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Functional impairment of the tumour-suppressorPTENis common in primary-prostate cancer and has been linked to relapse post-radiotherapy (RT). Pre-clinical modelling supports elevated CXC-chemokine signaling as a critical mediator ofPTEN-depleted disease progression and therapeutic resistance. We assessed the correlation ofPTEN-deficiency with CXC-chemokine signaling and its association with clinical outcomes. Gene expression analysis characterized aPTENLOW/CXCR1HIGH/CXCR2HIGHcluster of tumors that associates with earlier time-to-biochemical recurrence (HR 5.87 and HR 2.65 respectively) and development of systemic metastasis (HR 3.51).In vitro, CXCL-signaling was further amplified following exposure ofPTEN-deficient prostate cancer cell lines to ionizing radiation (IR). Inhibition of CXCR1/2-signaling inPTEN-depleted cell-based models increased IR-sensitivity.In vivo, administration of a CXCR1/2-targeted pepducin (x1/2pal-i3), or CXCR2-specific antagonist (AZD5069), in combination with IR toPTEN-deficient xenografts attenuated tumor growth and progression compared to control or IR alone. Post-mortem analysis confirmed that x1/2pal-i3 administration attenuated IR-induced CXCL-signaling and anti-apoptotic protein expression. Interventions targeting CXC-chemokine signaling may provide an effective strategy to combine with radiotherapy, in both locally-advanced and oligometastatic-prostate cancers, with known presence ofPTEN-deficient foci.

BackgroundAllograft models enable characterisation of genomic drivers and treatment responses by modelling immune and micro-environmental changes more accurately than xenografts. Despite this, few models are available to the prostate cancer (PCa) community. This study presents a novel allograft model of high-risk, localised PCa. In characterising this model we have focused on its response to radiotherapy (RT).MethodsThe DVL3 cell line was derived from a transgenic trp53-/-/Pten-/- mouse model and characterised both in vitro and in vivo. The DVL3 cells were allografted and response to RT was investigated and compared to the TRAMP-C1 model. Extensive tumour profiling in the DVL3 model was performed using flow cytometry, immunohistochemistry and RNA-seq.ResultsIn vitro the DVL3 cells expressed basal and luminal markers. DVL3 cells formed tumours with distinct glandular morphology which expressed androgen receptor, similar to human localised PC. DVL3 tumour growth was delayed following administration of fractionated RT, with infiltration of myeloid derived suppressor cells (MDSC).ConclusionsThe DVL3 allograft model represents substantial progress in PCa modelling, displaying; luminal differentiation, strong AR expression, and an immunosuppressive microenvironment, similar to observations in high-risk PCa patients. This model is ideally suited for development and validation of novel therapeutics, in particular immune-modulatory agents in combination with RT.

OBJECTIVE: To systematically develop a framework to improve sexual wellbeing communication in routine prostate cancer care.METHODS: The Theoretical Domains Framework was used to guide a multi-phase process used to identify components of the framework based on evidence reviews, semi-structured interviews and stakeholder workshops. 'Think-aloud' testing was used to explore usability, potential barriers and other factors relevant to implementation.RESULTS: A conceptual communication framework consisting of 'Engagement' (E), 'Assessment' (A), information and 'Support' (S) and 'Sign-posting' (Si) sections was developed. The framework emphasises routine engagement to normalise sexual concerns, brief, non-sensitive assessment, personalised advice based on treatment type and relationship status, and a mechanism for referral to additional support or self-management resources in the form of a patient and partner handout. Usability testing identified strategies to promote implementation.CONCLUSIONS: The proposed framework is appropriate for use in routine practice and appears to be acceptable to patients, partners and healthcare professionals. Its use may help address gaps in sexual wellbeing support for men and partners living with prostate cancer. Further work will be conducted evaluating an online engagement tool, modelled on the framework.PRACTICE IMPLICATIONS: The EASSi framework can facilitate and structure sexual wellbeing conversations and ensure fundamental but individualised support is provided routinely in prostate cancer care.

Context: The optimal treatment for men with high-risk localized or locally advanced prostate cancer (PCa) remains unknown. Objective: To perform a systematic review of the existing literature on the effectiveness of the different primary treatment modalities for high-risk localized and locally advanced PCa. The primary oncological outcome is the development of distant metastases at ≥5 yr of follow-up. Secondary oncological outcomes are PCa-specific mortality, overall mortality, biochemical recurrence, and need for salvage treatment with ≥5 yr of follow-up. Nononcological outcomes are quality of life (QoL), functional outcomes, and treatment-related side effects reported. Evidence acquisition: Medline, Medline In-Process, Embase, and the Cochrane Central Register of Randomized Controlled Trials were searched. All comparative (randomized and nonrandomized) studies published between January 2000 and May 2019 with at least 50 participants in each arm were included. Studies reporting on high-risk localized PCa (International Society of Urologic Pathologists [ISUP] grade 4-5 [Gleason score {GS} 8-10] or prostate-specific antigen [PSA] >20 ng/ml or ≥ cT2c) and/or locally advanced PCa (any PSA, cT3-4 or cN+, any ISUP grade/GS) or where subanalyses were performed on either group were included. The following primary local treatments were mandated: radical prostatectomy (RP), external beam radiotherapy (EBRT) (≥64 Gy), brachytherapy (BT), or multimodality treatment combining any of the local treatments above (±any systemic treatment). Risk of bias (RoB) and confounding factors were assessed for each study. A narrative synthesis was performed. Evidence synthesis: Overall, 90 studies met the inclusion criteria. RoB and confounding factors revealed high RoB for selection, performance, and detection bias, and low RoB for correction of initial PSA and biopsy GS. When comparing RP with EBRT, retrospective series suggested an advantage for RP, although with a low level of evidence. Both RT and RP should be seen as part of a multimodal treatment plan with possible addition of (postoperative) RT and/or androgen deprivation therapy (ADT), respectively. High levels of evidence exist for EBRT treatment, with several randomized clinical trials showing superior outcome for adding long-term ADT or BT to EBRT. No clear cutoff can be proposed for RT dose, but higher RT doses by means of dose escalation schemes result in an improved biochemical control. Twenty studies reported data on QoL, with RP resulting mainly in genitourinary toxicity and sexual dysfunction, and EBRT in bowel problems. Conclusions: Based on the results of this systematic review, both RP as part of multimodal treatment and EBRT + long-term ADT can be recommended as primary treatment in high-risk and locally advanced PCa. For high-risk PCa, EBRT + BT can also be offered despite more grade 3 toxicity. Interestingly, for selected patients, for example, those with higher comorbidity, a shorter duration of ADT might be an option. For locally advanced PCa, EBRT + BT shows promising result but still needs further validation. In this setting, it is important that patients are aware that the offered therapy will most likely be in the context a multimodality treatment plan. In particular, if radiation is used, the combination of local with systemic treatment provides the best outcome, provided the patient is fit enough to receive both. Until the results of the SPCG15 trial are known, the optimal local treatment remains a matter of debate. Patients should at all times be fully informed about all available options, and the likelihood of a multimodal approach including the potential side effects of both local and systemic treatment. Patient summary: We reviewed the literature to see whether the evidence from clinical studies would tell us the best way of curing men with aggressive prostate cancer that had not spread to other parts of the body such as lymph glands or bones. Based on the results of this systematic review, there is good evidence that both surgery and radiation therapy are good treatment options, in terms of prolonging life and preserving quality of life, provided they are combined with other treatments. In the case of surgery this means including radiotherapy (RT), and in the case of RT this means either hormonal therapy or combined RT and brachytherapy.

PURPOSE Provide evidence- and expert-based recommendations for optimal use of imaging in advanced prostate cancer. Due to increases in research and utilization of novel imaging for advanced prostate cancer, this guideline is intended to outline techniques available and provide recommendations on appropriate use of imaging for specified patient subgroups. METHODS An Expert Panel was convened with members from ASCO and the Society of Abdominal Radiology, American College of Radiology, Society of Nuclear Medicine and Molecular Imaging, American Urological Association, American Society for Radiation Oncology, and Society of Urologic Oncology to conduct a systematic review of the literature and develop an evidence-based guideline on the optimal use of imaging for advanced prostate cancer. Representative index cases of various prostate cancer disease states are presented, including suspected high-risk disease, newly diagnosed treatment-naïve metastatic disease, suspected recurrent disease after local treatment, and progressive disease while undergoing systemic treatment. A systematic review of the literature from 2013 to August 2018 identified fully published English-language systematic reviews with or without meta-analyses, reports of rigorously conducted phase III randomized controlled trials that compared ≥ 2 imaging modalities, and noncomparative studies that reported on the efficacy of a single imaging modality. RESULTS A total of 35 studies met inclusion criteria and form the evidence base, including 17 systematic reviews with or without meta-analysis and 18 primary research articles. RECOMMENDATIONS One or more of these imaging modalities should be used for patients with advanced prostate cancer: conventional imaging (defined as computed tomography [CT], bone scan, and/or prostate magnetic resonance imaging [MRI]) and/or next-generation imaging (NGI), positron emission tomography [PET], PET/CT, PET/MRI, or whole-body MRI) according to the clinical scenario.

Prostate cancer; Olaparib; Gene aberrations Càncer de pròstata; Olaparib; Aberracions de gens Cáncer de próstata; Olaparib; Aberraciones de genes Background: Metastatic castration-resistant prostate cancer is enriched in DNA damage response (DDR) gene aberrations. The TOPARP-B trial aims to prospectively validate the association between DDR gene aberrations and response to olaparib in metastatic castration-resistant prostate cancer. Methods: In this open-label, investigator-initiated, randomised phase 2 trial following a selection (or pick-the-winner) design, we recruited participants from 17 UK hospitals. Men aged 18 years or older with progressing metastatic castration-resistant prostate cancer previously treated with one or two taxane chemotherapy regimens and with an Eastern Cooperative Oncology Group performance status of 2 or less had tumour biopsies tested with targeted sequencing. Patients with DDR gene aberrations were randomly assigned (1:1) by a computer-generated minimisation method, with balancing for circulating tumour cell count at screening, to receive 400 mg or 300 mg olaparib twice daily, given continuously in 4-week cycles until disease progression or unacceptable toxicity. Neither participants nor investigators were masked to dose allocation. The primary endpoint of confirmed response was defined as a composite of all patients presenting with any of the following outcomes: radiological objective response (as assessed by Response Evaluation Criteria in Solid Tumors 1.1), a decrease in prostate-specific antigen (PSA) of 50% or more (PSA50) from baseline, or conversion of circulating tumour cell count (from ≥5 cells per 7·5 mL blood at baseline to

Radiation therapy is a common treatment for prostate cancer, however recurrence remains a problem. MicroRNA expression is altered in prostate cancer and may promote therapy resistance. Through bioinformatic analyses of TCGA and CPC-GENE patient cohorts, we identified higher miR-191 expression in tumor versus normal tissue, and increased expression in higher Gleason scores. In vitro and in vivo experiments demonstrated that miR-191 overexpression promotes radiation survival, and contributes to a more aggressive phenotype. Retinoid X receptor alpha, RXRA, was discovered to be a novel target of miR-191, and knockdown recapitulated radioresistance. Furthermore, treatment of prostate cancer cells with the RXRA agonist 9-cis-retinoic acid restored radiosensitivity. Supporting this relationship, patients with high miR-191 and low RXRA abundance experienced quicker biochemical recurrence. Reduced RXRA translated to a higher risk of distant failure after radiotherapy. Notably, this miR-191/RXRA interaction was conserved in a novel primary cell line derived from radiorecurrent prostate cancer. Together, our findings demonstrate that miR-191 promotes prostate cancer survival after radiotherapy, and highlights retinoids as a potential option to improve radiotherapy response.

Background In this study, a novel pelvic phantom was developed and used to assess the visibility and presence of artefacts from different types of commercial fiducial markers (FMs) on multi-modality imaging relevant to prostate cancer. Methods and materials The phantom was designed with 3D printed hollow cubes in the centre. These cubes were filled with gel to mimic the prostate gland and two parallel PVC rods were used to mimic bones in the pelvic region. Each cube was filled with gelatine and three unique FMs were positioned with a clinically-relevant spatial distribution. The FMs investigated were; Gold Marker (GM) CIVCO, GM RiverPoint, GM Gold Anchor (GA) line and ball shape, and polymer marker (PM) from CIVCO. The phantom was scanned using several imaging modalities typically used to image prostate cancer patients; MRI, CT, CBCT, planar kV-pair, ExacTrac, 6MV, 2.5MV and integrated EPID imaging. The visibility of the markers and any observed artefacts in the phantom were compared to in-vivo scans of prostate cancer patients with FMs. Results All GMs were visible in volumetric scans, however, they also had the most visible artefacts on CT and CBCT scans, with the magnitude of artefacts increasing with FM size. PM FMs had the least visible artefacts in volumetric scans but they were not visible on portal images and had poor visibility on lateral kV images. The smallest diameter GMs (GA) were the most difficult GMs to identify on lateral kV images. Conclusion The choice between different FMs is also dependent on the adopted IGRT strategy. PM was found to be superior to investigated gold markers in the most commonly used modalities in the management of prostate cancer; CT, CBCT and MRI imaging.

Sexual issues and treatment side effects are not routinely discussed with men receiving treatment for prostate cancer, and support to address these concerns is not consistent across settings. This study evaluates a brief e-learning resource designed to improve sexual wellbeing support and examine its effects on healthcare professionals’ sexual attitudes and beliefs. Healthcare professionals (n = 44) completed an online questionnaire at baseline which included a modified 12-item sexual attitudes and beliefs survey (SABS). Follow-up questionnaires were completed immediately after the e-learning and at 4 weeks. Data were analysed using one-way, repeat measures ANOVAs to assess change in attitudes and beliefs over time. Significant improvements were observed at follow-up for a number of survey statements including ‘knowledge and understanding’, ‘confidence in discussing sexual wellbeing’ and the extent to which participants felt ‘equipped with the language to initiate conversations’. The resource was seen as concise, relevant to practice and as providing useful information on potential side effects of treatment. In brief, e-learning has potential to address barriers to sexual wellbeing communication and promote delivery of support for prostate cancer survivors. Practical methods and resources should be included with these interventions to support implementation of learning and long-term changes in clinical behaviour.

Background Sexual dysfunction is a frequent side effect associated with different prostate cancer treatment approaches. It can have a substantial impact on men and their partners and is associated with increased psychological morbidity. Despite this, sexual concerns are often not adequately addressed in routine practice. Evidence-based web-based interventions have the potential to provide ongoing information and sexual well-being support throughout all stages of care. Objective The aim of this study is to examine the efficacy of a web-based self-management intervention designed to maximize sexual well-being in men living with prostate cancer and explore user perspectives on usability and acceptability. Methods We used a single-arm study design, and participants were provided with access to the 5-step intervention for a period of 3 months. The intervention content was tailored based on responses to brief screening questions on treatment type, relationship status, and sexual orientation. Efficacy was assessed by using two-tailed, paired sample t tests for comparing the mean differences between pre- and postintervention measurements for exploring the participants’ self-reported knowledge and understanding, sexual satisfaction, and comfort in discussing sexual issues. Usability and acceptability were determined based on the program use data and a postintervention survey for exploring perceived usefulness. Results A total of 109 participants were recruited for this study. Significant postintervention improvements at follow-up were observed in the total scores (out of 20) from the survey (mean 12.23/20 points, SD 2.46 vs mean 13.62/20, SD 2.31; t88=9.570; P=.001) as well as in individual item scores on the extent to which the participants agreed that they had sufficient information to manage the impact that prostate cancer had on their sex life (mean 2.31/4 points, SD 0.86 vs mean 2.57/4, SD 0.85; t88=3.660; P=.001) and had the potential to have a satisfying sex life following treatment (mean 2.38/4 points, SD 0.79 vs mean 3.17/4, SD 0.78; t88=7.643; P=.001). The median number of intervention sessions was 3 (range 1-11), and intervention sessions had a median duration of 22 minutes (range 8-77). Acceptable usability scores were reported, with the highest result observed for the question on the extent to which the intervention provided relevant information. Conclusions This study provides evidence on the efficacy of a tailored web-based intervention for maximizing sexual well-being in men living with prostate cancer. The results indicate that the intervention may improve one’s self-perceived knowledge and understanding of how to manage sexual issues and increase self-efficacy or the belief that a satisfactory sex life could be achieved following treatment. The findings will be used to refine the intervention content before testing as part of a larger longitudinal study for examining its effectiveness.

Introduction Dysregulated lipid metabolism is a hallmark of prostate cancer. Furthermore, use of the cholesterol lowering statin drugs has been linked to a reduced risk of lethal prostate cancer. To understand the molecular pathways implicated in this relationship, we examined the association between differential expression of genes involved in intratumoral cholesterol metabolism in prostate tumor biopsies and prostate cancer-specific outcomes. Methods Tumor biopsy gene expression data from 242 men diagnosed with localized/locally advanced prostate cancer and treated with radiotherapy and androgen deprivation therapy was analyzed. A total of 71 genes involved in cholesterol transport, biosynthesis and regulation were selected from the Reactome pathway database, with additional genes involved in cholesterol metabolism extracted from literature. For each gene, expression levels were dichotomized by median expression level. Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations of gene expression with biochemical recurrence and metastasis. Models were adjusted for age at diagnosis and Gleason score. Multiple-testing correction was performed using the Bonferroni correction method. Results During a median follow-up of 10.4 years, 72 (30%) patients experienced biochemical recurrence and 32 (13%) developed metastatic disease. Differential expression of several genes was found to be associated with risk of biochemical recurrence and metastasis, though none remained statistically significant following Bonferroni correction. However, several genes showed similar patterns of association with risk of biochemical recurrence and of metastasis, an association which remained similar following adjustment for age and Gleason score. Low (below median) expression of FDFT1, a gene encoding squalene synthase, a key enzyme in cholesterol biosynthesis, was associated with an increased risk of biochemical recurrence (HR 1.87; 95% CI, 1.15-3.01) and metastasis (HR 3.52; 95% CI, 1.52-8.16). High (above median) expression of SLCO1B3, a gene encoding an organic anion transporting polypeptide transporting a variety of small molecules including statins, was associated with higher risk of biochemical recurrence (HR 2.14; 95% CI, 1.31-3.49) and metastasis (HR 2.70; 95% CI, 1.25-5.90). Conclusion These hypothesis-generating results point to a potential role for altered intratumoral cholesterol metabolism in prostate cancer-specific outcomes. Our findings highlighting differential expression of FDFT1 and SLCO1B3, genes involved in cholesterol biosynthesis and anion transport, respectively, in association with risk of biochemical recurrence and metastasis may provide clues as to the mechanistic pathways of most importance. Validation in other prostate cancer gene expression datasets is required. Citation Format: Sarah J. Winter, Sophia Halliday, Konrad H. Stopsack, Sarah O. Osman, Alan R. Hounsell, Gillian Prue, Suneil Jain, Emma H. Allott. Cholesterol metabolism gene expression and prostate cancer-specific outcomes in radiotherapy-treated patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 162.

To assess the association between colorectal cancer (CRC) histology, dose, and local failure (LF) after stereotactic ablative radiation therapy (SABR) for pulmonary metastases, and to describe subsequent cancer progression, change of systemic therapy (CST), survival, and their association with treatment indications.From a prospective SABR cohort, 180 pulmonary metastases in 120 patients were identified. Treatment indications were single metastasis, oligometastases, oligoprogression, and dominant areas of progression. Doses of 48 to 52 Gy/4 to 5 fractions were delivered. Since 2010 the dose for peripheral CRC metastases was increased to 60 Gy/4 fractions. Cumulative incidence function (CIF) was used to report LF, progression probability, and CST. The Kaplan-Meier method estimated overall survival (OS). Univariate and multivariable analyses to assess variable associations were conducted.Median follow-up was 22 months (interquartile range, 14-33 months). At 24 months, the CIF of LF was 23.6% (95% confidence interval [CI] 15.1%-33.3%) and 8.3% (95% CI 2.6%-18.6%), respectively, for CRC and non-CRC metastases (P.001). This association remained significant after adjusting for confounders (subdistribution hazard ratio [SHR] 13.6, 95% CI 4.2-44.1, P.001). Among CRC metastases, 56 and 45 received60 Gy and 60 Gy, respectively. Delivering 60 Gy was independently associated with a lower hazard of LF (SHR 0.271, 95% CI 0.078-0.940, P=.040). At 12 months the CIF of progression was 41.67% (95% CI 21.69%-60.56%), 42.51% (95% CI 29.09%-55.29%), 62.96% (95% CI 41.25%-78.53%), and 78.57% (95% CI 42.20%-93.48%), respectively, for patients treated for single metastasis, oligometastases, oligoprogression, and dominant area of progression (P.001). A CST was observed, respectively, in 4 (17%), 17 (31%), 12 (44%), and 10 (71%) patients with a median time of 13.1, 11.1, 8.4, and 8.4 months.Colorectal cancer lung metastases are associated with a higher hazard of LF and require higher SABR doses. Outcomes for patients with oligometastases and oligoprogression treated with SABR seem favorable. Prospective clinical trials are needed to confirm these benefits.

Purpose This work presents the application of a machine learning (ML) algorithm to automatically generate high-quality, prostate low-dose-rate (LDR) brachytherapy treatment plans. The ML algorithm can mimic characteristics of preoperative treatment plans deemed clinically acceptable by brachytherapists. The planning efficiency, dosimetry, and quality (as assessed by experts) of preoperative plans generated with an ML planning approach was retrospectively evaluated in this study. Methods and Materials Preimplantation and postimplantation treatment plans were extracted from 100 high-quality LDR treatments and stored within a training database. The ML training algorithm matches similar features from a new LDR case to those within the training database to rapidly obtain an initial seed distribution; plans were then further fine-tuned using stochastic optimization. Preimplantation treatment plans generated by the ML algorithm were compared with brachytherapist (BT) treatment plans in terms of planning time (Wilcoxon rank sum, α = 0.05) and dosimetry (1-way analysis of variance, α = 0.05). Qualitative preimplantation plan quality was evaluated by expert LDR radiation oncologists using a Likert scale questionnaire. Results The average planning time for the ML approach was 0.84 ± 0.57 minutes, compared with 17.88 ± 8.76 minutes for the expert planner ( P =.020). Preimplantation plans were dosimetrically equivalent to the BT plans; the average prostate V150% was 4% lower for ML plans ( P =.002), although the difference was not clinically significant. Respondents ranked the ML-generated plans as equivalent to expert BT treatment plans in terms of target coverage, normal tissue avoidance, implant confidence, and the need for plan modifications. Respondents had difficulty differentiating between plans generated by a human or those generated by the ML algorithm. Conclusions Prostate LDR preimplantation treatment plans that have equivalent quality to plans created by brachytherapists can be rapidly generated using ML. The adoption of ML in the brachytherapy workflow is expected to improve LDR treatment plan uniformity while reducing planning time and resources.

Purpose: To assess the applicability of active surveillance in patients with intermediate risk prostate cancer, we compared the survival outcomes of patients with low risk and intermediate risk disease.Materials and Methods: Active surveillance was offered to all patients with low risk (cT1-T2b and Gleason score 6 and prostate specific antigen 10 ng/ml or less) and select intermediate risk disease (age greater than 70 years with cT2c or prostate specific antigen 15 ng/ml or less, or Gleason score 3+4 or less). Data from November 1995 to May 2013 were extracted from a prospectively collected database. The primary outcome was metastasis-free survival, and secondary outcomes were overall survival, cause specific survival and treatment-free survival.Results: A total of 213 intermediate risk and 732 low risk cases were identified. Median age was 72 years (IQR 67.3, 76.8) in the intermediate risk cohort and 67 years (IQR 60.6, 71.9) in the low risk group. Median followup was comparable (6.7 years for intermedia...

Prostate cancer (PCa) is the most common non-cutaneous cancer in men and a notable cause of cancer mortality when it metastasises. Localised disease is mostly treated with surgery or radiotherapy. As PCa develops and treatment resistance emerges, the unfolded protein response (UPR) arises as an important adaptive biology co-amplifying with key cancer drivers [1]. The UPR can be cytoprotective but when acutely activated can lead to cell death. In this study we sought to enhance the acute activation of the UPR using radiation and ONC201, previously reported to be an UPR activator [2]. We found that treating PCa cells with ONC201 quickly increases the expression of components in all arms of the UPR – ATF4, ATF6 and IRE1-XBP1 – culminating in the subsequent cell death. During this time window between UPR activation and cell death we tested the priming effect of short-term administration of ONC201 on radiation responses. Pre-treatment with ONC201 for 24 hours prior to irradiation led to enhanced cytotoxicity compared to radiation alone assessed by cell viability and clonogenic assays. With priming, RNA-Seq analysis showed a sustained suppression of transcripts encoding cell cycle regulators as well as components of the DNA damage response pathways. Phenotypically this was reflected in enhanced cell cycle arrest and induction of necrosis and apoptosis. Furthermore, we demonstrated that short-term administration of inhibitors of cell cycle regulators (Dinaciclib and BI2536), could replicate this priming effect. Thus, we propose future studies to assess the impact of the short-term administration of drugs targeting the UPR and cell cycle regulation to enhance radiotherapy response.

Purpose: To explore the role of Computed tomography (CT)-based radiomics features in prostate cancer risk stratification.Methods and Materials: The study population consisted of 506 patients with prostate cancer collected from a clinically annotated database. After applying exclusion criteria, 342 patients were included in the final analysis. CT-based radiomics features were extracted from planning CT scans for prostate gland-only structure, and machine learning was used to train models for Gleason score (GS) and risk group (RG) classifications. Repeated cross-validation was used. The discriminatory performance of the developed models was assessed using receiver operating characteristic area under the curve (AUC) analysis.Results: Classifiers using CT-based radiomics features distinguished between GS = 7 with AUC = 0.90 and GS 7(3 + 4) versus GS 7(4 + 3) with AUC = 0.98. Developed classifiers also showed excellent performance in distinguishing low versus high RG (AUC = 0.96) and low versus intermediate RG (AUC = 1.00), but poorer performance was observed for GS 7 versus GS > 7 (AUC = 0.69). An overall modest performance was observed for validation on holdout data sets with the highest AUC of 0.75 for classifiers of low versus high RG and an AUC of 0.70 for GS 7 versus GS > 7.Conclusions: Our results show that radiomics features from routinely acquired planning CT scans could provide insights into prostate cancer aggressiveness in a noninvasive manner. Assessing models on training data sets, the classifiers were especially accurate in discerning high-risk from low-risk patients and in classifying GS 7 versus GS > 7 and GS 7(3 + 4) versus G 7(4 + 3); however, classifiers were less adept at distinguishing high RG versus intermediate RG. External validation and prospective studies are warranted to verify the presented findings. These findings could potentially guide targeted radiation therapy strategies in radical intent radiation therapy for prostate cancer. (C) 2019 Elsevier Inc. All rights reserved.

OBJECTIVE:: To assess the accuracy and efficiency of four different techniques, thus determining the optimum method for recalculating dose on cone beam CT (CBCT) images acquired during radiotherapy treatments.METHODS:: Four established techniques were investigated and their accuracy assessed via dose calculations: (1) applying a standard planning CT (pCT) calibration curve, (2) applying a CBCT site-specific calibration curve, (3) performing a density override and (4) using deformable registration. Each technique was applied to 15 patients receiving volumetric modulated arc therapy to one of three treatment sites, head and neck, lung and prostate. Differences between pCT and CBCT recalculations were determined with dose volume histogram metrics and 2.0%/0.1 mm gamma analysis using the pCT dose distribution as a reference.RESULTS:: Dose volume histogram analysis indicated that all techniques yielded differences from expected results between 0.0 and 2.3% for both target volumes and organs at risk. With volumetric gamma analysis, the dose recalculation on deformed images yielded the highest pass-rates. The median pass-rate ranges at 50% threshold were 99.6-99.9%, 94.6-96.0%, and 94.8.0-96.0% for prostate, head and neck and lung patients, respectively.CONCLUSION:: Deformable registration, HU override and site-specific calibration curves were all identified as dosimetrically accurate and efficient methods for dose calculation on CBCT images.ADVANCES IN KNOWLEDGE:: With the increasing adoption of CBCT, this study provides clinical radiotherapy departments with invaluable information regarding the comparison of dose reconstruction methods, enabling a more accurate representation of a patient's treatment. It can also integrate studies in which CBCT is used in image-guided radiation therapy and for adaptive radiotherapy planning processes.

High-dose-rate brachytherapy boost plus external beam radiation therapy is an established option for intermediate-risk prostate cancer (PCa). Stereotactic body radiation therapy (SBRT) boost can potentially mimic high-dose-rate boost and could be a viable alternative. Here we report the long-term outcomes of a phase 1 dose-escalation trial of single-fraction SBRT boost.Patients had intermediate-risk PCa and were accrued to 3 different SBRT single-fraction dose-level cohorts (10 Gy, 12.5 Gy, and 15 Gy). All received supplemental radiation therapy afterwards (37.5 Gy in 15 fractions). Three gold fiducials were implanted for image guidance. Patients were simulated and treated with a foley catheter and intrarectal balloon. A T2 magnetic resonance imaging scan was used for contouring, and a cine magnetic resonance imaging scan was used to calculate patient-specific internal target volume margins. Toxicity and quality-of-life data were collected using Common Terminology Criteria for Adverse Events v3.0 and the Expanded Prostate Cancer Index Composite.30 patients were accrued, 10 in each cohort. Median follow-up was 72 months. 60% had unfavorable intermediate-risk PCa. Two patients in the 15 Gy cohort developed late grade ≥3 gastrointestinal and genitourinary toxicity, with 1 patient suffering from a grade-4 rectal fistula after a rectal ulcer was biopsied repeatedly. Two patients had biochemical failure. Median PSA nadir was 0.4 ng/mL with 10 Gy, 0.09 ng/mL with 12.5 Gy and 0.07 ng/mL with 15 Gy. Median PSA at 4 years as well as proportion achieving a nadir0.2 ng/mL improved significantly with higher doses. There was no significant change in quality of life from baseline in any of the domains, and the minimal clinically important change was not statistically different between the 3 cohorts.Other than a grade 4 toxicity, which may in part be due to repeated biopsies of a rectal ulcer, single-fraction SBRT boost was feasible and well tolerated. Larger studies are warranted to better document the outcomes of such an approach.

Men with metastatic castrate-resistant prostate cancer can experience an array of treatment-related side effects. Accumulating evidence suggests exercise may alleviate some of these adversities and assist in disease management. However, empirical evidence in advanced prostate cancer patients remains limited. The purpose of this study is to determine whether men with metastatic prostate cancer, who are ineligible for high-intensity exercise, can partake in a home-based, moderate-intensity exercise program and the impact of doing so on quality of life and physical fitness parameters. Thirty men with adenocarcinoma of the prostate and progressive systemic, metastatic disease will be recruited. Clinicians will screen patients against inclusion criteria to determine eligibility. All men enrolled will be prescribed a tailored, home-based, moderate-intensity exercise intervention consisting of aerobic and strengthening components for 12 weeks. Patients will receive supplementary education materials and weekly behavioural change consultations throughout the intervention. The primary outcome will be the feasibility of delivering such an intervention in men with metastatic disease. Secondary endpoints including skeletal events will be monitored for safety, as will the feasibility of patient-reported outcome measures and the sampling time points, generating data pertaining to completion rates and potential effect in future trials. General physical fitness will be assessed during these visits, using timed sit-to-stand testing and a 6-min walking test. Prior to each visit, objective physical activity levels will be captured for 7 days using an accelerometer, to determine the feasibility of this technology and the quality of data obtained. In parallel with the feasibility aspects of the trial, changes compared to baseline will be reported. Direct regular contact will also serve as a feedback loop, should any issues arise. This study has received ethical approval from the Office for Research Ethics Committees Northern Ireland. This study aims to determine the potential utility of a home-based exercise intervention in managing side effects associated with advanced prostate cancer and its treatment. This feasibility trial will inform the design and implementation of a larger randomised control trial to determine the efficacy of moderate aerobic and strengthening exercise as an adjuvant therapy in men with metastatic prostate cancer. Collecting such evidence provides further support for exercise in this paradigm and potential for its inclusion as a low-toxicity therapy in standard cancer care, in the longer term. ClinicalTrials.gov, NCT03658486 Trial sponsor: Queen’s University Belfast (Reference: B18/15). Contact: Dr. Paula Tighe, Research and Enterprise, Queen’s University Belfast. Telephone: 02890 973,296. Email: p.tighe@qub.ac.uk . The sponsor reviewed the protocol and ethical application prior to submission. Protocol issue: Version 1 (18th May 2018). Authors: MB, MM, SJ and GP.

Additional file 1 : Figure S1. Typical IGRT workflow used for EBRT with CBCT. Figure S2. Distribution of CIVCO FMs in 6 consecutive patients in 3D, each colour represents a different FM location and the solid circle represents the average position for each marker. Table ST1. FM position consistency over a four weeks period. Table ST2. Scanners and scanning parameters and specifications patients’ volumetric imaging for patients presented in Fig. 4 of the main manuscript. Table ST3. Image specification and window levels settings used for planar images presented on Fig. 3. Figure S3. Intensity profiles showing each fiducial and surrounding intensities on CT (left) and CBCT scans using the pelvic phantom (red solid lines) and from prostate cancer patient with matching FMs (black dotted). Figure S4. Intensity profiles showing each fiducial and surrounding intensities on MRI scans using the pelvic phantom (red solid lines) and prostate cancer patients (black dotted lines). Original MRI signal intensity values on the left and normalized values on the right. Figure S5. Line profiles across corresponding axial slices of one of the boxes with Gold Anchor FMs and surrounding intensities on different sequences of MRI scans. Figure S6. Axial CT slices of boxes with different FM acquired using different CT slice thickness and the corresponding contrast-to-noise ratio (CNR) and HighHU artefact and LowHU artefacts. The CNR value for each FM were calculated using the Eclipse TPS. Background HU for gel (Mean±SD) were; 52.8 ± 33.6 for CT with 0.625 mm slice thickness, 52.8 ± 29.3 for CT with 1.25 mm scans and 50.5 ± 20.8 for CT with 2.5 mm slice thickness. The HighHU and LowHU artefacts were calculated relative to background (Gel) HU ± 3SD. * Indicates the presence of artefact from the box wall leading to unreliable measurements.

248 Background: Stereotactic Ablative Radiotherapy (SABR) is increasingly used to treat low/intermediate risk localised prostate cancer (PCa). However, data on SABR +/- pelvic nodal irradiation (PNI) in high-risk disease is limited to single institution, single-arm studies. The Stereotactic Prostate Radiotherapy (SPORT) trial examined the feasibility of delivering a randomised trial of SABR ± PNI. The composite primary endpoint to determine feasibility comprised: recruitment rate, technical feasibility, acute toxicity (CTCAE v4.0) and quality of life (QoL)(EPIC). Secondary and exploratory endpoints including late toxicity (RTOG) and QoL and potential biomarkers of toxicity (plasma citrulline and DNA damage in circulating lymphocytes) are also presented. Methods: Men with localised PCa demonstrating one of T3a, Gleason score ≥4+3 or PSA>20 were eligible. T3b and T4 disease were excluded. 30 participants were randomised 1:1 to prostate SABR (P-SABR) or prostate and pelvis SABR (PPN-SABR). The prostate and proximal 1-2cm seminal vesicles received 36.25 Gy in 5 fractions over 29 days (prostate CTV 40Gy). The PPN-SABR arm also received 25 Gy in 5 fractions to the pelvic nodes. All patients had fiducial markers and a rectal spacer gel in-situ. As initial toxicity rates were low, the final 10 men received an additional integrated boost to the dominant intraprostatic lesion of up to 50 Gy, irrespective of randomisation. Results: Feasibility was demonstrated. The target recruitment of 30 men was met (83% high risk). Treatment, including an integrated boost plus PNI, was achievable using strict normal tissue constraints. Acute toxicity and QoL were acceptable (Table: Grade≥2 GU 7%, 27% and GI 0%, 7%; minimal clinically important change (MCIC) in EPIC urinary 40%, 60% and bowel score 33%, 47% in P and PPN arms respectively). At median follow up of 30 months (range 18-42 months), late toxicity and QoL were acceptable (Grade≥2 GU 7%, 20% and GI 0%, 13%; MCIC in EPIC urinary 33%, 67% and bowel score 33%, 67% in P and PPN arms respectively). All toxicity was ≤ grade 2 with the exception of one late grade 3 GU toxicity occurring in the PPN arm. Serum citrulline, a marker of small bowel function, trended towards lower levels in the PPN arm, in keeping with a significantly higher dose delivered to the small bowel in this arm. DNA damage foci in circulating lymphocytes increased at 1 hour after radiation. Foci count and repair correlated to toxicity measures will be presented. Conclusions: A randomised clinical trial comparing P-SABR to PPN-SABR is feasible. There was a suggestion of increased toxicity with PPN-SABR, but this remained acceptable. This data will inform a UK multi-centre phase 2 study. Clinical trial information: NCT03253978 . [Table: see text]

Objectives: The isotope bone scan (IBS) is the gold-standard imaging modality for detecting skeletal metastases as part of prostate cancer staging. However, its clinical utility for assessing skeletal metastatic burden is limited due to the need for subjective interpretation. We designed and tested a novel custom software tool, the Metastatic Bone Scan Tool (MetsBST), aimed at improving interpretation of IBSs, and compared its performance with that of an established software programme. Methods: We used IBS images from 62 patients diagnosed with prostate cancer and suspected bone metastases to design and implement MetsBST in MATLAB by defining thresholds used to identify the texture and size of metastatic bone lesions. The results of MetsBST were compared with those of the commercially available automated Bone Scan Index (aBSI) with regression analysis. Results: There was strong agreement between the MetsBST and aBSI results (R2 = 0.9189). In a subregional analysis, MetsBST quantified the extent of metastatic disease in multiple bone sites in patients receiving multimodality therapy (radium-223 and external beam radiotherapy) to illustrate the differences in bone metastatic response to different treatments. Conclusion: The results of MetsBST and the commercial software aBSI were highly consistent. MetsBST introduces novel clinical utility by its ability to differentiate between the responses of different bone metastases to multimodality therapies. Advances in knowledge: MetsBST reduces the variability in assessment of tumour burden caused by subjective interpretation. Therefore, it is a useful aid to physicians reporting nuclear medicine scans, and may improve decision-making in the treatment of metastatic prostate cancer.

Background and purpose Stereotactic ablative radiotherapy (SABR) has become standard for inoperable early-stage non-small cell lung cancer (NSCLC). However, there is no randomized evidence demonstrating benefit over more fractionated radiotherapy. We compared accelerated hypofractionation (AH) and SABR using a propensity score-matched analysis. Materials and methods From 1997–2007, 119 patients (T1–3N0M0 NSCLC) were treated with AH (48–60 Gy, 12–15 fractions). Prior to SABR, this represented our institutional standard. From 2008–2012, 192 patients (T1–3N0M0 NSCLC) were treated with SABR (48–52 Gy, 4–5 fractions). A total of 114 patients (57 per cohort) were matched (1:1 ratio, caliper: 0.10) using propensity scores. Results Median follow-up (range) for the AH cohort was 36.3 (2.5–109.1) months, while that for the SABR group was 32.5 (0.3–62.6) months. Three-year overall survival (OS) and local control (LC) rates were 49.5% vs. 72.4% [p = 0.024; hazard ratio (HR): 2.33 (1.28, 4.23), p = 0.006] and 71.9% vs. 89.3% [p = 0.077; HR: 5.56 (1.53, 20.2), p = 0.009], respectively. On multivariable analysis, tumour diameter and PET staging were predictive for OS, while the only predictive factor for LC was treatment cohort. Conclusions OS and LC were improved with SABR, although OS is more closely related to non-treatment factors. This represents one of the few studies comparing AH to SABR for early-stage lung cancer.

To determine the incidence and predictive factors of rib fracture and chest wall pain after lung stereotactic ablative radiotherapy (SABR).Patients were treated with lung SABR of 48-60 Gy in four to five fractions. The treatment plan and follow-up computed tomography scans of 289 tumours in 239 patients were reviewed. Dose-volume histogram (DVH) metrics and clinical factors were evaluated as potential predictors of chest wall toxicity.The median follow-up was 21.0 months (range 6.2-52.1). Seventeen per cent (50/289) developed a rib fracture, 44% (22/50) were symptomatic; the median time to fracture was 16.4 months. On univariate analysis, female gender, osteoporosis, tumours adjacent (within 5 mm) to the chest wall and all of the chest wall DVH metrics predicted for rib fracture, but only tumour location adjacent to the chest wall remained significant on the multivariate model (P0.01). The 2 year fracture-free probability for those adjacent to the chest wall was 65.6%. Among those tumours adjacent to the chest wall, only osteoporosis (P = 0.02) predicted for fracture, whereas none of the chest wall DVH metrics were predictive. Eight per cent (24/289) experienced chest wall pain without fracture.None of the chest wall DVH metrics independently predicted for SABR-induced rib fracture when tumour location is taken into account. Patients with tumours adjacent (within 5 mm) to the chest wall are at greater risk of rib fracture after lung SABR, and among these, an additional risk was observed in osteoporotic patients.

136 Background: Radiotherapy to the Prostate in mHSPC improves overall survival (OS) and Progression free survival (PFS) for patients with low-volume-disease[1]. Radium-223 in metastatic castration resistant prostate cancer (mCRPC) improves OS [2]. We conducted a prospective phase 1/2 clinical trial in mHSPC, testing the combination of with LHRHa, concurrent pelvic radiotherapy and radium-223. Methods: Thirty patients were recruited with mHSPC; they had a minimum of 3 bone metastases (majority had > 20 bone mets), nil visceral metastases, PS0-1. Patients were encouraged to receive up front docetaxel. They were treated with ongoing LHRHa, pelvic radiotherapy aiming for 74Gy in 37 fractions to prostate PTV with 60Gy concomitantly delivered to pelvic nodal PTV. Concurrently, patients received radium-223, 55kBq/kg for 6 cycles q28 days; fraction 1 radiotherapy was synchronous with cycle 1 day 1 radium-223. Results: Median age was 63 years and 28 (93%) received at least 4 cycles of docetaxel. One patient received prostate only radiotherapy due to bowel constraints. Three patients had cycle 6 radium-223 omitted. At a median follow-up of 28 months, there have been 415 Adverse events, (3% Grade >3), and 6 serious adverse events (SAEs) ( 2 episodes of UTI, 1 each of cystitis non-infective, cardiac chest pain, pyrexia and AKI). Commonest AEs by number were: leucopenia, neutropenia, and diarrhoea. Ten SSE’s have occurred including 8 courses of palliative radiotherapy for bone pain, 1 course of radiotherapy for impending MSCC and 1 pathological fracture. At median follow up 28.0 months, median biochemical PFS is 17.9 months, median OS not yet reached. Conclusions: This trial shows clear tolerability and promising early efficacy data requiring further exploration in a randomised phase 3 trial. Clinical trial information: 2014-000273-39.

IntroductionProstate cancer is the most common male cancer with one in four developing non-curable metastatic disease. Initial treatment responses to hormonal therapies are transient and further management options lie between (1) further hormone therapy or (2) a non-hormonal approach involving additional chemotherapy or molecular radiotherapy (radium-223). There is no clear rationale for choosing between these mechanistically different treatment approaches. The biology of hormone resistance is driven through abnormal androgen receptor activity and we can assay this through a blood test measuring androgen receptor variant 7 (AR-V7) expression in circulating tumour cells. Despite increasing evidence supporting AR-V7’s role as a prognostic marker, the clinical utility of such measures remains unknown in helping personalise treatment decisions.Methods and designThe VARIANT feasibility trial is a pragmatic design, to be run over 18 months with participants randomised into the intervention arm receiving biomarker (AR-V7) guided clinical treatment and participants randomised into the control arm with conventional standard management (no biomarker guidance). AR-V7 positive participants (likely to be insensitive to further hormone treatment) will receive chemotherapy or in other cases radium-223 (where routinely available). Seventy male ≥18 years old participants with metastatic castrate resistant prostate cancer clinically indicated to proceed to further hormone therapy or chemotherapy, will be recruited from three National Health Service Trusts based in England, Scotland and Wales. The feasibility primary outcome is willingness of patients to be randomised and clinicians to recruit to a biomarker-based treatment strategy, with trial data informing the basis of a definitive and appropriately powered randomised control trial.Ethics and disseminationFormal ethics review was undertaken with a favourable opinion, through Wales NRES Committee 2 18/WA/0419. Findings to be disseminated through patient and professional organisations that have expressed their support, media outlets and peer-reviewed journal publication.Trial registration numberNCT10246848

This study aims to quantify the incidence and distribution of prostatic calculi in a population of prostate radiotherapy patients and assess their potential role in prostate image guided radiotherapy (IGRT).A retrospective analysis of trans-rectal ultrasound (TRUS), computed tomography (CT) planning and treatment verification cone beam CT (CBCT) scans from radical prostate radiotherapy patients (external beam and brachytherapy) between 2012 and 2014 was undertaken by a single experienced observer. An internationally validated schema from the Prostate Imaging Reporting and Data system (PIRADS) was used to map the location of calculi. The association of calculi with patient and disease characteristics was explored. Data was analysed using SPSS (IBM version 22.0) using descriptive statistical methods and logistic binary regression analysis.389 scan sets from 254 patients were included in the analysis. The overall incidence of calculi was 85% (n = 218) of which 79% (n = 201) were intra-prostatic calculi. The mean number of intra-prostatic calculi was 2 (range 1-10) and the mean size of calculi was 3.7 mm (range 0.5-15 mm). Calculi were most frequently observed in the posterior of the mid-gland (PI-RADs 3p, 9p) and posterior of the apex (PI-RADs 5p, 11p). 99% (n = 135) of CT planning scans with a corresponding CBCT had calculi in the same PIRADs location and all calculi were visible at the last fraction. There was no statistically significant association of calculi and N stage, M stage or Gleason score.A significant proportion of prostate radiotherapy patients have prostatic calculi detectable on pre radiotherapy imaging. Calculi observed on CT were also detectable on CBCT in 99% of cases and remain visible at the end of treatment. These findings add to the growing evidence base supporting the potential of calculi as an alternative to fiducial markers to aid prostate IGRT.

Purpose: To document the current prostate brachytherapy practice across the UK and Ireland and compare with previously published audit results. Material and methods: Participants from 25 centers attending the annual UK & Ireland Prostate Brachytherapy Conference were invited to complete an online survey. Sixty-three questions assessed the center’s experience and staffing, clinician’s experience, clinical selection criteria and scheduling, number of cases per modality in the preceding three years, low-dose-rate (LDR) pre- and post-implant technique and high-dose-rate (HDR) implant technique. Responses were collated, and descriptive statistical analysis performed. Results: Eighteen (72%) centers responded with 17 performing LDR only, 1 performing HDR only, and 6 performing both LDR and HDR. Seventy-one percent of centers have > 10 years of LDR brachytherapy experience, whereas 71% centers that perform HDR brachytherapy have > 5 years of experience. Thirteen centers have 2 or more clinicians performing brachytherapy with 61% of lead consultants performing > 25 cases (LDR + HDR) in 2016. The number of implants (range), that includes LDR and HDR, performed by individual practitioners in 2016 was > 50 by 21%, 25-50 by 38%, and < 25 by 41%. Eight centers reported a decline in LDR monotherapy case numbers in 2016. Number of center’s performing HDR brachytherapy increased in last five years. Relative uniformity in patient selection is noted, and LDR pre- and post-implant dosimetry adheres to published quality guidelines, with an average post-implant D90 of > 145 Gy in 69% of centers in 2014 and 2015 compared to 63% in 2016. The median CT/US volume ratios were > 0.9 ≤ 1.0 (n = 4), > 1.0 ≤ 1.1 (n = 7), and > 1.1 (n = 2). Conclusion: There is considerable prostate brachytherapy experience in the UK and Ireland. An apparent fall in LDR case numbers is noted. Maintenance of case numbers and ongoing compliance with published quality guidelines is important to sustain high quality outcomes.

OBJECTIVE: This study assessed the use of implanted hydrogel rectal spacers for stereotactic ablative radiotherapy-volumetric modulated arc therapy (SABR-VMAT) patients, investigating practicality, dosimetric impact, normal tissue complication probability (NTCP) and early toxicity. METHODS: Data from the first 6 patients treated within a prostate SABR and rectal spacer trial were examined to determine spacer insertion tolerability, resultant changes in treatment planning and dosimetry and early toxicity effects. CT scans acquired prior to spacer insertion were used to generate SABR plans which were compared to post-insertion plans. Plans were evaluated for target coverage, conformity, and organs at risk doses with NTCPs also determined from resultant dose fluences. Early toxicity data were also collected. RESULTS: All patients had successful spacer insertion under local anaesthetic with maximal Grade 1 toxicity. All plans were highly conformal, with no significant differences in clinical target volume dose coverage between pre- and post-spacer plans. Substantial improvements in rectal dose metrics were observed in post-spacer plans, e.g. rectal volume receiving 36 Gy reduced by ≥42% for all patients. Median NTCP for Grade 2 + rectal bleeding significantly decreased from 4.9 to 0.8% with the use of a rectal spacer (p = 0.031). To date, two episodes of acute Grade 1 proctitis have been reported following treatment. CONCLUSION: The spacer resulted in clinically and statistically significant reduction in rectal doses for all patients. ADVANCESIN KNOWLEDGE: This is one of the first studies to investigate the efficacy of a hydrogel spacer in prostate SABR treatments. Observed dose sparing of the rectum is predicted to result in meaningful clinical benefit.

Introduction A study was proposed to examine the impact to patients and the Oncology review team, of extending the role of the Therapeutic Radiographer to undertake follow up review of prostate cancer patients who have completed a radical course of external beam radiotherapy treatment. Method A total of 30 patients attending for routine radiotherapy follow up were included in an observational study. Patients were assigned for review with a Doctor or a Therapeutic Radiographer using 1:1 randomisation and a number of time points were recorded and analysed. Results Of the 44 patients screened, 30 patients were recruited. Average time from scheduled appointment time to departure from clinic was 36 min for both the doctor and Therapeutic Radiographer. The average length of Consultation was 19 min for the Therapeutic Radiographer and 10 min for the Doctor. Average length of wait for patients from scheduled appointment time to being taken for review was 17 min for the Therapeutic Radiographer and 25 min for the Doctor. Of the patients who completed questionnaires, 23/28 had no preference of reviewer, 2/28 declared a preference to be seen by a doctor, whilst 3/28 stated a preference for review with a Therapeutic Radiographer. Conclusion The results of the study are encouraging and should be further investigated in an attempt of developing what would be a very rewarding aspect of the Therapeutic Radiographers role.

To evaluate the permanent prostate brachytherapy (PPB) learning curve using postimplant multisector dosimetric analysis and to assess the correlation between sector -specific dosimetry and patient-reported outcome measures (PROMs).First 200 patients treated with (125)I PPB monotherapy (145 Gy) at a single institution were assessed. Postimplant dosimetry (PID) using CT was evaluated for whole prostate (global) and 12 sectors, assessing minimum dose to 90% of prostate (D90) and dose to 0.1 cm(3) of rectum (D0.1cc). Global and sector PID results were evaluated to investigate changes in D90 with case number. Urinary and bowel PROMs were assessed using the International Prostate Symptom Score and the Expanded Prostate Cancer Index Composite questionnaire. The correlation between global and individual sector PID and urinary/bowel PROMs was also evaluated.Linear regression confirmed a significant improvement in global D90 with case number (r(2) = 0.20; p = 0.001) at a rate of 0.11 Gy/case. Postimplant D90 of base sectors increased at a rate of 0.11-0.15 Gy/case (p = 0.0001) and matched global improvement. The regression lines of midgland and apex sectors were significantly different from global D90 (p = 0.01). Posterior midgland sectors showed a significant reduction in D90 with case number at a rate of 0.13-0.19 Gy/case (p = 0.01). Dose to posterior midgland sectors correlated with rectal D0.1cc dose but not bowel PROMs. Dose to posterior midgland sectors correlated with urinary International Prostate Symptom Score change, which was not apparent when global D90 alone was considered.Sector analysis provided increased spatial information regarding the PPB learning curve. Furthermore, sector analysis correlated with urinary PROMs and rectal dose.

Purpose Active surveillance is increasingly accepted as a treatment option for favorable-risk prostate cancer. Long-term follow-up has been lacking. In this study, we report the long-term outcome of a large active surveillance protocol in men with favorable-risk prostate cancer. Patients and Methods In a prospective single-arm cohort study carried out at a single academic health sciences center, 993 men with favorable- or intermediate-risk prostate cancer were managed with an initial expectant approach. Intervention was offered for a prostate-specific antigen (PSA) doubling time of less than 3 years, Gleason score progression, or unequivocal clinical progression. Main outcome measures were overall and disease-specific survival, rate of treatment, and PSA failure rate in the treated patients. Results Among the 819 survivors, the median follow-up time from the first biopsy is 6.4 years (range, 0.2 to 19.8 years). One hundred forty-nine (15%) of 993 patients died, and 844 patients are alive (censored rate, 85.0%). There were 15 deaths (1.5%) from prostate cancer. The 10- and 15-year actuarial cause-specific survival rates were 98.1% and 94.3%, respectively. An additional 13 patients (1.3%) developed metastatic disease and are alive with confirmed metastases (n = 9) or have died of other causes (n = 4). At 5, 10, and 15 years, 75.7%, 63.5%, and 55.0% of patients remained untreated and on surveillance. The cumulative hazard ratio for nonprostate-to-prostate cancer mortality was 9.2:1. Conclusion Active surveillance for favorable-risk prostate cancer is feasible and seems safe in the 15-year time frame. In our cohort, 2.8% of patients have developed metastatic disease, and 1.5% have died of prostate cancer. This mortality rate is consistent with expected mortality in favorable-risk patients managed with initial definitive intervention.

Aims We report the outcomes of a large lung stereotactic ablative body radiotherapy (SABR) programme for primary non-small cell lung cancer (NSCLC) and pulmonary metastases. The primary study aim was to identify factors predictive for local control. Materials and methods In total, 311 pulmonary tumours in 254 patients were treated between 2008 and 2011 with SABR using 48–60 Gy in four to five fractions. Local, regional and distant failure data were collected prospectively, whereas other end points were collected retrospectively. Potential clinical and dosimetric predictors of local control were evaluated using univariate and multivariate analyses. Results Of the 311 tumours, 240 were NSCLC and 71 were other histologies. The 2 year local control rate was 96% in stage I NSCLC, 76% in colorectal cancer (CRC) metastases and 91% in non-lung/non-CRC metastases. Predictors of better local control on multivariate analysis were non-CRC tumours and a larger proportion of the planning target volume (PTV) receiving ≥100% of the prescribed dose (higher PTV V100). Among the 45 CRC metastases, a higher PTV V100 and previous chemotherapy predicted for better local control. Conclusions Lung SABR of 48–60 Gy/four to five fractions resulted in high local control rates for all tumours except CRC metastases. Covering more of the PTV with the prescription dose (a higher PTV V100) also resulted in superior local control.

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.

Background Radiotherapy is an effective treatment of intermediate/high-risk locally advanced prostate cancer, however,>30% of patients relapse within 5 years. Clinicopathological parameters currently fail to identify patients prone to systemic relapse and those whom treatment intensification may be beneficial. The purpose of this study was to independently validate the performance of a 70-gene Metastatic Assay in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy. Patients and methods A bridging cohort of prostate cancer diagnostic biopsy specimens was profiled to enable optimization of the Metastatic Assay threshold before further independent clinical validation in a cohort of diagnostic biopsies from patients treated with radical radiotherapy and androgen deprivation therapy. Multivariable Cox proportional hazard regression analysis was used to assess assay performance in predicting biochemical failure-free survival (BFFS) and metastasis-free survival (MFS). Results Gene expression analysis was carried out in 248 patients from the independent validation cohort and the Metastatic Assay applied. Ten-year MFS was 72% for Metastatic Assay positive patients and 94% for Metastatic Assay negative patients [HR¼3.21 (1.35–7.67); P¼0.003]. On multivariable analysis the Metastatic Assay remained predictive for development of distant metastases [HR¼2.71 (1.11–6.63); P¼0.030]. The assay retained independent prognostic performance for MFS when assessed with the Cancer of the Prostate Assessment Score (CAPRA) [HR¼3.23 (1.22–8.59); P¼0.019] whilst CAPRA itself was not significant [HR¼1.88, (0.52–6.77); P¼0.332]. A high concordance [100% (61.5–100)] for the assay result was noted between two separate foci taken from 11 tumours, whilst Gleason score had low concordance. Conclusions The Metastatic Assay demonstrated significant prognostic performance in patients treated with radical radiotherapy both alone and independent of standard clinical and pathological variables. The Metastatic Assay could have clinical utility when deciding upon treatment intensification in high-risk patients. Genomic and clinical data are available as a public resource.

Top; dose rate (cGy/h) as a function of time since implant for 125I monotherapy plotted using the equation, Dose rate t = m P D ln 2 t 1 2 .2 t t 1 2 $$ Dose\ rate\ (t)= m P D\left(\frac{ \ln 2}{t_{\raisebox{1ex}{$1$}\!\left/ \!\raisebox{-1ex}{$2$}\right.}}\right){.2}^{\left(\frac{t}{t_{\raisebox{1ex}{$1$}\!\left/ \!\raisebox{-1ex}{$2$}\right.}}\right)} $$ , where t is the elapsed time, mPD is the minimum peripheral dose (=145 Gy for 125I) and t 1 2 $$ {t}_{\raisebox{1ex}{$1$}\!\left/ \!\raisebox{-1ex}{$2$}\right.} $$ is the half-life (=59.43 days for 125I). Bottom; the time required to deliver relative fraction of the prescribed dose, Fractional dose t = 1 − e − t . ln 2 t 1 2 $$ Fractional\ dose(t)=1-{e}^{-\left(\frac{t. \ln 2}{t_{\raisebox{1ex}{$1$}\!\left/ \!\raisebox{-1ex}{$2$}\right.}}\right)} $$ . Reference: Dale RG. The applications of the linear-quadratic dose effect equation to fractionated and protracted therapy. Br J Radiol 1985; 58: 515–28. (PDF 178 kb)

Twelve-sector analysis created by dividing the prostate into three equal lengths along the cranio-caudal axis to form the base, mid-gland, and apex and then subdivide with vertical and horizontal plans generating right/left posterior sectors (reused from (21) with permission from AB Mohamed Yoosuf). (PDF 61 kb)

Appendix A: PTV Expansion Percentage Overlap Example. (DOCX 1032 kb)

Appendix B: Derivation of Population Margins. (DOCX 75Â kb)