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Background and Objective: Delivering radiotherapy to the bladder is challenging as it is a mobile, deformable structure. Dose-escalated adaptive image-guided radiotherapy could improve outcomes. RAIDER aimed to demonstrate the safety of such a schedule., Methods: RAIDER is an international phase 2 noncomparative randomised controlled trial (ISRCTN26779187). Patients with unifocal T2-T4a urothelial bladder cancer were randomised (1:1:2) to standard whole bladder radiotherapy (WBRT), standard-dose adaptive radiotherapy (SART), or dose-escalated adaptive radiotherapy (DART). Two fractionation (f) schedules recruited independently. WBRT and SART dose was 55 Gy/20f or 64 Gy/32f, and DART dose was 60 Gy/20f or 70 Gy/32f. For SART and DART, a radiotherapy plan (small, medium, or large) was chosen daily. The primary endpoint was the proportion of patients with radiotherapy-related late Common Terminology Criteria for Adverse Events grade ≥3 toxicity; the trial was designed to rule out >20% toxicity with DART., Key Findings and Limitations: A total of 345 patients were randomised between October 2015 and April 2020: 41/46 WBRT, 41/46 SART, and 81/90 DART patients in the 20f/32f cohorts, respectively. The median age was 72/73 yr; 78%/85% had T2 tumours, 46%/52% had neoadjuvant chemotherapy, and 70%/71% had radiosensitising therapy. The median follow-up was 42.1/38.2 mo. Sixty-six of 77 (86%) 20f and 74 of 82 (90%) 32f participants planned for DART met the mandatory medium plan dose constraints. Radiotherapy-related grade ≥3 toxicity was reported in one of 58 patients (90% confidence interval [CI] 0.1, 7.9) with 20f DART and zero of 56 patients with 32f DART. Two-year overall survival was 77% (95% CI 69, 82) for WBRT + SART and 80% (95% CI 73, 85) for DART (hazard ratio = 0.84, 95% CI 0.59, 1.21, p = 0.4). Thirteen of 345 (3.8%) participants had salvage cystectomy., Conclusions and Clinical Implications: Grade ≥3 late toxicity was low. DART was safe and feasible to deliver, meeting preset toxicity thresholds. Disease-related outcomes are promising for dose-escalated treatments, with a low salvage cystectomy rate and overall survival similar to that seen in cystectomy cohorts., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: The adoption of hypo-fractionated stereotactic body radiotherapy (SBRT) for treating prostate cancer has led to an increase in specialised techniques for monitoring prostate motion. The aim of this study was to comprehensively review a radiation therapist (RTT) led treatment process in which two such systems were utilised, and present initial findings on their use within a SBRT prostate clinical trial., Materials and Methods: 18 patients were investigated, nine were fitted with the Micropos RayPilot TM (RP) system (Micropos Medical, Gothenburg, SE) and nine were fitted with the Micropos Raypilot Hypocath TM (HC) system. 36.25 Gray (Gy) was delivered in 5 fractions over 7 days with daily pre- and post-treatment cone beam computed tomography (CBCT) images acquired. Acute toxicity was reported on completion of treatment at six- and 12-weeks post-treatment, using the Radiation Therapy Oncology Group (RTOG) grading system and vertical (Vrt), longitudinal (Lng) and lateral (Lat) transmitter displacements recorded., Results: A significant difference was found in the Lat displacement between devices (P=0.003). A more consistent bladder volume was reported in the HC group (68.03 cc to 483.7 cc RP, 196.11 cc to 313.85 cc HC). No significant difference was observed in mean dose to the bladder, rectum and bladder dose maximum between the groups. Comparison of the rectal dose maximum between the groups reported a significant result (P=0.09). Comparing displacements with toxicity endpoints identified two significant correlations: Grade 2 Genitourinary (GU) at 6 weeks, P=0.029; and no toxicity, Gastrointestinal (GI) at 12 weeks P=0.013., Conclusion: Both the directly implanted RP device and the urinary catheter-based HC device are capable of real time motion monitoring. Here, the HC system was advantageous in the SBRT prostate workflow., 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., (© 2024 The Authors. Published by Elsevier B.V. on behalf of European Society for Radiotherapy & Oncology.)

Precision radiotherapy refers to the ability to deliver radiation doses with sub-millimetre accuracy. It does not however consider individual variation in tumour or normal tissue response, failing to maximise tumour control and minimise toxicity. Combining precise delivery with personalised dosing, through analysis of cell-free DNA, would redefine precision in radiotherapy., (© 2023. The Author(s).)

Aims: Adding concurrent (chemo)therapy to radiotherapy improves outcomes for muscle-invasive bladder cancer patients. A recent meta-analysis showed superior invasive locoregional disease control for a hypofractionated 55 Gy in 20 fractions schedule compared with 64 Gy in 32 fractions. In the RAIDER clinical trial, patients undergoing 20 or 32 fractions of radical radiotherapy were randomised (1:1:2) to standard radiotherapy or to standard-dose or escalated-dose adaptive radiotherapy. Neoadjuvant chemotherapy and concomitant therapy were permitted. We report exploratory analyses of acute toxicity by concomitant therapy-fractionation schedule combination., Materials and Methods: Participants had unifocal bladder urothelial carcinoma staged T2-T4a N0 M0. Acute toxicity was assessed (Common Terminology Criteria for Adverse Events) weekly during radiotherapy and at 10 weeks after the start of treatment. Within each fractionation cohort, non-randomised comparisons of the proportion of patients reporting treatment emergent grade 2 or worse genitourinary, gastrointestinal or other adverse events at any point in the acute period were carried out using Fisher's exact tests., Results: Between September 2015 and April 2020, 345 (163 receiving 20 fractions; 182 receiving 32 fractions) patients were recruited from 46 centres. The median age was 73 years; 49% received neoadjuvant chemotherapy; 71% received concomitant therapy, with 5-fluorouracil/mitomycin C most commonly used: 44/114 (39%) receiving 20 fractions; 94/130 (72%) receiving 32 fractions. The acute grade 2+ gastrointestinal toxicity rate was higher in those receiving concomitant therapy compared with radiotherapy alone in the 20-fraction cohort [54/111 (49%) versus 7/49 (14%), P < 0.001] but not in the 32-fraction cohort (P = 0.355). Grade 2+ gastrointestinal toxicity was highest for gemcitabine, with evidence of significant differences across therapies in the 32-fraction cohort (P = 0.006), with a similar pattern but no significant differences in the 20-fraction cohort (P = 0.099). There was no evidence of differences in grade 2+ genitourinary toxicity between concomitant therapies in either the 20- or 32-fraction cohorts., Conclusion: Grade 2+ acute adverse events are common. The toxicity profile varied by type of concomitant therapy; the gastrointestinal toxicity rate seemed to be higher in patients receiving gemcitabine., (Copyright © 2023. Published by Elsevier Ltd.)

Background and Purpose: This study aims to build machine learning models to predict radiation-induced rectal toxicities for three clinical endpoints and explore whether the inclusion of radiomic features calculated on radiotherapy planning computerised tomography (CT) scans combined with dosimetric features can enhance the prediction performance., Materials and Methods: 183 patients recruited to the VoxTox study (UK-CRN-ID-13716) were included. Toxicity scores were prospectively collected after 2 years with grade ≥ 1 proctitis, haemorrhage (CTCAEv4.03); and gastrointestinal (GI) toxicity (RTOG) recorded as the endpoints of interest. The rectal wall on each slice was divided into 4 regions according to the centroid, and all slices were divided into 4 sections to calculate region-level radiomic and dosimetric features. The patients were split into a training set (75%, N = 137) and a test set (25%, N = 46). Highly correlated features were removed using four feature selection methods. Individual radiomic or dosimetric or combined (radiomic + dosimetric) features were subsequently classified using three machine learning classifiers to explore their association with these radiation-induced rectal toxicities., Results: The test set area under the curve (AUC) values were 0.549, 0.741 and 0.669 for proctitis, haemorrhage and GI toxicity prediction using radiomic combined with dosimetric features. The AUC value reached 0.747 for the ensembled radiomic-dosimetric model for haemorrhage., Conclusions: Our preliminary results show that region-level pre-treatment planning CT radiomic features have the potential to predict radiation-induced rectal toxicities for prostate cancer. Moreover, when combined with region-level dosimetric features and using ensemble learning, the model prediction performance slightly improved., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The irradiation of sub-regions of the parotid has been linked to xerostomia development in patients with head and neck cancer (HNC). In this study, we compared the xerostomia classification performance of radiomics features calculated on clinically relevant and de novo sub-regions of the parotid glands of HNC patients., Material and Methods: All patients ( N  = 117) were treated with TomoTherapy in 30-35 fractions of 2-2.167 Gy per fraction with daily mega-voltage-CT (MVCT) acquisition for image-guidance purposes. Radiomics features ( N  = 123) were extracted from daily MVCTs for the whole parotid gland and nine sub-regions. The changes in feature values after each complete week of treatment were considered as predictors of xerostomia (CTCAEv4.03, grade ≥ 2) at 6 and 12 months. Combinations of predictors were generated following the removal of statistically redundant information and stepwise selection. The classification performance of the logistic regression models was evaluated on train and test sets of patients using the Area Under the Curve (AUC) associated with the different sub-regions at each week of treatment and benchmarked with the performance of models solely using dose and toxicity at baseline., Results: In this study, radiomics-based models predicted xerostomia better than standard clinical predictors. Models combining dose to the parotid and xerostomia scores at baseline yielded an AUC test of 0.63 and 0.61 for xerostomia prediction at 6 and 12 months after radiotherapy while models based on radiomics features extracted from the whole parotid yielded a maximum AUC test of 0.67 and 0.75, respectively. Overall, across sub-regions, maximum AUC test was 0.76 and 0.80 for xerostomia prediction at 6 and 12 months. Within the first two weeks of treatment, the cranial part of the parotid systematically yielded the highest AUC test ., Conclusion: Our results indicate that variations of radiomics features calculated on sub-regions of the parotid glands can lead to earlier and improved prediction of xerostomia in HNC patients.

Background and Purpose: While core to the scientific approach, reproducibility of experimental results is challenging in radiomics studies. A recent publication identified radiomics features that are predictive of late irradiation-induced toxicity in head and neck cancer (HNC) patients. In this study, we assessed the generalisability of these findings., Materials and Methods: The procedure described in the publication in question was applied to a cohort of 109 HNC patients treated with 50-70 Gy in 20-35 fractions using helical radiotherapy although there were inherent differences between the two patient populations and methodologies. On each slice of the planning CT with delineated parotid and submandibular glands, the imaging features that were previously identified as predictive of moderate-to-severe xerostomia and sticky saliva 12 months post radiotherapy (Xer12m and SS12m) were calculated. Specifically, Short Run Emphasis (SRE) and maximum CT intensity (maxHU) were evaluated for improvement in prediction of Xer12m and SS12m respectively, compared to models solely using baseline toxicity and mean dose to the salivary glands., Results: None of the associations previously identified as statistically significant and involving radiomics features in univariate or multivariate models could be reproduced on our cohort., Conclusion: The discrepancies observed between the results of the two studies delineate limits to the generalisability of the previously reported findings. This may be explained by the differences in the approaches, in particular the imaging characteristics and subsequent methodological implementation. This highlights the importance of external validation, high quality reporting guidelines and standardisation protocols to ensure generalisability, replication and ultimately clinical implementation., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: NB, LJC, RJ, AB, WHN, DJN, GB, LEAS, TB, DM, TM report grants from Chief Scientist Office (CSO) Scotland grant (TCS/17/26 - CSO Award), during the conduct of the study. The authors alone are responsible for the content and writing of the paper. LJC reports personal fees from BrainLAB - Novalis Certified, outside the submitted work; RJ reports personal fees from Microsoft, outside the submitted work; DJN reports grants from Cancer Research UK Clinical Research Fellowship (Ref: C20/A20917), grants from Cancer Research UK Programme Grant (Ref: C8857/A13405), during the conduct of the study; LEAS reports grants from University of Cambridge WD Armstrong Trust, outside the submitted work. AD, CP, and ST have nothing to disclose., (© 2022 The Authors.)

Background and Purpose: The images acquired during radiotherapy for image-guidance purposes could be used to monitor patient-specific response to irradiation and improve treatment personalisation. We investigated whether the kinetics of radiomics features from daily mega-voltage CT image-guidance scans (MVCT) improve prediction of moderate-to-severe xerostomia compared to dose/volume parameters in radiotherapy of head-and-neck cancer (HNC)., Materials and Methods: All included HNC patients (N = 117) received 30 or more fractions of radiotherapy with daily MVCTs. Radiomics features were calculated on the contra-lateral parotid glands of daily MVCTs. Their variations over time after each complete week of treatment were used to predict moderate-to-severe xerostomia (CTCAEv4.03 grade ≥ 2) at 6, 12 and 24 months post-radiotherapy. After dimensionality reduction, backward/forward selection was used to generate combinations of predictors.Three types of logistic regression model were generated for each follow-up time: 1) a pre-treatment reference model using dose/volume parameters, 2) a combination of dose/volume and radiomics-based predictors, and 3) radiomics-based predictors. The models were internally validated by cross-validation and bootstrapping and their performance evaluated using Area Under the Curve (AUC) on separate training and testing sets., Results: Moderate-to-severe xerostomia was reported by 46 %, 33 % and 26 % of the patients at 6, 12 and 24 months respectively. The selected models using radiomics-based features extracted at or before mid-treatment outperformed the dose-based models with an AUC train /AUC test of 0.70/0.69, 0.76/0.74, 0.86/0.86 at 6, 12 and 24 months, respectively., Conclusion: Our results suggest that radiomics features calculated on MVCTs from the first half of the radiotherapy course improve prediction of moderate-to-severe xerostomia in HNC patients compared to a dose-based pre-treatment model., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: NB, LJC, RJ, AB, WHN, DJN, GB, LEAS, TB, DM, TM report grants from Chief Scientist Office (CSO) Scotland grant (TCS/17/26 - CSO Award), during the conduct of the study. The authors alone are responsible for the content and writing of the paper. LJC reports personal fees from BrainLAB - Novalis Certified, outside the submitted work; RJ reports personal fees from Microsoft, outside the submitted work; DJN reports grants from Cancer Research UK Clinical Research Fellowship (Ref: C20/A20917), grants from Cancer Research UK Programme Grant (Ref: C8857/A13405), during the conduct of the study; LEAS reports grants from University of Cambridge WD Armstrong Trust, outside the submitted work; AD, CP, and ST have nothing to disclose., (© 2022 The Authors. Published by Elsevier B.V. on behalf of European Society of Radiotherapy & Oncology.)

Background: STAMPEDE previously reported adding upfront docetaxel improved overall survival for prostate cancer patients starting long-term androgen deprivation therapy. We report long-term results for non-metastatic patients using, as primary outcome, metastatic progression-free survival (mPFS), an externally demonstrated surrogate for overall survival., Methods: Standard of care (SOC) was androgen deprivation therapy with or without radical prostate radiotherapy. A total of 460 SOC and 230 SOC plus docetaxel were randomly assigned 2:1. Standard survival methods and intention to treat were used. Treatment effect estimates were summarized from adjusted Cox regression models, switching to restricted mean survival time if non-proportional hazards. mPFS (new metastases, skeletal-related events, or prostate cancer death) had 70% power (α = 0.05) for a hazard ratio (HR) of 0.70. Secondary outcome measures included overall survival, failure-free survival (FFS), and progression-free survival (PFS: mPFS, locoregional progression)., Results: Median follow-up was 6.5 years with 142 mPFS events on SOC (3 year and 54% increases over previous report). There was no good evidence of an advantage to SOC plus docetaxel on mPFS (HR = 0.89, 95% confidence interval [CI] = 0.66 to 1.19; P = .43); with 5-year mPFS 82% (95% CI = 78% to 87%) SOC plus docetaxel vs 77% (95% CI = 73% to 81%) SOC. Secondary outcomes showed evidence SOC plus docetaxel improved FFS (HR = 0.70, 95% CI = 0.55 to 0.88; P = .002) and PFS (nonproportional P = .03, restricted mean survival time difference = 5.8 months, 95% CI = 0.5 to 11.2; P = .03) but no good evidence of overall survival benefit (125 SOC deaths; HR = 0.88, 95% CI = 0.64 to 1.21; P = .44). There was no evidence SOC plus docetaxel increased late toxicity: post 1 year, 29% SOC and 30% SOC plus docetaxel grade 3-5 toxicity., Conclusions: There is robust evidence that SOC plus docetaxel improved FFS and PFS (previously shown to increase quality-adjusted life-years), without excess late toxicity, which did not translate into benefit for longer-term outcomes. This may influence patient management in individual cases., (© The Author(s) 2022. Published by Oxford University Press.)

Volatile organic compounds (VOCs) in human breath can reveal a large spectrum of health conditions and can be used for fast, accurate and non-invasive diagnostics. Gas chromatography-mass spectrometry (GC-MS) is used to measure VOCs, but its application is limited by expert-driven data analysis that is time-consuming, subjective and may introduce errors. We propose a machine learning-based system to perform GC-MS data analysis that exploits deep learning pattern recognition ability to learn and automatically detect VOCs directly from raw data, thus bypassing expert-led processing. We evaluate this new approach on clinical samples and with four types of convolutional neural networks (CNNs): VGG16, VGG-like, densely connected and residual CNNs. The proposed machine learning methods showed to outperform the expert-led analysis by detecting a significantly higher number of VOCs in just a fraction of time while maintaining high specificity. These results suggest that the proposed novel approach can help the large-scale deployment of breath-based diagnosis by reducing time and cost, and increasing accuracy and consistency., Competing Interests: The authors have declared that no competing interests exist.

Aims: To externally validate a proposed biochemical definition of cure following low dose rate (LDR) brachytherapy for prostate cancer - 4-year post-implant prostate-specific antigen (PSA) ≤0.2 ng/ml - in a UK population, and report the long-term (10- and 15-year) outcomes for patients stratified by National Comprehensive Cancer Network (NCCN) risk groups, through analysis of a large, prospectively collected, single-centre database., Materials and Methods: All patients treated with LDR brachytherapy for prostate cancer at a single UK centre between 2001 and November 2020 (n = 1142) were eligible; 632 patients met the inclusion criteria for the analysis. The primary end point was disease-free survival (DFS), defined as freedom from clinical, radiological or PSA progression requiring androgen deprivation therapy. Four-year PSA was categorised as ≤0.2, >0.2 to ≤0.5, >0.5 to ≤1.0 and >1.0 ng/ml. Kaplan-Meier analysis to 15 years was undertaken for each group, and sensitivity and specificity of 4-year PSA as a surrogate for long-term cure were calculated. Kaplan-Meier analysis to 15 years was repeated, stratifying patients by NCCN risk groups., Results: The median cohort age was 63 years; the median follow-up was 9.1 years (range 3.5-18.7). In total, 248 patients were available for analysis at year 10, 46 at year 15. Sixty-four patients (10.1%) relapsed during the study period. The 10-year DFS for 4-year PSA categories ≤0.2, >0.2 to ≤0.5, >0.5 to ≤1.0 and >1.0 ng/ml (95% confidence intervals) were 97.5% (95.4-99.6), 89.0% (82.4-96.1), 81.5% (70.5-94.2) and 41.8% (29.7-58.9), respectively. The 10-year DFS results for NCCN low, favourable-intermediate and unfavourable-intermediate risk disease were 93.1% (89.6-96.7), 92.1% (87.6-96.9) and 75.9% (67.8-84.9), respectively., Conclusions: Patients with 4-year PSA ≤0.2 ng/ml may be considered cured, and could be discharged to general practitioner follow-up. LDR brachytherapy is an excellent treatment option for patients with low and favourable-intermediate risk prostate cancer, but those with unfavourable-intermediate risk disease should be considered for treatment intensification strategies., (Copyright © 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Rapid and relentless technological advances in an ever-more globalized world have shaped the field of radiation oncology in which we practise today. These developments have drastically modified the habitus 1 of health professionals and researchers at an individual and organisational level. In this article we present an analysis of trends in radiation oncology research over the last half a century. To do so, the data from >350,000 scientific publications pertaining to a yearly search of the PubMed database with the keywords cancer radiotherapy was analysed. This analysis revealed that, over the years, radiotherapy research output has declined relative to alternative cancer therapies, representing 64% in 1970 it decreased to 31% in 2019. Also, the pace of research has significantly accelerated with, in the last 15 years, a doubling in the number of articles published by the 10% most productive researchers. Researchers are also facing stronger competition today with a proportion of first authors that will never get to publish as a last author increasing steadily from 58% in 1970 to 84% in 2000. Additionally, radiotherapy research output is extremely unequally distributed in the world, with Africa and South America contributing to ∼3% of radiotherapy articles in 2019 while representing 23% of the world's population. This disparity, reflecting economic situations and radiotherapy capabilities, has a knock-on effect for the provision of routine clinical treatment. Since research activity is inherent to delivery of high quality clinical care, this contributes to the global inequity of radiotherapy services. Learning from these trends is crucial for the future not only of radiation oncology research but also for effective and equitable cancer care., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Daily radiotherapy delivered with radiosensitisation offers patients with muscle invasive bladder cancer (MIBC) comparable outcomes to cystectomy with functional organ preservation. Most recurrences following radiotherapy occur within the bladder. Increasing the delivered radiotherapy dose to the tumour may further improve local control. Developments in image-guided radiotherapy have allowed bladder tumour-focused 'plan of the day' radiotherapy delivery. We aim to test within a randomised multicentre phase II trial whether this technique will enable dose escalation with acceptable rates of toxicity., Methods and Analysis: Patients with T2-T4aN0M0 unifocal MIBC will be randomised (1:1:2) between standard/control whole bladder single plan radiotherapy, standard dose adaptive tumour-focused radiotherapy or dose-escalated adaptive tumour-focused radiotherapy (DART). Adaptive tumour-focused radiotherapy will use a library of three plans (small, medium and large) for treatment. A cone beam CT taken prior to each treatment will be used to visualise the anatomy and inform selection of the most appropriate plan for treatment.Two radiotherapy fractionation schedules (32f and 20f) are permitted. A minimum of 120 participants will be randomised in each fractionation cohort (to ensure 57 evaluable DART patients per cohort).A comprehensive radiotherapy quality assurance programme including pretrial and on-trial components is instituted to ensure standardisation of radiotherapy planning and delivery.The trial has a two-stage non-comparative design. The primary end point of stage I is the proportion of patients meeting predefined normal tissue constraints in the DART group. The primary end point of stage II is late Common Terminology Criteria for Adverse Events grade 3 or worse toxicity aiming to exclude a rate of >20% (80% power and 5% alpha, one sided) in each DART fractionation cohort. Secondary end points include locoregional MIBC control, progression-free survival overall survival and patient-reported outcomes., Ethics and Dissemination: This clinical trial is approved by the London-Surrey Borders Research Ethics Committee (15/LO/0539). The results when available will be disseminated via peer-reviewed scientific journals, conference presentations and submission to regulatory authorities., Trial Registration Number: NCT02447549; Pre-results., Competing Interests: Competing interests: SH reports non-financial support from Elekta (Elekta AB, Stockholm, Sweden), non-financial support from Merck Sharp & Dohme (MSD), personal fees and non-financial support from Roche outside the submitted work; AC reports grants from National Institute of Health Research Manchester Biomedical Research Centre, grants from Cancer Research, UK, grants from Medical Research Council, UK, grants from Prostate Cancer, UK, grants from Bayer, UK, personal fees from Janssen Pharmaceutical, non-financial support from ASCO, grants and non-financial support from Elekta AB, outside the submitted work; AH reports grants from CRUK, grants from MRC, grants from NIHR, outside the submitted work; TK reports reports grants from Cancer Australia, during the conduct of the study; and his group has a research collaborative agreement with Varian Medical System not related to this project; EH reports grants from Cancer Research UK during the conduct of the study; grants from Accuray Inc., grants from Varian Medical Systems Inc., outside the submitted work; RH reports non-financial support from Janssen, grants and personal fees from MSD, personal fees from Bristol Myers Squibb, grants from Cancer Research UK, other from Nektar Therapeutics, personal fees and non-financial support from Roche outside the submitted work., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Radiation dose is important in radiotherapy. Too little, and the treatment is not effective, too much causes radiation toxicity. A biochemical measurement of the effect of radiotherapy would be useful in personalisation of this treatment. This study evaluated changes in exhaled breath volatile organic compounds (VOC) associated with radiotherapy with thermal desorption gas chromatography mass-spectrometry followed by data processing and multivariate statistical analysis. Further the feasibility of adopting gas chromatography ion mobility spectrometry for radiotherapy point-of-care breath was assessed. A total of 62 participants provided 240 end-tidal 1 dm 3 breath samples before radiotherapy and at 1, 3, and 6 h post-exposure, that were analysed by thermal-desorption/gas-chromatography/quadrupole mass-spectrometry. Data were registered by retention-index and mass-spectra before multivariate statistical analyses identified candidate markers. A panel of sulfur containing compounds (thio-VOC) were observed to increase in concentration over the 6 h following irradiation. 3-methylthiophene (80 ng.m -3 to 790 ng.m -3 ) had the lowest abundance while 2-thiophenecarbaldehyde(380 ng.m -3 to 3.85 μg.m -3 ) the highest; note, exhaled 2-thiophenecarbaldehyde has not been observed previously. The putative tumour metabolite 2,4-dimethyl-1-heptene concentration reduced by an average of 73% over the same time. Statistical scoring based on the signal intensities thio-VOC and 3-methylthiophene appears to reflect individuals' responses to radiation exposure from radiotherapy. The thio-VOC are hypothesised to derive from glutathione and Maillard-based reactions and these are of interest as they are associated with radio-sensitivity. Further studies with continuous monitoring are needed to define the development of the breath biochemistry response to irradiation and to determine the optimum time to monitor breath for radiotherapy markers. Consequently, a single 0.5 cm 3 breath-sample gas chromatography-ion mobility approach was evaluated. The calibrated limit of detection for 3-methylthiophene was 10 μg.m -3 with a lower limit of the detector's response estimated to be 210 fg.s -1 ; the potential for a point-of-care radiation exposure study exists.

Background: Independent verification of the dose delivered by complex radiotherapy can be performed by electronic portal imaging device (EPID) dosimetry. This paper presents 5-yr EPID in vivo dosimetry (IVD) data obtained using the Dosimetry Check (DC) software on a large cohort including breast, lung, prostate, and head and neck (H&N) cancer patients., Material and Methods: The difference between in vivo dose measurements obtained by DC and point doses calculated by the Eclipse treatment planning system was obtained on 3795 radiotherapy patients treated with volumetric modulated arc therapy (VMAT) (n = 842) and three-dimensional conformal radiotherapy (3DCRT) (n = 2953) at 6, 10, and 15 MV. In cases where the dose difference exceeded ±10% further inspection and additional phantom measurements were performed., Results: The mean and standard deviation ( μ ± σ ) of the percentage difference in dose obtained by DC and calculated by Eclipse in VMAT was: 0.19 ± 3.89 % in brain, 1.54 ± 4.87 % in H&N, and 1.23 ± 4.61 % in prostate cancer. In 3DCRT, this was 1.79 ± 3.51 % in brain, - 2.95 ± 5.67 % in breast, - 1.43 ± 4.38 % in bladder, 1.66 ± 4.77 % in H&N, 2.60 ± 5.35% in lung and - 3.62 ± 4.00 % in prostate cancer. A total of 153 plans exceeded the ±10% alert criteria, which included: 88 breast plans accounting for 7.9% of all breast treatments; 28 H&N plans accounting for 4.4% of all H&N treatments; and 12 prostate plans accounting for 3.5% of all prostate treatments. All deviations were found to be as a result of patient-related anatomical deviations and not from procedural errors., Conclusions: This preliminary data shows that EPID-based IVD with DC may not only be useful in detecting errors but has the potential to be used to establish site-specific dose action levels. The approach is straightforward and has been implemented as a radiographer-led service with no disruption to the patient and no impact on treatment time., (© 2018 Lothian Health Board Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Background: Results from large randomised controlled trials have shown that adding docetaxel to the standard of care (SOC) for men initiating hormone therapy for prostate cancer (PC) prolongs survival for those with metastatic disease and prolongs failure-free survival for those without. To date there has been no formal assessment of whether funding docetaxel in this setting represents an appropriate use of UK National Health Service (NHS) resources., Objective: To assess whether administering docetaxel to men with PC starting long-term hormone therapy is cost-effective in a UK setting., Design, Setting, and Participants: We modelled health outcomes and costs in the UK NHS using data collected within the STAMPEDE trial, which enrolled men with high-risk, locally advanced metastatic or recurrent PC starting first-line hormone therapy., Intervention: SOC was hormone therapy for ≥2 yr and radiotherapy in some patients. Docetaxel (75mg/m 2 ) was administered alongside SOC for six three-weekly cycles., Outcome Measurements and Statistical Analysis: The model generated lifetime predictions of costs, changes in survival duration, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs)., Results and Limitations: The model predicted that docetaxel would extend survival (discounted quality-adjusted survival) by 0.89 yr (0.51) for metastatic PC and 0.78 yr (0.39) for nonmetastatic PC, and would be cost-effective in metastatic PC (ICER £5514/QALY vs SOC) and nonmetastatic PC (higher QALYs, lower costs vs SOC). Docetaxel remained cost-effective in nonmetastatic PC when the assumption of no survival advantage was modelled., Conclusions: Docetaxel is cost-effective among patients with nonmetastatic and metastatic PC in a UK setting. Clinicians should consider whether the evidence is now sufficiently compelling to support docetaxel use in patients with nonmetastatic PC, as the opportunity to offer docetaxel at hormone therapy initiation will be missed for some patients by the time more mature survival data are available., Patient Summary: Starting docetaxel chemotherapy alongside hormone therapy represents a good use of UK National Health Service resources for patients with prostate cancer that is high risk or has spread to other parts of the body., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

When people in laboratory studies sample products in a sequence, they tend to prefer options presented first and last. To what extent do these primacy and recency effects carry over to real-world settings where numerous sources of information determine preferences? To investigate this question, we coded archival data from 136 actual whisky tastings each featuring seven whiskies. We analyzed people's ratings of whiskies featured at different serial positions in the tastings. We found a recency effect: people gave their highest rating to whiskies in the last position, and voted the last whisky as their favorite more frequently. This recency effect persisted when we controlled for the counter explanation that whiskies with higher alcohol content tended to occupy later serial positions. The recency effect also persisted when we controlled for the age of the whiskies. Taken together, our findings suggest that the order of presentation matters in real-world settings, closely resembling what happens in laboratory settings with longer sequences of options., Competing Interests: The authors have declared that no competing interests exist.

Objectives: To test the feasibility of a randomised trial in muscle-invasive bladder cancer (MIBC) and compare outcomes in patients who receive neoadjuvant chemotherapy followed by radical cystectomy (RC) or selective bladder preservation (SBP), where definitive treatment [RC or radiotherapy (RT)] is determined by response to chemotherapy., Patients and Methods: SPARE is a multicentre randomised controlled trial comparing RC and SBP in patients with MIBC staged T2-3 N0 M0, fit for both treatment strategies and receiving three cycles of neoadjuvant chemotherapy. Patients were randomised between RC and SBP before a cystoscopy after cycle three of neoadjuvant chemotherapy. Patients with ≤T1 residual tumour received a fourth cycle of neoadjuvant chemotherapy in both groups, followed by radical RT in the SBP group and RC in in the RC group; non-responders in both groups proceeded immediately to RC following cycle three. Feasibility study primary endpoints were accrual rate and compliance with assigned treatment strategy. The phase III trial was designed to demonstrate non-inferiority of SBP in terms of overall survival (OS) in patients whose tumours responded to neoadjuvant chemotherapy. Secondary endpoints included patient-reported quality of life, clinician assessed toxicity, loco-regional recurrence-free survival, and rate of salvage RC after SBP., Results: Trial recruitment was challenging and below the predefined target with 45 patients recruited in 30 months (25 RC; 20 SBP). Non-compliance with assigned treatment strategy was frequent, six of the 25 patients (24%) randomised to RC received RT. Long-term bladder preservation rate was 11/15 (73%) in those who received RT per protocol. OS survival was not significantly different between groups., Conclusions: Randomising patients with MIBC between RC and SBP based on response to neoadjuvant chemotherapy was not feasible in the UK health system. Strong clinician and patient preferences for treatments impacted willingness to undergo randomisation and acceptance of treatment allocation. Due to the few participants, firm conclusions about disease and toxicity outcomes cannot be drawn., (© 2017 The Authors. BJU International published by John Wiley & Sons Ltd on behalf of BJU International.)

Correction for 'Measuring the effects of fractionated radiation therapy in a 3D prostate cancer model system using SERS nanosensors' by Victoria L. Camus, et al., Analyst, 2016, 141, 5056-5061.

Use of multicellular tumor spheroids (MTS) to investigate therapies has gained impetus because they have potential to mimic factors including zonation, hypoxia and drug-resistance. However, analysis remains difficult and often destroys 3D integrity. Here we report an optical technique using targeted nanosensors that allows in situ 3D mapping of redox potential gradients whilst retaining MTS morphology and function. The magnitude of the redox potential gradient can be quantified as a free energy difference (ΔG) and used as a measurement of MTS viability. We found that by delivering different doses of radiotherapy to MTS we could correlate loss of ΔG with increasing therapeutic dose. In addition, we found that resistance to drug therapy was indicated by an increase in ΔG. This robust and reproducible technique allows interrogation of an in vitro tumor-model's bioenergetic response to therapy, indicating its potential as a tool for therapy development.

Multicellular tumour spheroids (MTS) are three-dimensional cell cultures that possess their own microenvironments and provide a more meaningful model of tumour biology than monolayer cultures. As a result, MTS are becoming increasingly used as tumor models when measuring the efficiency of therapies. Monitoring the viability of live MTS is complicated by their 3D nature and conventional approaches such as fluorescence often require fixation and sectioning. In this paper we detail the use of Surface Enhanced Raman Spectroscopy (SERS) to measure the viability of MTS grown from prostate cancer (PC3) cells. Our results show that we can monitor loss of viability by measuring pH and redox potential in MTS and furthermore we demonstrate that SERS can be used to measure the effects of fractionation of a dose of radiotherapy in a way that has potential to inform treatment planning.

Background: Long-term hormone therapy has been the standard of care for advanced prostate cancer since the 1940s. STAMPEDE is a randomised controlled trial using a multiarm, multistage platform design. It recruits men with high-risk, locally advanced, metastatic or recurrent prostate cancer who are starting first-line long-term hormone therapy. We report primary survival results for three research comparisons testing the addition of zoledronic acid, docetaxel, or their combination to standard of care versus standard of care alone., Methods: Standard of care was hormone therapy for at least 2 years; radiotherapy was encouraged for men with N0M0 disease to November, 2011, then mandated; radiotherapy was optional for men with node-positive non-metastatic (N+M0) disease. Stratified randomisation (via minimisation) allocated men 2:1:1:1 to standard of care only (SOC-only; control), standard of care plus zoledronic acid (SOC + ZA), standard of care plus docetaxel (SOC + Doc), or standard of care with both zoledronic acid and docetaxel (SOC + ZA + Doc). Zoledronic acid (4 mg) was given for six 3-weekly cycles, then 4-weekly until 2 years, and docetaxel (75 mg/m(2)) for six 3-weekly cycles with prednisolone 10 mg daily. There was no blinding to treatment allocation. The primary outcome measure was overall survival. Pairwise comparisons of research versus control had 90% power at 2·5% one-sided α for hazard ratio (HR) 0·75, requiring roughly 400 control arm deaths. Statistical analyses were undertaken with standard log-rank-type methods for time-to-event data, with hazard ratios (HRs) and 95% CIs derived from adjusted Cox models. This trial is registered at ClinicalTrials.gov (NCT00268476) and ControlledTrials.com (ISRCTN78818544)., Findings: 2962 men were randomly assigned to four groups between Oct 5, 2005, and March 31, 2013. Median age was 65 years (IQR 60-71). 1817 (61%) men had M+ disease, 448 (15%) had N+/X M0, and 697 (24%) had N0M0. 165 (6%) men were previously treated with local therapy, and median prostate-specific antigen was 65 ng/mL (IQR 23-184). Median follow-up was 43 months (IQR 30-60). There were 415 deaths in the control group (347 [84%] prostate cancer). Median overall survival was 71 months (IQR 32 to not reached) for SOC-only, not reached (32 to not reached) for SOC + ZA (HR 0·94, 95% CI 0·79-1·11; p=0·450), 81 months (41 to not reached) for SOC + Doc (0·78, 0·66-0·93; p=0·006), and 76 months (39 to not reached) for SOC + ZA + Doc (0·82, 0·69-0·97; p=0·022). There was no evidence of heterogeneity in treatment effect (for any of the treatments) across prespecified subsets. Grade 3-5 adverse events were reported for 399 (32%) patients receiving SOC, 197 (32%) receiving SOC + ZA, 288 (52%) receiving SOC + Doc, and 269 (52%) receiving SOC + ZA + Doc., Interpretation: Zoledronic acid showed no evidence of survival improvement and should not be part of standard of care for this population. Docetaxel chemotherapy, given at the time of long-term hormone therapy initiation, showed evidence of improved survival accompanied by an increase in adverse events. Docetaxel treatment should become part of standard of care for adequately fit men commencing long-term hormone therapy., Funding: Cancer Research UK, Medical Research Council, Novartis, Sanofi-Aventis, Pfizer, Janssen, Astellas, NIHR Clinical Research Network, Swiss Group for Clinical Cancer Research., (Copyright © 2016 James et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

The field of veterinary radiation therapy (RT) has gained substantial momentum in recent decades with significant advances in conformal treatment planning, image-guided radiation therapy (IGRT), and intensity-modulated (IMRT) techniques. At the root of these advancements lie improvements in tumor imaging, image alignment (registration), target volume delineation, and identification of critical structures. Image registration has been widely used to combine information from multimodality images such as computerized tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) to improve the accuracy of radiation delivery and reliably identify tumor-bearing areas. Many different techniques have been applied in image registration. This review provides an overview of medical image registration in RT and its applications in veterinary oncology. A summary of the most commonly used approaches in human and veterinary medicine is presented along with their current use in IGRT and adaptive radiation therapy (ART). It is important to realize that registration does not guarantee that target volumes, such as the gross tumor volume (GTV), are correctly identified on the image being registered, as limitations unique to registration algorithms exist. Research involving novel registration frameworks for automatic segmentation of tumor volumes is ongoing and comparative oncology programs offer a unique opportunity to test the efficacy of proposed algorithms., (© 2016 American College of Veterinary Radiology.)

To establish the optimal radiotherapy fields for treating brain cancer patients, the tumour volume is often outlined on magnetic resonance (MR) images, where the tumour is clearly visible, and mapped onto computerised tomography images used for radiotherapy planning. This process requires considerable clinical experience and is time consuming, which will continue to increase as more complex image sequences are used in this process. Here, the potential of image analysis techniques for automatically identifying the radiation target volume on MR images, and thereby assisting clinicians with this difficult task, was investigated. A gradient-based level set approach was applied on the MR images of five patients with grades II, III and IV malignant cerebral glioma. The relationship between the target volumes produced by image analysis and those produced by a radiation oncologist was also investigated. The contours produced by image analysis were compared with the contours produced by an oncologist and used for treatment. In 93% of cases, the Dice similarity coefficient was found to be between 60 and 80%. This feasibility study demonstrates that image analysis has the potential for automatic outlining in the management of brain cancer patients, however, more testing and validation on a much larger patient cohort is required.

Aims: To analyse our 5 and 10 year prostate brachytherapy outcome data and to assess the impact of PSA nadir on relapse free survival and whether an alternative definition of PSA relapse could detect men destined to fail by the Phoenix definition at an earlier time point., Materials and Methods: 474 men were treated over a 10 year period between 20012 and 2011 and divided into 2 five year cohorts for the purpose of the analysis., Results: The risk of relapse is strongly predicted by post treat prostate-specific antigen (PSA) nadir. After 3 years post-treatment, PSA nadir plus 0.4 ng/ml identified men at risk of relapse 17 months earlier than the Phoenix definition., Conclusion: The Phoenix definition of nadir plus 2.0 ng/ml does not allow the early identification of men destined to relapse. The initiation of salavage therapy at the earliest opportunity could potentially affect subsequent survival and an outline randomised controlled trial proposal is presented., (Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: High quality human biosamples with associated high quality clinical data are essential for successful translational research. Despite this, the traditional approach is for the surgeon to act as a technician in the tissue collection act. Biomarker research presents multiple challenges and the field is littered with failures. Tissue quality, poor clinical information, small sample numbers and lack of validation cohorts are just a few reasons for failure. It is clear that the surgeon involved in tissue acquisition must be fully engaged in the process of biosampling for a specific condition, as this will negate many of the issues for translational research failure due to an inadequate bioresource., Approach: In this Matter for Debate paper, the Scottish Collaboration On Translational Research into Renal Cell Cancer (SCOTRRCC) is discussed as an example of a urological surgery lead bioresource which has resulted in a National collection of renal cancer tissue and blood (from over 900 patients to date), negating all of the traditional issues with biobanks because of close enagagement and acknowledgement of urologists and uropathologists from seven centres around Scotland. SCOTRRCC has leveraged renal cancer research in Scotland resulting in several high impact publications and providing a springboard for future research in this disease in Scotland and beyond., Conclusions: The SCOTRRCC model presented here can be transferred to other surgical disciplines for success in translational research., (Copyright © 2015 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.)

Background: Prostate cancer is now the only solid organ cancer in which therapy is commonly applied to the whole gland. One of the main challenges in adopting focal boost or true focal therapy is in the accurate mapping of cancer foci defined on magnetic resonance (MR) images onto the computerised tomography (CT) images used for radiotherapy planning., Material and Methods: Prostate cancer patients (n = 14) previously treated at the Edinburgh Cancer Centre (ECC) were selected for this study. All patients underwent MR scanning for the purpose of diagnosis and staging. Patients received three months of androgen deprivation hormone therapy followed by a radiotherapy planning CT scan. The dominant focal prostate lesions were identified on MR scans by a radiologist and a novel image analysis approach was used to map the location of the dominant focal lesion from MR to CT. An offline planning study was undertaken on suitable patients (n = 7) to investigate boosting of the radiation dose to the tumour using a stereotactic ablative body radiotherapy (SABR) technique., Results: The non-rigid registration algorithm showed clinically acceptable estimates of the location of the dominant focal disease on all CT image data of patients suitable for a boost treatment. Standard rigid registration was found to produce unacceptable estimates of the dominant focal lesion on CT. A SABR boost dose of 47.5 Gy was delivered to the dominant focal lesion of all patients whilst meeting all dose-volume histogram (DVH) constraints. Normal tissue complication probability (NTCP) for the rectum decreased from 1.28% to 0.73% with this method., Conclusions: These preliminary results demonstrate the potential of this image analysis method for reliably mapping dominant focal disease within the prostate from MR images onto planning CT images. Significant dose escalation using a simultaneous integrated SABR boost was achieved in all patients.

Background: The purpose of the study was to determine the prevalence and associations of clinically relevant fatigue (CRF) in men with biochemically controlled prostate cancer on long-term androgen deprivation therapy (ADT)., Patients and Methods: One hundred and ninety-eight men were surveyed and the prevalence of CRF (Brief Fatigue Inventory score >3) determined. Associations with other measures (Hospital Anxiety and Depression Scale; International Prostate Symptom Score; European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; Brief Pain Inventory worst pain; clinical and demographic information) were explored in univariate and multivariate analyses., Results: Eight-one per cent (160 of 198) of questionnaires were analysable. CRF prevalence was 43% (68 of 160). CRF associations included moderate/severe urinary symptoms, anxiety and medical co-morbidities; the strongest associations were depression [odds ratio (OR) 9.8, 95% confidence interval (CI) 4.3-22.8] and pain (OR 9.2, 95% CI 4.0-21.5). After controlling for other factors, the independent associations were depression (OR 4.7, 95% CI 1.6-14.0) and pain (OR 3.1, 95% CI 1.0-8.9). There was no association with age, disease burden or treatment duration., Conclusions: Two-fifths of men with biochemically controlled prostate cancer on long-term ADT report CRF that interferes with function. Management aimed at improving CRF should address depression and pain.

Background: Little is known about the prevalence and associations of clinically relevant fatigue (CRF) in recurrence-free prostate cancer survivors., Patients and Methods: Four hundred and sixteen recurrence-free prostate cancer survivors who were >1 year post-radiotherapy or radical prostatectomy were surveyed. The prevalence of CRF (defined as Brief Fatigue Inventory >3) was determined and compared with a noncancer control group. Other measures included the Hospital Anxiety and Depression Scale, International Prostate Symptom Score, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. Relationships between these factors and CRF were explored in univariate and multivariate analyses., Results: Analyzable data were obtained from 91% (377/416) of patients. The prevalence of CRF was 29% (108/377) versus 16% (10/63) in the controls (P=0.031). CRF was more common in post-radiotherapy than in post-prostatectomy 33% (79/240) versus 22% (29/133), P=0.024. However, when other factors (current depression, anxiety, urinary symptoms, medical comorbidities, pain and insomnia) were controlled for, previous treatment did not predict CRF. Current depression [Hospital Anxiety and Depression Scale≥8 was by far the strongest association [odds ratio 9.9, 95% confidence interval 4.2-23.5)]., Conclusions: Almost one-third of recurrence-free prostate cancer survivors report CRF. Depression, anxiety, urinary symptoms, pain and insomnia measured at outcome are more strongly associated than type of cancer treatment previously received.

Prostate cancer cells can exist in a hypoxic microenvironment, causing radioresistance. Nitric oxide (NO) is a radiosensitiser of mammalian cells. NO-NSAIDs are a potential means of delivering NO to prostate cancer cells. This study aimed to determine the effect and mechanism of action of NO-sulindac and radiation, on prostate cancer cells and stroma, under normoxia (21% oxygen) and chronic hypoxia (0.2% oxygen). Using clonogenic assays, at a surviving fraction of 10% the sensitisation enhancement ratios of radiation plus NO-sulindac over radiation alone on PC-3 cells were 1.22 and 1.42 under normoxia and hypoxia, respectively. 3D culture of PC-3 cells revealed significantly reduced sphere diameter in irradiated spheres treated with NO-sulindac. Neither NO-sulindac nor sulindac radiosensitised prostate stromal cells under normoxia or hypoxia. HIF-1α protein levels were reduced by NO-sulindac exposure and radiation at 21 and 0.2% oxygen. Alkaline Comet assay analysis suggested an increased rate of single strand DNA breaks and slower repair of these lesions in PC-3 cells treated with NO-sulindac prior to irradiation. There was a higher level of γ-H2AX production and hence double strand DNA breaks following irradiation of NO-sulindac treated PC-3 cells. At all radiation doses and oxygen levels tested, treatment of 2D and 3D cultures of PC-3 cells with NO-sulindac prior to irradiation radiosensitised PC-3, with minimal effect on stromal cells. Hypoxia response inhibition and increased DNA double strand breaks are potential mechanisms of action. Neoadjuvent and concurrent use of NO-NSAIDs have the potential to improve radiotherapy treatment of prostate cancer under normoxia and hypoxia., (2010 Elsevier Inc. All rights reserved.)

Research into the hypoxic tumour microenvironment is accelerating and the reversal of hypoxia is increasingly being suggested as a mechanism for improving cancer treatment. Recent studies have suggested that hypoxia is also a feature in prostate cancer and is associated with a poor prognosis. Hypoxia has been shown to cause radio-resistance and hence hamper one of the major treatments for prostate cancer. However, unlike other solid tumours, such as cervical and head-and-neck cancer, there are inconsistencies and unanswered questions about the relevance of hypoxia in prostate cancer. This review outlines the role of low-oxygen conditions in prostate cancer and the areas where further studies are required.

Computer-based artificial intelligence methods for classification and delineation of the gross tumour volume (GTV) on computerised tomography (CT) and magnetic resonance (MR) images do not, at present, provide the accuracy required for radiotherapy applications. This paper describes an image analysis method for classification of distinct regions within the GTV, and other clinically relevant regions, on CT images acquired on eight bladder cancer patients at the radiotherapy planning stage and thereafter at regular intervals during treatment. Statistical and fractal textural features (N=27) were calculated on the bladder, rectum and a control region identified on axial, coronal and sagittal CT images. Unsupervised classification results demonstrate that with a reduced feature set (N=3) the approach offers significant classification accuracy on axial, coronal and sagittal CT image planes and has the potential to be developed further for radiotherapy applications, particularly towards an automatic outlining approach.

Aims: To identify clinicopathological features and outcomes in patients with late relapse (LR) of testicular germ cell tumours (GCTs) in order to guide follow-up policy., Materials and Methods: The Edinburgh Cancer Centre (ECC) database identified all patients diagnosed with testicular GCT between 1988 and 2002. Of 703 patients, six relapsed more than 24 months after their initial treatment. A retrospective casenote review was performed to extract clinical, pathological, treatment and outcome data., Results: Six patients (0.85%) underwent late relapse. All patients presented initially with stage I disease and five were classified as good risk (International Germ Cell Consensus Classification, IGCCC). Median time to LR was 31 months. Two patients had previously relapsed less than 24 months from initial diagnosis. Markers at the time of relapse were normal in all patients. In all cases of late relapse disease was confined to axial lymphadenopathy. Three patients were treated with chemotherapy alone, two patients underwent surgical resection and one patient received combined treatment. All patients obtained a complete response and all remain disease free with a median follow-up of 52 months., Conclusions: The incidence of late relapse in this series is low. Chemo-naive patients with LR were successfully salvaged with chemotherapy alone and patients previously exposed to cisplatin-based chemotherapy were salvaged with complete surgical excision. The optimal length of follow-up in patients with testicular germ cell tumours is not known and practice varies widely. In this cohort of 703 patients, only one patient who relapsed was picked up by additional clinic follow-up between 5 and 10 years. Thus, on the basis of this small series, the authors suggest that follow-up after five years may not be justified.

Purpose: Neoadjuvant androgen deprivation and radical radiotherapy is an established treatment for localized prostate carcinoma. This study sought to analyze the outcomes of patients treated with relatively low-dose hypofractionated radiotherapy., Methods and Materials: Three hundred patients with T1-T3 prostate cancer were treated between 1996 and 2001. Patients were prescribed 3 months of neoadjuvant androgen deprivation before receiving 5250 cGy in 20 fractions. Patients' case notes and the oncology database were used to retrospectively assess outcomes. Median follow-up was 58 months., Results: Patients presented with prostate cancer with poorer prognostic indicators than that reported in other series. At 5 years, the actuarial cause-specific survival rate was 83.2% and the prostate-specific antigen (PSA) relapse rate was 57.3%. Metastatic disease had developed in 23.4% of patients. PSA relapse continued to occur 5 years from treatment in all prognostic groups. Independent prognostic factors for relapse included treatment near the start of the study period, neoadjuvant oral anti-androgen monotherapy rather than neoadjuvant luteinizing hormone releasing hormone therapy, and diagnosis through transurethral resection of the prostate rather than transrectal ultrasound., Conclusion: This is the largest reported series of patients treated with neoadjuvant androgen deprivation and hypofractionated radiotherapy in the United Kingdom. Neoadjuvant hormonal therapy did not appear to adequately compensate for the relatively low effective radiation dose used.

Neoadjuvant chemotherapy in transitional-cell carcinoma of the bladder (TCC) improves survival. This is one of the most important developments in the management of muscle-invasive bladder cancer in recent times. There is an improved absolute 5-year survival of at least 5% for T2-T4 disease. To achieve this benefit, a cisplatin-containing combination is required. There is no difference in survival whether radical radiotherapy or radical cystectomy is given as subsequent definitive treatment.

Aims: The aim of this retrospective analysis was to review the outcome of patients with germ-cell tumours treated in the Edinburgh Cancer Centre over the past 15 years, and to see whether there had been any changes over three 5-year cohorts., Materials and Methods: Patients referred with gonadal and extra-gonadal primary germ-cell tumours, between 1988 and 2002, were identified from the departmental database, and survival by stage and prognostic group was analysed., Results and Conclusions: The proportion of patients with stage I seminoma has significantly increased. The good prognosis of patients with early stage disease is confirmed, with the outcome for some groups of patients being better than expected. There is a non-significant trend to improved results over the three 5-year cohorts. The outcome for patients with stage IV seminoma is worse than would be expected, but numbers are small. The poor prognosis of patients with non-seminomatous germ-cell tumours who fall into the International Germ Cell Consensus Classification (IGCCC) poor-prognostic group is confirmed. Failure of patients with metastatic non-seminomatous germ-cell tumours to achieve a complete response to initial therapy is shown to be a poor prognostic indicator.

Aims: Sex cord-stromal tumours of the testis are uncommon tumours, accounting for around 5% of testicular neoplasms. Treatment is primarily surgical, with no adjuvant therapy of proven benefit. We present a single-centre experience over a period of 15 years., Materials and Methods: From 1988 to 2002, 18 patients with a diagnosis of sex cord-stromal tumour were referred to our centre. A retrospective analysis of their case notes was made and a pathological review undertaken., Results: Sixteen were Leydig-cell tumours and two were Sertoli cell. For the Leydig-cell tumours, the median age at presentation was 42 years, 50% presented with a testicular mass and 31% with gynaecomastia. Two patients followed a malignant course: one revealing disease dissemination at initial staging, and a second 12 months after potentially curative orchidectomy. Salvage retroperitoneal lymphadenectomy in the latter patient proved unsuccessful. Clinical outcome correlated strongly with the presence of adverse pathological features described previously in the literature. After a median follow-up of 46 months, two patients have developed progressive disease, and two patients have died, one of metastatic Leydig-cell tumour. No patient defined as being of low malignant potential on pathological examination has relapsed outside our review period of 2 years., Conclusion: We confirm the overall excellent prognosis for most of the patients with sex cord-stromal tumours of the testis. Compared with most previous reports, pathological features seem to predict with reasonable accuracy the risk of malignant behaviour, and can adequately inform the subsequent review policy.

Background and Purpose: Different treatment margins and fractionation schedules are used in conformal radiotherapy (CRT) of urinary bladder cancer. This study compared intestine and rectum dose-volume histogram (DVH) data and normal tissue complication probability (NTCP) estimates for various clinically applied margins and fractionation schedules in bladder irradiation., Patients and Methods: Normal tissue dose distributions in fifteen bladder cancer patients treated with CRT were studied using standard three- and four-field configurations. The impact of margin width on intestine and rectum dose distributions was initially evaluated using DVH data. NTCP modelling with the probit model was used to compare the impact of choice of margin size and fractionation schedule. The analysis included margin combinations of 1.0 cm isotropic (narrow margins) and 1.2-2.0 cm non-isotropic (wide margins) and fractionation schedule alternatives of 52.5Gy/20, 55Gy/20, 57.5Gy/20 and 64Gy/32., Results: Using wide as compared to narrow margins, the volumes of intestine and rectum receiving high doses increased by factors of approximately two and four, respectively. Similar differences between wide and narrow margins were found when calculating intestine and rectum NTCPs. The impact of margin size depended strongly on the volume effect expressed by the NTCP model parameters. With standard parameters, however, the choice of margins and fractionation schedule had a similar impact on intestine NTCPs, while for the rectum, the choice of margin had a greater impact than the choice of fractionation. For a given margin size, the intestine and rectum NTCPs for the 55Gy/20 and the 64Gy/32 schedules were comparable. For clinics using narrow margins and a fractionation of 52.5Gy/20, the NTCP modelling suggested that a change in fractionation schedule (to 55Gy/20 or 64Gy/32) or a change to wide margins would have a similar effect on the intestine NTCP predictions., Conclusions: This modelling study documented that the choice of margins was as important as the choice of fractionation in terms of intestine and rectum DVH data and NTCP predictions.

The objective of this study was to review the results of our policy of primary radiotherapy (RT) and salvage cystectomy for transitional carcinoma (TCC) of the bladder in the light of changes in our radiotherapy planning procedure, in particular the introduction of CT planning. The case notes of 163 patients treated with radical radiotherapy using a CT planning technique were examined. The main endpoint for assessment was response at the time of the check cystoscopy 6 months after the completion of treatment. In addition survival was estimated by stage of disease and by response at the time of first cystoscopy. Patterns of relapse and time to relapse were analysed. All percentages quoted in the text use the initial 163 patients as the denominator. One hundred patients (61%) achieved a complete response. The complete response rate was significantly related to T stage at presentation being 90% for T1, 75% for T2, and 53% for T3 disease respectively. Of these patients 78 remain disease free in the bladder (47%). Twenty-two have relapsed in the bladder, of whom 5 have also relapsed at metastatic sites. Fifteen patients have relapsed outside the bladder whilst remaining disease free within the bladder. At the time of last follow up or death from other causes 63 of the 100 patients who had a complete response remained disease free with an intact bladder. There were 18 (11%) partial responders. Seven of these patients went on to have a cystectomy. Ten remain alive, 7 disease free, 4 with intact bladders. In 24 patients (15%) there was no response and these patients have all died, the median survival being 10 months. In 21 patients (13%) a postradiotherapy cystoscopy was not performed. In all but one patient, who was lost to follow up, this was because of progressive disease. The median survival of these 20 patients was 6 months. Of the 163 patients 35% are alive and well with an intact bladder. If patients dying from other causes are included then 42% were rendered disease free. Cause specific survival was significantly related to stage of disease at presentation with 5 year actuarial survival being 87%, 48% and 26%, for T1, T2 and T3 disease respectively. Survival was also related to response to treatment at 6 months with 5 year survival being 64%, and 52% for complete and partial responders respectively. Survival was extremely poor for non-responders with only 37.5% surviving 1 year and none 5 years. There was a highly significant relationship between response and the development of, and the time to developing metastatic disease. Of those who exhibited a response 21% developed metastatic disease compared to 78% of non-responders. Salvage cystectomy offers the possibility of cure in those who achieve a complete or partial response with 42% of such patients being rendered disease free. Results however are poor in those who did not respond with all patients dying of their disease. Response rates for all stages, and survival for stages T1 and T2 are much improved from those previously reported from this centre and compare favourably with other published series. These results confirm the place of radiotherapy and salvage cystectomy in the management of TCC of the bladder in selected patients. In about one-third of patients the desired outcome of curing the patient of their cancer with organ preservation is achieved. The prognostic significance of cystoscopic response at 6 months and stage at presentation is confirmed. The outcome for patients with early stage disease is excellent. The relationship between response and the development of metastatic disease would suggest that even if these patients had had a primary cystectomy they may have fared badly, a conclusion supported by the fact that these results are comparable with surgical series. This series supports the role of radiotherapy in the management of this disease and suggests that modern RT techniques including CT planning have had a beneficial effect on the results of radical radiotherapy.

The comet assay is a single-cell gel electrophoresis technique that measures DNA damage in individual cells. Since radiation produces 3-4 times more DNA damage in well-oxygenated cells compared with hypoxic cells, this assay can quantify the fraction of radiation-resistant hypoxic cells found in many solid tumours. This paper summarizes our results with 73 accessible metastatic tumours irradiated with palliative intent. Hypoxic fractions ranged from 0.0 to 0.67 with a mean of 0.15; 62% of these advanced tumours showed a hypoxic fraction > 0.05. Comparisons between two sequential aspirates in 33 tumours gave a slope of 0.92 (r2 = 0.88), suggesting that a single aspirate is generally representative of the tumour. A limitation, however, is that the hypoxic fraction could not be measured in clinical samples given a conventional dose of 2 Gy.

Background: Prostate specific antigen doubling time (PSAdt) is a dynamic model of prostate tumor biology. It predicts aggressive disease and subsequent clinical recurrence after radical treatment. However, as yet there is only limited evidence for its validity in the watchful waiting population., Methods: One hundred and thirteen previously untreated patients with adenocarcinoma of the prostate who were referred to the British Columbia Cancer Agency for a management opinion subsequently were placed into a prospective watchful waiting program. The reasons for watchful waiting, previous medical history, serial PSA, and histopathologic data were recorded., Results: The median age of patients was 75 years (range, 49-85 years). The median follow-up from the time of the first appointment was 14 months (range, 0-58 months). The reasons for watchful waiting were correlated highly with T classification (P = 0.003) and past medical history (P = 0.002). Approximately 40% of T1 patients and 51% of T2 patients had clinical progression by 2 years, increasing to 60% at 3 years. On multivariate analysis PSAdt strongly correlated with clinical progression (P < 0.0001), stage progression (P = 0.01), and time to treatment (P = 0.0001); tumor grade and initial stage were not found to be predictive for any of the endpoints studied. Initial PSA only was significant in predicting for time to treatment (P = 0.03). Approximately 50% of patients with a PSAdt of <18 months progressed within 6 months. At last follow-up, no deaths from prostate carcinoma had been recorded. Overall survival at 2 and 5 years was 92% and 68%, respectively., Conclusions: Using digital rectal examination, the findings of this study demonstrated high rates of clinical tumor progression within the watchful waiting population. PSAdt rather than standard histopathologic criteria was found to be the most powerful indicator of disease activity.

Background and Purpose: Nicotinamide has been shown to reduce hypoxia in experimental tumours, but there are no data that measure the hypoxic fraction at the time of irradiation in humans. This study investigates whether nicotinamide with radiation can reduce human tumour hypoxia., Materials and Methods: Twenty-two patients undergoing palliative radiotherapy for treatment of accessible metastatic tumours were exposed to two doses of radiation (3.5-8 Gy, median 6 Gy) separated by 1-6 days. Directly on completion of the first dose, two fine needle aspirate biopsies (FNAB) were taken and analyzed for hypoxic fraction using the alkaline comet assay. On the second day of radiation, 13 patients were given 80 mg/kg nicotinamide post-operatively on an empty stomach 2 h before treatment; the remaining nine patients acted as controls. A second comparative pair of aspirates were obtained immediately on completion of the second fraction., Results: Sixteen tumours were suitable for analysis (nine nicotinamide and seven controls). Marked inter-tumour variations in hypoxic fraction were noted (0-67%). Both nicotinamide treated tumours and controls demonstrated a significant increase in the percentage of cells containing heavily damaged DNA following the second dose of radiation (P = 0.01). A significant reduction in mean hypoxic fraction after the second radiation treatment was noted (22 to 13%, P = 0.04). This reduction was predominantly due to the nicotinamide treated group, where mean hypoxic fraction fell from 25 to 11% (P = 0.08) compared to the much smaller change in the radiation only control group, 18 to 15% (P = 0.3)., Conclusions: The decrease in hypoxic fraction suggests that nicotinamide can improve tumour hypoxia measured at the time of irradiation. Exposure to the first dose of radiation, or an effect of the first FNAB on microregional tumour blood flow may also contribute.