.

Background and Purpose: Oxygen-enhanced magnetic resonance imaging (MRI) and T1-mapping was used to explore its effectiveness as a prognostic imaging biomarker for chemoradiotherapy outcome in anal squamous cell carcinoma., Materials and Methods: T2-weighted, T1 mapping, and oxygen-enhanced T1 maps were acquired before and after 8-10 fractions of chemoradiotherapy and examined whether the oxygen-enhanced MRI response relates to clinical outcome. Patient response to treatment was assessed 3 months following completion of chemoradiotherapy. A mean T1 was extracted from manually segmented tumour regions of interest and a paired two-tailed t -test was used to compare changes across the patient population. Regions of subcutaneous fat and muscle tissue were examined as control ROIs., Results: There was a significant increase in T1 of the tumour ROIs across patients following the 8-10 fractions of chemoradiotherapy (paired t -test, p < 0.001, n = 7). At baseline, prior to receiving chemoradiotherapy, there were no significant changes in T1 across patients from breathing oxygen (n = 9). In the post-chemoRT scans (8-10 fractions), there was a significant decrease in T1 of the tumour ROIs across patients when breathing 100% oxygen (paired t -test, p < 0.001, n = 8). Out of the 12 patients from which we successfully acquired a visit 1 T1-map, only 1 patient did not respond to treatment, therefore, we cannot correlate these results with clinical outcome., Conclusions: These clinical data demonstrate feasibility and potential for T1-mapping and oxygen enhanced T1-mapping to indicate perfusion or treatment response in tumours of this nature. These data show promise for future work with a larger cohort containing more non-responders, which would allow us to relate these measurements to clinical outcome., 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 Author(s).)

Background: Concurrent chemoradiotherapy is the standard treatment for anal cancer. Following national UK implementation of intensity-modulated radiotherapy (IMRT), this prospective, national cohort evaluates the one-year oncological outcomes and patient-reported toxicity outcomes (PRO) after treatment., Materials and Methods: A national cohort of UK cancer centers implementing IMRT was carried out between February to July 2015. Cancer centers provided data on oncological outcomes, including survival, and disease and colostomy status at one-year. EORTC-QLQ core (C30) and colorectal (CR29) questionnaires were completed at baseline and one-year followup. The PRO scores at baseline and one year were compared., Results: 40 UK Cancer Centers returned data with a total of 187 patients included in the analysis. 92% received mitomycin with 5-fluorouracil or capecitabine. One-year overall survival was 94%; 84% were disease-free and 86% colostomy-free at one-year followup. At one year, PRO results found significant improvements in buttock pain, blood and mucus in stools, pain, constipation, appetite loss, and health anxiety compared to baseline. No significant deteriorations were reported in diarrhea, bowel frequency, and flatulence. Urinary symptom scores were low at one year. Moderate impotence symptoms at baseline remained at one year, and a moderate deterioration in dyspareunia reported., Conclusions: With national anal cancer IMRT implementation, at this early pre-defined time point, one-year oncological outcomes were reassuring and resulted in good disease-related symptom control. one-year symptomatic complications following CRT for anal cancer using IMRT techniques appear to be relatively mild. These PRO results provide a basis to benchmark future studies., Competing Interests: Declaration of competing interest None declared., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Delivery of SBRT to central thoracic tumours within 2 cm of the proximal bronchial tree (PBT), and especially ultra-central tumours which directly abut the PBT, has been controversial due to concerns about high risk of toxicity and treatment-related death when delivering high doses close to critical mediastinal structures. We present dosimetric and clinical outcomes from a group of oligometastatic patients treated with a risk-adapted SBRT approach., Methods: Between September 2015 and October 2018, 27 patients with 28 central thoracic oligometastases (6 moderately central, 22 ultra-central) were treated with 60 Gy in 8 fractions under online CBCT guidance. PTV dose was compromised where necessary to meet mandatory OAR constraints. Patients were followed up for toxicity and disease status., Results: Mandatory OAR constraints were met in all cases; this required PTV coverage compromise in 23 cases, with V100% reduced to <70% in 11 cases. No acute or late toxicities of Grade ≥ 3 were reported. One and 2 year in-field control rates were 95.2% and 85.7% respectively, progression-free survival rates were 42.8% and 23.4% respectively, and overall survival rates were 82.7% and 69.5% respectively. No significant differences were seen in control or survival rates by extent of PTV underdosage or between moderately and ultra-central cases., Conclusion: It appears that compromising PTV coverage to meet OAR constraints allows safe and effective delivery of SBRT to moderately and ultra-central tumours, with low toxicity rates and high in-field control rates. This treatment can be delivered on standard linear accelerators with widely available imaging technology., 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.)

Purpose: To analyse changes in 2-year overall survival (OS 2yr ) with radiotherapy (RT) dose, dose-per-fraction, treatment duration and chemotherapy use, in data compiled from prospective trials of RT and chemo-RT (CRT) for locally-advanced non-small cell lung cancer (LA-NSCLC)., Material and Methods: OS 2yr data was analysed for 6957 patients treated on 68 trial arms (21 RT-only, 27 sequential CRT, 20 concurrent CRT) delivering doses-per-fraction ≤4.0 Gy. An initial model considering dose, dose-per-fraction and RT duration was fitted using maximum-likelihood techniques. Model extensions describing chemotherapy effects and survival-limiting toxicity at high doses were assessed using likelihood-ratio testing, the Akaike Information Criterion (AIC) and cross-validation., Results: A model including chemotherapy effects and survival-limiting toxicity described the data significantly better than simpler models (p < 10 -14 ), and had better AIC and cross-validation scores. The fitted α/β ratio for LA-NSCLC was 4.0 Gy (95%CI: 2.8-6.0 Gy), repopulation negated 0.38 (95%CI: 0.31-0.47) Gy EQD2/day beyond day 12 of RT, and concurrent CRT increased the effective tumour EQD2 by 23% (95%CI: 16-31%). For schedules delivered in 2 Gy fractions over 40 days, maximum modelled OS 2yr for RT was 52% and 38% for stages IIIA and IIIB NSCLC respectively, rising to 59% and 42% for CRT. These survival rates required 80 and 87 Gy (RT or sequential CRT) and 67 and 73 Gy (concurrent CRT). Modelled OS 2yr rates fell at higher doses., Conclusions: Fitted dose-response curves indicate that gains of ~10% in OS 2yr can be made by escalating RT and sequential CRT beyond 64 Gy, with smaller gains for concurrent CRT. Schedule acceleration achieved via hypofractionation potentially offers an additional 5-10% improvement in OS 2yr . Further 10-20% OS 2yr gains might be made, according to the model fit, if critical normal structures in which survival-limiting toxicities arise can be identified and selectively spared., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: To determine the impact of abdominal compression (AC) on setup error and image matching time., Materials and Methods: This study included 72 liver, pancreas and abdominal node patients treated radically from 2016 to 2019 in a single centre. Patients received either SBRT or conventional radical fractionation (CRF). Compressed patients were supine, arms up with kneefix and AC equipment. Uncompressed patients were supine, arms up with kneefix. All patients received daily online-matched CBCTs before treatment. Initial setup error was determined for all patients. Registration error was assessed for 10 liver and 10 pancreas patients. Image matching times were determined using beam on times. Statistical tests conducted were an F-test to compare variances in setup error, Student's t-tests for setup error and average image analysis, and a Wilcoxon Mann Whitney test for imaging matching time analysis., Results: Initial setup displacement was similar between compressed and uncompressed patients. Displacements > 1 cm occurred more frequently in the longitudinal direction for most patients. SBRT patients required more additional manual positioning following imaging. Mean absolute registration error in the SI direction was 5.4 mm and 3.3 mm for uncompressed and compressed pancreas patients respectively and 1.7 mm and 0.8 mm for uncompressed and compressed liver patients respectively. Compressed patients required less time for image matching and fewer images per fraction on average. Repeat imaging occurred more frequently in SBRT and uncompressed patients., Conclusions: Although abdominal compression has no significant impact on setup error, it can reduce imaging matching times resulting in improved treatment accuracy., Competing Interests: The authors declared that there is no conflict of interest., (© 2019 The Authors.)

Purpose: To identify frequency, clinical relevance and risk factors for vertebral compression fracture (VCF) after spine stereotactic body radiation therapy (SBRT) with long-term follow up (FU)., Methods: From 2012 to 2015, 61 lesions (56 patients) were treated within a prospective multicenter phase 2 study (NCT01594892) of SBRT for painful vertebral metastases. Post-SBRT VCF were identified. Anatomical segments, normal and tumor tissue of treated vertebrae were segmented for volumetric analyses. Predictive factors for VCF were identified by logistic regression., Results: Median clinical and radiological FU for all patients was 16.2 months (range, 0-68.2) and 7.8 months (range, 0-66.9), respectively. Local metastasis control was observed in 82% of lesions at last imaging FU. Post-SBRT VCF occurred in 21 lesions (34.4%): 16.4% showed a progressive VCF, while a new VCF occurred in 18.0%. 3/56 (5.4%) patients developed painful VCF defined as pain increase by ≥2 on the visual analogue scale (VAS) and 2 (3.6%) patients required surgical stabilization. Pre-SBRT VCF, localization in the thoracic spine, Bilsky score >0, SINS score, pre-SBRT osteolytic volume and metastatic vertebral body (VB) involvement were predictive factors for VCF on univariate analysis. Relative VB involvement, osteolytic volume and pre-SBRT VCF remained in the multivariate logistic regression model that had AUC = 0.930, 83.3% sensitivity and 96.6% specificity., Conclusion: Spine SBRT resulted in favorable long-term pain and local metastasis control. Despite post-SBRT VCF being observed after one third of treatments, this was symptomatic in only 5% of patients. Predictive factors for developing VCF were identified which could contribute to better selection of patients for spine SBRT., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background and Purpose: With high treatment costs and limited capacity, decisions on which adult patients to treat with proton beam therapy (PBT) must be based on the relative value compared to the current standard of care. Cost-utility analyses (CUAs) are the gold-standard method for doing this. We aimed to appraise the methodology and quality of CUAs in this area., Materials and Methods: We performed a systematic review of the literature to identify CUA studies of PBT in adult disease using MEDLINE, EMBASE, EconLIT, NHS Economic Evaluation Database (NHS EED), Web of Science, and the Tufts Medical Center Cost-Effectiveness Analysis Registry from 1st January 2010 up to 6th June 2018. General characteristics, information relating to modelling approaches, and methodological quality were extracted and synthesized narratively., Results: Seven PBT CUA studies in adult disease were identified. Without randomised controlled trials to inform the comparative effectiveness of PBT, studies used either results from one-armed studies, or dose-response models derived from radiobiological and epidemiological studies of PBT. Costing methods varied widely. The assessment of model quality highlighted a lack of transparency in the identification of model parameters, and absence of external validation of model outcomes. Furthermore, appropriate assessment of uncertainty was often deficient., Conclusion: In order to foster credibility, future CUA studies must be more systematic in their approach to evidence synthesis and expansive in their consideration of uncertainties in light of the lack of clinical evidence., 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, (Crown Copyright © 2019 Published by Elsevier B.V. on behalf of European Society for Radiotherapy and Oncology.)

Introduction: The limited radiation tolerance of the small-bowel causes toxicity for patients receiving conventionally-fractionated radiotherapy for rectal cancer. Safe radiotherapy dose-escalation will require a better understanding of such toxicity. We conducted a systematic review and meta-analysis using published datasets of small bowel dose-volume and outcomes to analyse the relationship with acute toxicity., Materials and Methods: SCOPUS, EMBASE & MEDLINE were searched to identify twelve publications reporting small-bowel dose-volumes and toxicity data or analysis. Where suitable data were available (mean absolute volume with parametric error measures), fixed-effects inverse-variance meta-analysis was used to compare cohorts of patients according to Grade ≥3 toxicity. For other data, non-parametric examinations of irradiated small-bowel dose-volume and incidence of toxicity were conducted, and a univariate logistic regression model was fitted., Results: On fixed-effects meta-analysis of three studies (203 patients), each of the dose-volume measures V 5Gy -V 40Gy were significantly greater (p < 0.00001) for patients with Grade ≥3 toxicity than for those without. Absolute difference was largest for the lowest dose-volume parameter; however relative difference increases with increasing dose. On logistic regression multiple small-bowel DVH parameters were predictive of toxicity risk (V 5Gy , V 10Gy , V 30Gy - V 45Gy ), with V 10Gy the strongest (p = 0.004)., Conclusions: Analysis of published clinical cohort dose-volume data provides evidence for a significant dose-volume-toxicity response effect for a wide range of clinically-relevant doses in the treatment of rectal cancer. Both low dose and high dose are shown to predict toxicity risk, which has important implications for radiotherapy planning and consideration of dose escalation for these patients., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aims: To investigate the potential role for a biological boost in anal cancer by assessing whether subvolumes of high 18F-fluorodeoxyglucose (FDG) avidity, identified at outset, are spatially consistent during a course of chemoradiotherapy (CRT)., Materials and Methods: FDG-positron emission tomography (FDG-PET) scans from 21 patients enrolled into the ART study (NCT02145416) were retrospectively analysed. In total, 29 volumes including both primary tumours and involved nodes >2 cm were identified. FDG-PET scans were carried out before treatment and on day 8 or 9 of CRT. FDG subvolumes were created using a percentage of maximum FDG avidity at thresholds of 34%, 40%, 50%, on the pre-treatment scans, and 70% and 80% on the subsequent scans. Both FDG-PET scans were deformably registered to the planning computed tomography scan. The overlap fraction and the vector distance were calculated to assess spatial consistency. FDG subvolumes for further investigation had an overlap fraction >0.7, as this has been defined in previous publications as a 'good' correlation., Results: The median overlap fractions between the diagnostic FDG-PET subvolumes 34%, 40% and 50% of maximum standardised uptake value (SUV max ) and subsequent FDG-PET subvolumes of 70% of SUV max were 0.97, 0.92 and 0.81. The median overlap fraction between the diagnostic FDG-PET subvolumes 34%, 40% and 50% and subsequent FDG-PET subvolumes of 80% were 1.00, 1.00 and 0.92. The median (range) vector distance values between diagnostic FDG-PET subvolumes 34%, 40% and 50% and subsequent FDG-PET subvolumes of 80% were 0.74 mm (0.19-2.94) 0.74 mm (0.19-3.39) and 0.71 mm (0.2-3.29), respectively. Twenty of 29 volumes (69.0%) achieved a threshold > 0.7 between the FDG 50% subvolume on the diagnostic scan and the FDG 80% subvolume on the subsequent scan., Conclusion: FDG-avid subvolumes identified at baseline were spatially consistent during a course of CRT treatment. The subvolume of 50% of SUV max on the pre-treatment scan could be considered as a potential target for dose escalation., (Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.)

Aims: Gastrointestinal toxicity impedes dose escalation in chemoradiotherapy for hepatobiliary malignancies. Toxicity risk depends on clinical and radiotherapy metrics. We aimed to identify predictive factors using data from two prospective phase II clinical trials of locally advanced pancreatic cancer (LAPC)., Materials and Methods: Ninety-one patients with available data from the ARCII (59.4 Gy in 33 fractions with gemcitabine, cisplatin and nelfinavir, n = 23) and SCALOP (50.4 Gy in 28 fractions with capecitabine or gemcitabine, n = 74) trials were studied. The independent variables analysed comprised age, sex, performance status, baseline symptoms, tumour size, weight loss, chemotherapy regimen and dose-volume histogram of stomach and duodenum in 5 Gy bins. The outcome measures used were Common Terminology Criteria of Adverse Events (CTCAE) grade and risk of CTCAE grade ≥2 acute upper gastrointestinal toxicity (anorexia, pain, nausea and/or vomiting). The risk of CTCAE grade ≥2 events was modelled using multivariable logistic regression and prediction of severity grade using ordinal regression., Results: CTCAE grade ≥2 symptoms occurred in 38 patients (42%). On univariate analysis, stomach V 35-45Gy was predictive of risk (odds ratio 1.035, 95% confidence interval 1.007-1.063) and grade (1.023, 1.003-1.044) of toxicity . The area under the curve was 0.632 (0.516-0.747) with toxicity risk 33/66 (50%) above and 5/25 (20%) below the optimal discriminatory threshold (7.1 cm 3 ). Using a threshold of 30 cm 3 , risk was 13/20 (65%) versus 25/71 (35%). The optimal multivariable logistic regression model incorporated patient sex, chemotherapy regimen and stomach V 35-45Gy . Receiving gemcitabine rather than capecitabine (odds ratio 3.965, 95% confidence interval 1.274-12.342) and weight loss during induction chemotherapy (1.216, 1.043-1.419) were significant predictors for the SCALOP cohort, whereas age predicted toxicity risk in ARCII only (1.344, 1.015-1.780). Duodenum dose-volume did not predict toxicity risk or severity in any cohort., Conclusions: In chemoradiotherapy for LAPC the volume of stomach irradiated to a moderately high dose (35-45 Gy) predicts the incidence and severity of acute toxicity. Other predictive factors can include age, sex, recent weight loss and concomitant chemotherapy agents., (Copyright © 2018 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Recent technological innovations have increased the amount of tobacco products available to smokers. In particular, electronic cigarettes, sometimes call e-cigarettes, have received substantial attention as their sales have rapidly increased. Electronic cigarettes were invented in China and now have become prevalent worldwide. Electronic cigarettes can be considered fashionable and come in numerous flavors; accordingly, many young adults and students have begun to use e-cigarettes. However, like traditional tobacco products, e-cigarettes have negative influences on human health. After e-cigarettes were introduced into Taiwan, they have not been effectively managed and regulated because of insufficient supporting measures. Related legislation in developed countries can serve as a reference for Taiwan. For this study, the development of e-cigarettes is described and a theoretical analysis was performed from the administration and legal perspectives. In addition to clarifying related problems and offering measures to prevent students from using e-cigarettes, we propose suggestions to help governments improve their strategies to protect students' health., (Copyright © 2017 John Wiley & Sons, Ltd.)

Six UK studies investigating stereotactic ablative radiotherapy (SABR) are currently open. Many of these involve the treatment of oligometastatic disease at different locations in the body. Members of all the trial management groups collaborated to generate a consensus document on appropriate organ at risk dose constraints. Values from existing but older reviews were updated using data from current studies. It is hoped that this unified approach will facilitate standardised implementation of SABR across the UK and will allow meaningful toxicity comparisons between SABR studies and internationally., (Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Purpose: Radiation therapy dose escalation using a simultaneous integrated boost (SIB) is predicted to improve local tumor control in esophageal cancer; however, any increase in acute hematologic toxicity (HT) could limit the predicted improvement in patient outcomes. Proton therapy has been shown to significantly reduce HT in lung cancer patients receiving concurrent chemotherapy. Therefore, we investigated the potential of bone marrow sparing with protons for esophageal tumors., Methods and Materials: Twenty-one patients with mid-esophageal cancer who had undergone conformal radiation therapy (3D50) were selected. Two surrogates for bone marrow were created by outlining the thoracic bones (bone) and only the body of the thoracic vertebrae (TV) in Eclipse. The percentage of overlap of the TV with the planning treatment volume was recorded for each patient. Additional plans were created retrospectively, including a volumetric modulated arc therapy (VMAT) plan with the same dose as for 3D50; a VMAT SIB plan with a dose prescription of 62.5 Gy to the high-risk subregion within the planning treatment volume; a reoptimized TV-sparing VMAT plan; and a proton therapy plan with the same SIB dose prescription. The bone and TV dose metrics were recorded and compared across all plans and variations with respect to PTV and percentage of overlap for each patient., Results: The 3D50 plans showed the highest bone mean dose and TV percentage of volume receiving ≥30 Gy (V 30Gy ) for each patient. The VMAT plans irradiated a larger bone V 10Gy than did the 3D50 plans. The reoptimized VMAT62.5 VT plans showed improved sparing of the TV volume, but only the proton plans showed significant sparing for bone V 10Gy and bone mean dose, especially for patients with a larger PTV., Conclusions: The results of the present study have shown that proton therapy can reduced bone marrow toxicity., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: To perform a systematic review regarding the use of stereotactic ablative radiotherapy (SABR) for the re-irradiation of recurrent malignant disease within the pelvis, to guide the clinical implementation of this technique., Material and Methods: A systematic search strategy was adopted using the MEDLINE, EMBASE and Cochrane Library databases., Results: 195 articles were identified, of which 17 were appropriate for inclusion. Studies were small and data largely retrospective. In total, 205 patients are reported to have received pelvic SABR re-irradiation. Dose and fractionation schedules and re-irradiated volumes are highly variable. Little information is provided regarding organ at risk constraints adopted in the re-irradiation setting. Treatment appears well-tolerated overall, with nine grade 3 and six grade 4 toxicities amongst thirteen re-irradiated patients. Local control at one year ranged from 51% to 100%. Symptomatic improvements were also noted., Conclusions: For previously irradiated patients with recurrent pelvic disease, SABR re-irradiation could be a feasible intervention for those who otherwise have limited options. Evidence to support this technique is limited but shows initial promise. Based on the available literature, suggestions for a more formal SABR re-irradiation pathway are proposed. Prospective studies and a multidisciplinary approach are required to optimise future treatment., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: The heart receives high radiation doses during radiation therapy of advanced-stage lung cancer. We have explored associations between overall survival, cardiac radiation doses, and electrocardiographic (ECG) changes in patients treated in IDEAL-CRT, a trial of isotoxically escalated concurrent chemoradiation delivering tumor doses of 63 to 73 Gy., Methods and Materials: Dosimetric and survival data were analyzed for 78 patients. The whole heart, pericardium, AV node, and walls of left and right atria (LA/RA-Wall) and ventricles (LV/RV-Wall) were outlined on radiation therapy planning scans, and differential dose-volume histograms (dDVHs) were calculated. For each structure, dDVHs were approximated using the average dDVH and the 10 highest-ranked structure-specific principal components (PCs). ECGs at baseline and 6 months after radiation therapy were analyzed for 53 patients, dichotomizing patients according to presence or absence of "any ECG change" (conduction or ischemic/pericarditis-like change). All-cause death rate (DR) was analyzed from the start of treatment using Cox regression., Results: 38% of patients had ECG changes at 6 months. On univariable analysis, higher scores for LA-Wall-PC6, Heart-PC6, "any ECG change," and larger planning target volume (PTV) were significantly associated with higher DR (P=.003, .009, .029, and .037, respectively). Heart-PC6 and LA-Wall-PC6 represent larger volumes of whole heart and left atrial wall receiving 63 to 69 Gy. Cardiac doses ≥63 Gy were concentrated in the LA-Wall, and consequently Heart-PC6 was highly correlated with LA-Wall-PC6. "Any ECG change," LA-Wall-PC6 scores, and PTV size were retained in the multivariable model., Conclusions: We found associations between higher DR and conduction or ischemic/pericarditis-like changes on ECG at 6 months, and between higher DR and higher Heart-PC6 or LA-Wall-PC6 scores, which are closely related to heart or left atrial wall volumes receiving 63 to 69 Gy in this small cohort of patients., (Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.)

Oncolytic viruses and radiotherapy represent two diverse areas of cancer therapy, utilizing quite different treatment modalities and with non-overlapping cytotoxicity profiles. It is, therefore, an intriguing possibility to consider that oncolytic ("cancer-killing") viruses may act as cancer-selective radiosensitizers, enhancing the therapeutic consequences of radiation treatment on tumors while exerting minimal effects on normal tissue. There is a solid mechanistic basis for this potential synergy, with many viruses having developed strategies to inhibit cellular DNA repair pathways in order to protect themselves, during genome replication, from unwanted interference by cell processes that are normally triggered by DNA damage. Exploiting these abilities to inhibit cellular DNA repair following damage by therapeutic irradiation may well augment the anticancer potency of the approach. In this review, we focus on oncolytic adenovirus, the most widely developed and best understood oncolytic virus, and explore its various mechanisms for modulating cellular DNA repair pathways. The most obvious effects of the various adenovirus serotypes are to interfere with activity of the MRE11-Rad50-Nbs1 complex, temporally one of the first sensors of double-stranded DNA damage, and inhibition of DNA ligase IV, a central repair enzyme for healing double-stranded breaks by non-homologous end joining (NHEJ). There have been several preclinical and clinical studies of this approach and we assess the current state of progress. In addition, oncolytic viruses provide the option to promote a localized proinflammatory response, both by mediating immunogenic death of cancer cells by oncosis and also by encoding and expressing proinflammatory biologics within the tumor microenvironment. Both of these approaches provide exciting potential to augment the known immunological consequences of radiotherapy, aiming to develop systems capable of creating a systemic anticancer immune response following localized tumor treatment.

Aims: A proportion of patients with pancreatic cancer never develop metastatic disease. We evaluated a role for 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET) in identifying a subset of patients with locally advanced pancreatic cancer (LAPC) who never develop metastatic disease and only experience local disease and may therefore benefit from local treatment intensification., Material and Methods: Patients with histologically confirmed LAPC entered a single-centre phase II study of definitive upfront chemoradiotherapy (CRT). All patients underwent FDG-PET/CT before and 6 weeks after CRT. Tumour volume, standardised uptake values (SUV max , SUV peak , SUV mean , SUV median ) and total lesion glycolysis (TLG) were measured on each scan and the response in each parameter was evaluated. The presence or absence of metastatic disease was noted on contrast-enhanced CT carried out every 3 months for 1 year and then at clinician discretion., Results: Twenty-three patients with LAPC were recruited; 17/23 completed treatment and had interpretable sequential imaging. Twenty-four per cent of patients only ever experienced local disease. Median pre-CRT FDG-PET parameters were significantly lower in patients with local disease only during follow-up compared with those who developed metastatic disease: SUV max 3.8 versus 8.6 (P=0.006), SUV peak 2.5 versus 7.5 (P=0.002), SUV mean 1.8 versus 3.3 (P=0.001), SUV median 1.7 versus 3.0 (P=0.002), TLG 26.9 versus 115.9 (P=0.006). Tumour volume, post-CRT FDG-PET values and their relative change were not statistically different between local disease and metastatic disease groups. Receiver operating characteristic curves for pre-CRT FDG-PET parameters to predict those who never develop metastatic disease all had areas under the curve (AUCs) ≥ 0.932. Pre-CRT FDG-PET SUV max < 6.2 predicted patients with local disease only during follow-up with 100.0% sensitivity and 92.3% specificity, 80.0% positive predictive value and 100% negative predictive value., Conclusions: Our findings suggest that patients with less FDG-avid tumours are less likely to metastasise and may therefore benefit from upfront local treatment intensification., (Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background and Purpose: Gastro-intestinal toxicity is dose-limiting in abdominal radiotherapy and correlated with duodenum dose-volume parameters. We aimed to derive updated NTCP model parameters using published data and prospective radiotherapy quality-assured cohort data., Material and Methods: A systematic search identified publications providing duodenum dose-volume histogram (DVH) statistics for clinical studies of conventionally-fractionated radiotherapy. Values for the Lyman-Kutcher-Burman (LKB) NTCP model were derived through sum-squared-error minimisation and using leave-one-out cross-validation. Data were corrected for fraction size and weighted according to patient numbers, and the model refined using individual patient DVH data for two further cohorts from prospective clinical trials., Results: Six studies with published DVH data were utilised, and with individual patient data included outcomes for 531 patients in total (median follow-up 16months). Observed gastro-intestinal toxicity rates ranged from 0% to 14% (median 8%). LKB parameter values for unconstrained fit to published data were: n=0.070, m=0.46, TD 50(1) [Gy]=183.8, while the values for the model incorporating the individual patient data were n=0.193, m=0.51, TD 50(1) [Gy]=299.1., Conclusions: LKB parameters derived using published data are shown to be consistent to those previously obtained using individual patient data, supporting a small volume-effect and dependence on exposure to high threshold dose., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: UK guidance was recently developed for the treatment of anal cancer using intensity-modulated radiotherapy (IMRT). We audited the current use of radiotherapy in UK cancer centres for the treatment of anal cancer against such guidance. We describe the acute toxicity of IMRT in comparison with patient population in the audit treated with two-phase conformal radiotherapy and the previous published data from two-phase conformal radiotherapy, in the UK ACT2 trial., Materials and Methods: A Royal College of Radiologists' prospective national audit of patients treated with radiotherapy in UK cancer centres was carried out over a 6 month period between February and July 2015., Results: Two hundred and forty-two cases were received from 40/56 cancer centres (71%). In total, 231 (95%) underwent full dose radiotherapy with prophylactic nodal irradiation. Of these, 180 (78%) received IMRT or equivalent, 52 (22%) two-phase conformal (ACT2) technique. The number of interruptions in radiotherapy treatment in the ACT2 trial was 15%. Interruptions were noted in 7% (95% confidence interval 0-14%) of courses receiving two-phase conformal and 4% (95% confidence interval 1-7%) of those receiving IMRT. The percentage of patients completing the planned radiotherapy dose, irrelevant of gaps, was 90% (95% confidence interval 82-98%) and 96% (95% confidence interval 93-99%), in two-phase conformal and IMRT respectively. The toxicity reported in the ACT2 trial, in patients receiving two-phase conformal in the audit and in patients receiving IMRT in the audit was: any toxic effect 71%, 54%, 48%, non-haematological 62%, 49%, 40% and haematological 26%, 13%, 18%, respectively., Conclusions: IMRT implementation for anal cancer is well underway in the UK with most patients receiving IMRT delivery, although its usage is not yet universal. This audit confirms that IMRT results in reduced acute toxicity and minimised treatment interruptions in comparison with previous two-phase conformal techniques., (Copyright © 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Obesity is a prevalent health care issue associated with disability, premature morality, and high costs. Behavioral weight management interventions lead to clinically significant weight losses in overweight and obese individuals; however, many individuals are not able to participate in these face-to-face treatments due to limited access, cost, and/or time constraints. Technological advances such as widespread access to the Internet, increased use of smartphones, and newer behavioral self-monitoring tools have resulted in the development of a variety of eHealth weight management programs. In the present paper, a summary of the most current literature is provided along with potential solutions to methodological challenges (e.g., high attrition, minimal participant racial/ethnic diversity, heterogeneity of technology delivery modes). Dissemination and policy implications will be highlighted as future directions for the field of eHealth weight management.

Background: Subclinical cognitive impairment is prevalent in heart failure (HF); however, its role in important clinical outcomes, such as HF treatment adherence, is unclear. Given the complex polypharmacy in HF treatment, cognitive deficits may be important in predicting medication management. Thus, the objective of the current study was to examine the impact of cognitive function on medication adherence among community-dwelling patients with HF using objective assessments., Methods and Results: A prospective observational cohort design of 309 community-dwelling patients with HF (59.7% male, 68.7±9.7 years) and no history of dementia or neurological disease. Cognition was assessed using a neuropsychological battery at baseline. Medication adherence was objectively measured for 21 days using an electronic pillbox. Regression analyses tested whether attention, executive function, or memory predicted 21-day medication adherence. In unadjusted analyses, lower scores on all 3 cognitive domains predicted poorer medication adherence (β=0.52-85; P=0.001-0.009). After adjusting for demographic, clinical, and psychosocial variables, memory continued to predict medication adherence (β=0.51; P=0.008), whereas executive function (β=0.24; P=0.075) and attention were no longer a predictor (β=0.34; P=0.131)., Conclusions: Poorer cognitive function, especially in regard to memory, predicted reduced medication adherence among patients with HF and no history of dementia. This effect remained after adjustment for factors known to predict adherence, such as depressed mood, social support, and disease severity level. Future studies should examine the link from cognitive impairment and medication nonadherence to clinical outcomes (eg, hospitalization and mortality)., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01461629., (© 2016 American Heart Association, Inc.)

Background and Purpose: Esophageal cancer has a persistently low 5-year survival rate and has recently been classified as a cancer of unmet need by Cancer Research UK. Consequently, new approaches to therapy are urgently required. Here, we tested the hypothesis that an ATR inhibitor, VX-970, used in combination with standard therapies for esophageal cancer could improve treatment outcome., Material and Methods: Using esophageal cancer cell lines we evaluated the efficacy of combining VX-970 with cisplatin and carboplatin in vitro and with radiation in vitro and in vivo. Radiation experiments were also carried out in hypoxic conditions to mimic the tumor microenvironment., Results: Combining VX-970 with cisplatin, carboplatin and radiation increased tumor cell kill in vitro. A significant tumor growth delay was observed when VX-970 was combined with radiotherapy in vivo., Conclusions: VX-970 is an effective chemo/radiosensitizer which could be readily integrated in the current treatment paradigm to improve the treatment response in esophageal cancer and we plan to test it prospectively in the forthcoming phase I dose escalation safety study combining the ATR inhibitor VX-970 with chemoradiotherapy in esophageal cancer (EudraCT number: 2015-003965-27)., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)

Purpose: Toxicity dose-response models describe the correlation between dose delivered to an organ and a given toxic endpoint. Duodenal toxicity is a dose limiting factor in the treatment of pancreatic cancer with radiation but the relationship between dose and toxicity in the duodenum is not well understood. While there have been limited studies into duodenal toxicity through investigations of the volume of the organ receiving dose over a specific threshold, both dose-volume and dose-surface histograms lack spatial information about the dose distribution, which may be important in determining normal tissue response. Due to the complex geometry of the duodenum, previous methods for unwrapping tubular organs for spatial modeling of toxicity are insufficient. A geometrically robust method for producing 2D dose surface maps (DSMs), specifically for the duodenum, has been developed and tested in order to characterize the spatial dose distribution., Methods: The organ contour is defined using Delaunay triangulation. The user selects a start and end coordinate in the structure and a path is found by regulating both length and curvature. This path is discretized and rays are cast from each point on the plane normal to the vector between the previous and the next point on the path and the dose at the closest perimeter point recorded. These angular perimeter slices are "unwrapped" from the edge distal to the pancreas to ensure the high dose region (proximal to the tumor) falls in the centre of the dose map. Gamma analysis is used to quantify the robustness of this method and the effect of overlapping planes., Results: This method was used to extract DSMs for 15 duodena, with one esophagus case to illustrate the application to simpler geometries. Visual comparison indicates that a 30 × 30 map provides sufficient resolution to view gross spatial features of interest. A lookup table is created to store the area (cm 2 ) represented by each pixel in the DSMs in order to allow spatial descriptors in absolute size. The method described in this paper is robust, requires minimal human interaction, has been shown to be generalizable to simpler geometries, and uses readily available commercial software. The difference seen in DSMs due to overlapping planes is large and justifies the need for a solution that removes such planes., Conclusions: This is the first time 2D dose surface maps have been produced for the duodenum and provide spatial dose distribution information which can be explored to create models that may improve toxicity prediction in treatments for locally advanced pancreatic cancer.