Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Factors influencing implementation of evidence-based interventions in public health systems - a model

Objectives: Evidence that health interventions work is not enough to ensure implementation into policy and practice. The complexity of public health systems requires more diverse actions. This paper proposes a conceptual model to enhance understanding of interlinking factors that influence the evidence implementation process. Methods: A literature review was conducted to explore factors that influence the process of evidence implementation in complex public health systems, including research findings and observations from 32 case studies of injury prevention interventions underway in 24 countries and results from evidence research networks. Concepts and themes identified through a critical review were organised, ordered and interlinked to build the model. Results: An Evidence Implementation Model for Public Health Systems and four concepts or themes: Evidence implementation target; Actors involved in implementation; Knowledge transfer; and Barriers and facilitators to evidence implementation were developed to provide a simplified, yet broad framework that highlights multiple factors and back and forth inter-linkages within and between the concepts that influence the uptake of evidence into public health systems policy and practice. Conclusions: Understanding the factors discussed within and amongst the four concepts of this model should ultimately help to positively influence the uptake of evidence into real world public health systems. This model has relevance for decision makers, researchers, knowledge brokers, and implementers

Facilitators and barriers for the adoption, implementation and monitoring of child safety interventions: a multinational qualitative analysis

The efficiency and effectiveness of child safety interventions are determined by the quality of the implementation process. This multinational European study aimed to identify facilitators and barriers for the three phases of implementation: adoption, implementation and monitoring (AIM process). Twenty-seven participants from across the WHO European Region were invited to provide case studies of child safety interventions from their country. Cases were selected by the authors to ensure broad coverage of injury issues, age groups and governance level of implementation (eg, national, regional or local). Each participant presented their case and provided a written account according to a standardised template. Presentations and question and answer sessions were recorded. The presentation slides, written accounts and the notes taken during the workshops were analysed using thematic content analysis to elicit facilitators and barriers. Twenty-six cases (from 26 different countries) were presented and analysed. Facilitators and barriers were identified within eight general themes, applicable across the AIM process: management and collaboration; resources; leadership; nature of the intervention; political, social and cultural environment; visibility; nature of the injury problem and analysis and interpretation. The importance of the quality of the implementation process for intervention effectiveness, coupled with limited resources for child safety makes it more difficult to achieve successful actions. The findings of this study, divided by phase of the AIM process, provide practitioners with practical suggestions, where proactive planning might help increase the likelihood of effective implementation

Development of a Computing Utility to Measure Time-On- Task in Injury Research Studies

Abstract. Quantifying time-on-task is important in many areas, but is of considerable importance to researchers considering the relationships between exposure and injury risk. This paper describes the method used to develop a generic data collection, storage and retrieval program for measuring time-on-task. The program uses hypertext markup language, javaScript and Perl to provide an easily navigated computer interface for recording exposure variables on a tablet style computer (laptop). This method allows for data collection in the field and provides several benefits over traditional methods of data capture. This utility may have application in a range of research areas including education and skill acquisition, in addition to providing a precise measure of exposure to high-risk environments

Trends in the leading causes of injury mortality, Australia, Canada and the United States, 2000-2014

OBJECTIVES: The aim of this study was to highlight the differences in injury rates between populations through a descriptive epidemiological study of population-level trends in injury mortality for the high-income countries of Australia, Canada and the United States. METHODS: Mortality data were available for the US from 2000 to 2014, and for Canada and Australia from 2000 to 2012. Injury causes were defined using the International Classification of Diseases, Tenth Revision external cause codes, and were grouped into major causes. Rates were direct-method age-adjusted using the US 2000 projected population as the standard age distribution. RESULTS: US motor vehicle injury mortality rates declined from 2000 to 2014 but remained markedly higher than those of Australia or Canada. In all three countries, fall injury mortality rates increased from 2000 to 2014. US homicide mortality rates declined, but remained higher than those of Australia and Canada. While the US had the lowest suicide rate in 2000, it increased by 24% during 2000-2014, and by 2012 was about 14% higher than that in Australia and Canada. The poisoning mortality rate in the US increased dramatically from 2000 to 2014. CONCLUSION: Results show marked differences and striking similarities in injury mortality between the countries and within countries over time. The observed trends differed by injury cause category. The substantial differences in injury rates between similarly resourced populations raises important questions about the role of societal-level factors as underlying causes of the differential distribution of injury in our communities

Societal determinants of violent death:the extent to which social, economic, and structural characteristics explain differences in violence across Australia, Canada, and the United States

In this ecological study, we attempt to quantify the extent to which differences in homicide and suicide death rates between three countries, and among states/provinces within those countries, may be explained by differences in their social, economic, and structural characteristics. We examine the relationship between state/province level measures of societal risk factors and state/province level rates of violent death (homicide and suicide) across Australia, Canada, and the United States. Census and mortality data from each of these three countries were used. Rates of societal level characteristics were assessed and included residential instability, self-employment, income inequality, gender economic inequity, economic stress, alcohol outlet density, and employment opportunities). Residential instability, self-employment, and income inequality were associated with rates of both homicide and suicide and gender economic inequity was associated with rates of suicide only. This study opens lines of inquiry around what contributes to the overall burden of violence-related injuries in societies and provides preliminary findings on potential societal characteristics that are associated with differences in injury and violence rates across populations