Young People and Mental Health, Policy and Research Review

This brief focuses on issues relating to young people’s mental health. It draws on published research evidence and discussion at a Roundtable event organised by YouthAction Northern Ireland (YANI) and ARK and held in December 2012. Roundtable participants included officials from a number of government departments, Health Trusts, representatives from a range of NGOs, academics, and young people from YouthAction Northern Ireland’s Right Here Fermanagh
project and Young Men Talking Project who opened the debate with a contribution on what they think is important for young people’s mental health. The event was conducted under the anonymity of reporting allowed under the Chatham House Rule to encourage open debate.

Review of Marine Spatial Planning Best Practice of Relevance to Ireland

Making room for new marine uses and safeguarding more traditional uses, without degrading the marine environment, will require the adoption of new integrated management strategies. Current management frameworks do not facilitate the integrated management of all marine activities occurring in one area. To address this issue, the government developed Harnessing Our Ocean Wealth – An Integrated Marine Plan (IMP) for Ireland. Harnessing Our Ocean
Wealth presents a ‘roadmap’ for adopting an integrated approach to marine governance and for achieving the Government’s ambitious targets for the maritime sector, including: exceeding €6.4 billion turnover annually by 2020, and doubling its contribution to GDP to 2.4% by 2030. As part of this roadmap, Harnessing Our Ocean Wealth endorses the development of an appropriate Marine Spatial Planning (MSP) Framework. One way to develop an MSP Framework is to learn from early adapters. Critical assessments of key
elements of MSP as implemented in early initiatives can serve to inform the development of an appropriate framework. The aim of this project is to contribute to the development of this framework by reporting on
MSP best practice relevant to Ireland. Case study selection and evaluation criteria are outlined in the next section. This is followed by a presentation of case study findings. The final section of the report focuses on outlining how the lessons could be transferred to the Irish context.

A Review of Service Provision for men aged 50+ (Belfast)

Friday 26th September 2014 saw the launch of a report which examines service provision for men aged 50+ in the greater-Belfast area. This research was undertaken by a team from Queen’s University Belfast on behalf of the Older Men’s Steering Group within Age Partnership Belfast. The research sought to: (i) review the extent and impact of current community, voluntary, statutory or private sector services which are aimed at combating social isolation among men in the Belfast area, and (ii) identify how these services are meeting current need, and ways in which they may be developed to meet future requirements. The report is now available online at: www.volunteernow.co.uk/fs/doc/publications/men-aged-50-final-report.pdf

Accuracy of LightCycler SeptiFast for the detection and identification of pathogens in the blood of patients with suspected sepsis: a systematic review and meta-analysis

Purpose: There is an urgent need to develop diagnostic tests to improve the detection of pathogens causing life-threatening infection (sepsis). SeptiFast is a CE-marked multi-pathogen real-time PCR system capable of detecting DNA sequences of bacteria and fungi present in blood samples within a few hours. We report here a systematic review and meta-analysis of diagnostic accuracy studies of SeptiFast in the setting of suspected sepsis.

Methods: A comprehensive search strategy was developed to identify studies that compared SeptiFast with blood culture in suspected sepsis. Methodological quality was assessed using QUADAS. Heterogeneity of studies was investigated using a coupled forest plot of sensitivity and specificity and a scatter plot in receiver operator characteristic space. Bivariate model method was used to estimate summary sensitivity and specificity.

Results: From 41 phase III diagnostic accuracy studies, summary sensitivity and specificity for SeptiFast compared with blood culture were 0.68 (95 % CI 0.63–0.73) and 0.86 (95 % CI 0.84–0.89) respectively. Study quality was judged to be variable with important deficiencies overall in design and reporting that could impact on derived diagnostic accuracy metrics.

Conclusions: SeptiFast appears to have higher specificity than sensitivity, but deficiencies in study quality are likely to render this body of work unreliable. Based on the evidence presented here, it remains difficult to make firm recommendations about the likely clinical utility of SeptiFast in the setting of suspected sepsis.

Arts Council Ballet Policy Review

In May 2006 the Arts Council commissioned an independent review of the context and issues affecting professional ballet in Ireland. The findings were subsequently collated in a policy paper entitled Towards a Strategy of Support for Professional Ballet in Ireland, which was published in 2007 and adopted by the Council in the same year. The report acknowledged ballet as an integral part of cultural life and its importance to the development of many forms of professional dance. The document set forth a number of recommendations that have since formed the basis of art-form policy and funding relationships with ballet organisations.
In parallel since then, a number of important changes have taken place within the ballet sector. Some of these changes are the inevitable consequences of these difficult financial times. However, despite these funding challenges, the sector has managed to retain its vibrancy and popularity with national audiences. While the sector continues to evolve, the limited financial resources available to the Council have become an obstacle to implementing the road map envisioned in 2007. Given its significance and popularity, ballet remains an extraordinarily underdeveloped art form in Ireland. A key weakness of the sector is that future development of ballet provision remains fundamentally uncertain and is still overly dependent on the personal and professional commitment of a few individuals.
This review aims to analyse the current situation, discuss and consider how matters might be progressed and to propose a comprehensive framework for the development of ballet in Ireland. The purpose of the review is to provide an objective point of reference for the Arts Council‘s medium- term ballet policy and to inform and guide future public investment in the art form. The review also intends to progress the work undertaken since 2007 in response to the document Towards a Strategy of Support for Professional Ballet in Ireland.
Within a wider perspective, the review is expected to provide compelling evidence of ballet's relevance to Irish cultural life. It will also create an opportunity for the Council to engage with relevant stakeholders with a view to addressing the challenge of how best to provide for ballet on a sustainable basis within the context of a changed financial environment and an evolving professional sector. There is reason to expect this review will also assist the sector in giving voice to its aspirations and needs. This would certainly assist the Council in garnering support for a blueprint for the consolidation of professional ballet practice and education in Ireland.
It is envisioned the ballet policy review will be closely aligned to the Arts Council‘s own high-level objectives and will take account of developments that may arise from the broader process of strategic review the Council will undertake in 2014.

Rapid detection of health-care-associated bloodstream infection in critical care using multipathogen real-time polymerase chain reaction technology: a diagnostic accuracy study and systematic review

Background: There is growing interest in the potential utility of real-time polymerase chain reaction (PCR) in diagnosing bloodstream infection by detecting pathogen deoxyribonucleic acid (DNA) in blood samples within a few hours. SeptiFast (Roche Diagnostics GmBH, Mannheim, Germany) is a multipathogen probe-based system targeting ribosomal DNA sequences of bacteria and fungi. It detects and identifies the commonest pathogens causing bloodstream infection. As background to this study, we report a systematic review of Phase III diagnostic accuracy studies of SeptiFast, which reveals uncertainty about its likely clinical utility based on widespread evidence of deficiencies in study design and reporting with a high risk of bias. 

Objective: Determine the accuracy of SeptiFast real-time PCR for the detection of health-care-associated bloodstream infection, against standard microbiological culture. 

Design: Prospective multicentre Phase III clinical diagnostic accuracy study using the standards for the reporting of diagnostic accuracy studies criteria. 

Setting: Critical care departments within NHS hospitals in the north-west of England. 

Participants: Adult patients requiring blood culture (BC) when developing new signs of systemic inflammation. 

Main outcome measures: SeptiFast real-time PCR results at species/genus level compared with microbiological culture in association with independent adjudication of infection. Metrics of diagnostic accuracy were derived including sensitivity, specificity, likelihood ratios and predictive values, with their 95% confidence intervals (CIs). Latent class analysis was used to explore the diagnostic performance of culture as a reference standard. 

Results: Of 1006 new patient episodes of systemic inflammation in 853 patients, 922 (92%) met the inclusion criteria and provided sufficient information for analysis. Index test assay failure occurred on 69 (7%) occasions. Adult patients had been exposed to a median of 8 days (interquartile range 4–16 days) of hospital care, had high levels of organ support activities and recent antibiotic exposure. SeptiFast real-time PCR, when compared with culture-proven bloodstream infection at species/genus level, had better specificity (85.8%, 95% CI 83.3% to 88.1%) than sensitivity (50%, 95% CI 39.1% to 60.8%). When compared with pooled diagnostic metrics derived from our systematic review, our clinical study revealed lower test accuracy of SeptiFast real-time PCR, mainly as a result of low diagnostic sensitivity. There was a low prevalence of BC-proven pathogens in these patients (9.2%, 95% CI 7.4% to 11.2%) such that the post-test probabilities of both a positive (26.3%, 95% CI 19.8% to 33.7%) and a negative SeptiFast test (5.6%, 95% CI 4.1% to 7.4%) indicate the potential limitations of this technology in the diagnosis of bloodstream infection. However, latent class analysis indicates that BC has a low sensitivity, questioning its relevance as a reference test in this setting. Using this analysis approach, the sensitivity of the SeptiFast test was low but also appeared significantly better than BC. Blood samples identified as positive by either culture or SeptiFast real-time PCR were associated with a high probability (> 95%) of infection, indicating higher diagnostic rule-in utility than was apparent using conventional analyses of diagnostic accuracy. 

Conclusion: SeptiFast real-time PCR on blood samples may have rapid rule-in utility for the diagnosis of health-care-associated bloodstream infection but the lack of sensitivity is a significant limiting factor. Innovations aimed at improved diagnostic sensitivity of real-time PCR in this setting are urgently required. Future work recommendations include technology developments to improve the efficiency of pathogen DNA extraction and the capacity to detect a much broader range of pathogens and drug resistance genes and the application of new statistical approaches able to more reliably assess test performance in situation where the reference standard (e.g. blood culture in the setting of high antimicrobial use) is prone to error.

Tools for Assessing Outcomes in Studies of Chronic Cough: CHEST Guideline and Expert Panel Report

BACKGROUND: Since the publication of the 2006 American College of Chest Physicians (CHEST) cough guidelines, a variety of tools has been developed or further refined for assessing cough. The purpose of the present committee was to evaluate instruments used by investigators performing clinical research on chronic cough. The specific aims were to (1) assess the performance of tools designed to measure cough frequency, severity, and impact in adults, adolescents, and children with chronic cough and (2) make recommendations or suggestions related to these findings.

METHODS: By following the CHEST methodologic guidelines, the CHEST Expert Cough Panel based its recommendations and suggestions on a recently published comparative effectiveness review commissioned by the US Agency for Healthcare Research and Quality, a corresponding summary published in CHEST, and an updated systematic review through November 2013. Recommendations or suggestions based on these data were discussed, graded, and voted on during a meeting of the Expert Cough Panel.

RESULTS: We recommend for adults, adolescents (≥ 14 years of age), and children complaining of chronic cough that validated and reliable health-related quality-of-life (QoL) questionnaires be used as the measurement of choice to assess the impact of cough, such as the Leicester Cough Questionnaire and the Cough-Specific Quality-of-Life Questionnaire in adult and adolescent patients and the Parent Cough-Specific Quality of Life Questionnaire in children. We recommend acoustic cough counting to assess cough frequency but not cough severity. Limited data exist regarding the performance of visual analog scales, numeric rating scales, and tussigenic challenges.

CONCLUSIONS: Validated and reliable cough-specific health-related QoL questionnaires are recommended as the measurement of choice to assess the impact of cough on patients. How they compare is yet to be determined. When used, the reporting of cough severity by visual analog or numeric rating scales should be standardized. Previously validated QoL questionnaires or other cough assessments should not be modified unless the new version has been shown to be reliable and valid. Finally, in research settings, tussigenic challenges play a role in understanding mechanisms of cough.

The Carnian Humid Episode of the late Triassic: A Review

From 1989 to 1994 a series of papers outlined evidence for a brief episode of climate change from arid to humid, and then back to arid, during the Carnian Stage of the late Triassic. This time of climate change was compared to marine and terrestrial biotic changes, mainly extinction and then radiation of flora and fauna. Subsequently termed, albeit incorrectly, the Carnian Pluvial Event (CPE) by successive authors, interest in this episode of climatic change has increased steadily, with new evidence being published as well as several challenges to the theory. The exact nature of this humid episode, whether reflecting widespread precipitation or more local effects, as well as its ultimate cause remains equivocal. Bed-by-bed sampling of the Carnian in the Southern Alps (Dolomites), shows the episode began with a negative carbon isotope excursion that lasted for only part of one ammonoid zone (A. austriacum). However, that the Carnian Humid Episode represents a significantly longer period, both environmentally and biotically, is irrefutable. The evidence is strongest in the European, Middle East, Himalayan, North American and Japanese successions, but not always so clear in South America, Antarctica and Australia. The eruption of the Wrangellia Large Igneous Province and global warming (causing increased evaporation in the Tethyan and Panthalassic oceans) are suggested as causes for the humid episode.

Poverty and Ethnicity in Northern Ireland: An Evidence Review

This report provides an overview of the research evidence on the relationship between poverty and ethnicity in Northern Ireland. After a period of increasing ethnic diversity, the review was concerned with understanding how issues of poverty affect people from different minority ethnic communities and their ability to access and secure good outcomes from key services. A comprehensive literature review and focus groups with people from the Roma, Somali, Chinese and Polish communities, and with local stakeholders, provide the basis for the report. The report discusses: • how new migrants have joined long-standing communities of people from minority ethnic groups; • how the policy framework to address racial inequalities in Northern Ireland is relatively new; • how people from minority ethnic groups experience low incomes and access services; and • how the legacy of conflict in the region may affect minority ethnic groups.

A systematic review of population based epidemiological studies in Myasthenia Gravis

Background: The aim was to collate all myasthenia gravis (MG) epidemiological studies including AChR MG and MuSK MG specific studies. To synthesize data on incidence rate (IR), prevalence rate (PR) and mortality rate (MR) of the condition and investigate the influence of environmental and technical factors on any trends or variation observed.

Methods: Studies were identified using multiple sources and meta-analysis performed to calculate pooled estimates for IR, PR and MR.

Results: 55 studies performed between 1950 and 2007 were included, representing 1.7 billion population-years. For All MG estimated pooled IR (eIR): 5.3 per million person-years (C.I.: 4.4, 6.1), range: 1.7 to 21.3; estimated pooled PR: 77.7 per illion persons (C.I.: 64.0, 94.3), range 15 to 179; MR range 0.1 to 0.9 per millions person-years. AChR MG eIR: 7.3 (C.I.: 5.5, 7.8), range: 4.3 to 18.0; MuSK MG IR range: 0.1 to 0.32. However marked variation persisted between populations studied with similar methodology and in similar areas.

Conclusions: We report marked variation in observed frequencies of MG. We show evidence of increasing frequency of MG with year of study and improved study quality. This probably reflects improved case ascertainment. But other factors must also influence disease onset resulting in the observed variation in IR across geographically and genetically similar populations.

Pathways Project Final Report Volume 1: Field Investigation and Catchment Conceptual Models

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Executive Summary
The Pathways Project field studies were targeted at improving the understanding of contaminant transport along different hydrological pathways in Irish catchments, including their associated impacts on water quality and river ecology. The contaminants of interest were phosphorus, nitrogen and sediment. The working Pathways conceptual model included overland flow, interflow, shallow groundwater flow, and deep groundwater flow. This research informed the development of a set of Catchment Management Support Tools (CMSTs) comprising an Exploratory Tool, Catchment Characterization Tool (CCT) and Catchment Modelling Tool (CMT) as outlined in Pathways Project Final Reports Volumes 3 and 4.
In order to inform the CMST, four suitable study catchments were selected following an extensive selection process, namely the Mattock catchment, Co. Louth/Meath; Gortinlieve catchment, Co. Donegal; Nuenna catchment, Co. Kilkenny and the Glen Burn catchment, Co. Down. The Nuenna catchment is well drained as it is underlain by a regionally important karstified limestone aquifer with permeable limestone tills and gravels, while the other three catchments are underlain by poorly productive aquifers and low permeability clayey tills, and are poorly drained.
All catchments were instrumented, and groundwater, surface and near-surface water and aquatic ecology were monitored for a period of two years. Intensive water quality sampling during rainfall events was used to investigate the pathways delivering nutrients. The proportion of flow along each pathway was determined using chemical and physical hydrograph separation techniques, supported by numerical modelling.
The outcome of the field studies broadly supported the use of the initial four-pathway conceptual model used in the Pathways CMT (time-variant model). The artificial drainage network was found to be a significant contributing pathway in the poorly drained catchments, at low flows and during peak flows in wet antecedent conditions. The transition zone (TZ), i.e. the broken up weathered zone at the top of the bedrock, was also found to be an important pathway. It was observed to operate in two contrasting hydrogeological scenarios: in groundwater discharge zones the TZ can be regarded as being part of the shallow groundwater pathway, whereas in groundwater recharge zones it behaves more like interflow.
In the catchments overlying poorly productive aquifers, only a few fractures or fracture zones were found to be hydraulically active and the TZ, where present, was the main groundwater pathway. In the karstified Nuenna catchment, the springs, which are linked to conduits as well as to a diffuse fracture network, delivered the majority of the flow. These findings confirm the two-component groundwater contribution from bedrock but suggest that the size and nature of the hydraulically active fractures and the nature of the TZ are the dominant factors at the scale of a stream flow event.
Diffuse sources of nitrate were found to be typically delivered via the subsurface pathways, especially in the TZ and land drains in the poorly productive aquifer catchments, and via the bedrock groundwater in the Nuenna. Phosphorus was primarily transported via overland flow in both particulate and soluble forms. Where preferential flow paths existed in the soil and subsoil, soluble P, and to a lesser extent particulate P, were also transported via the TZ and in drains and ditches. Arable land was found to be the most important land use for
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the delivery of sediment, although channel bank and in-stream sources were the most significant in the Glen Burn catchment. Overland flow was found to be the predominant transport sediment pathway in the poorly productive catchments. These findings informed the development of the transport and attenuation equations used in the CCT and CMT. From an assessment of the relationship between physico-chemical and biological conditions, it is suggested that in the Nuenna, Glen Burn and Gortinlieve catchments, a relationship may exist between biological water quality and nitrogen concentrations, as well as with P. In the Nuenna, there was also a relationship between macroinvertebrate status and alkalinity.
Further research is recommended on the transport and delivery of phosphorus in groundwater, the transport and attenuation dynamics in the TZ in different hydrogeological settings and the relationship between macroinvertebrates and co-limiting factors. High resolution temporal and spatial sampling was found to be important for constraining the conceptual understanding of nutrient and sediment dynamics which should also be considered in future studies.

Somatic Cough Syndrome (Previously Referred to as Psychogenic Cough) and Tic Cough (Previously Referred to as Habit Cough) in Adults and Children: CHEST Guideline and Expert Panel Report

BACKGROUND: We conducted a systematic review on the management of psychogenic cough, habit cough, and tic cough to update the recommendations and suggestions of the 2006 guideline on this topic.

METHODS: We followed the American College of Chest Physicians (CHEST) methodologic guidelines and the Grading of Recommendations, Assessment, Development, and Evaluation framework. The Expert Cough Panel based their recommendations on data from the systematic review, patients' values and preferences, and the clinical context. Final grading was reached by consensus according to Delphi methodology.

RESULTS: The results of the systematic review revealed only low-quality evidence to support how to define or diagnose psychogenic or habit cough with no validated diagnostic criteria. With respect to treatment, low-quality evidence allowed the committee to only suggest therapy for children believed to have psychogenic cough. Such therapy might consist of nonpharmacologic trials of hypnosis or suggestion therapy, or combinations of reassurance, counseling, and referral to a psychologist, psychotherapy, and appropriate psychotropic medications. Based on multiple resources and contemporary psychologic, psychiatric, and neurologic criteria (Diagnostic and Statistical Manual of Mental Disorders, 5th edition and tic disorder guidelines), the committee suggests that the terms psychogenic and habit cough are out of date and inaccurate.

CONCLUSIONS: Compared with the 2006 CHEST Cough Guidelines, the major change in suggestions is that the terms psychogenic and habit cough be abandoned in favor of somatic cough syndrome and tic cough, respectively, even though the evidence to do so at this time is of low quality.

Match-fixing and Money-laundering

his essay is premised on the following: a conspiracy to fix or otherwise manipulate the outcome of a sporting event for profitable purpose. That conspiracy is in turn predicated on the conspirators’ capacity to: (a) ensure that the fix takes place as pre-determined; (b) manipulate the betting markets that surround the sporting event in question; and (c) collect their winnings undetected by either the betting industry’s security systems or the attention of any national regulatory body or law enforcement agency.

Unlike many essays on this topic, this contribution does not focus on the “fix”– part (a) of the above equation. It does not seek to explain how or why a participant or sports official might facilitate a betting scam through either on-field behaviour that manipulates the outcome of a game or by presenting others with privileged inside information in advance of a game. Neither does this contribution seek to give any real insight into the second part of the above equation: how such conspirators manipulate a sports betting market by playing or laying the handicap or in-play or other offered betting odds. In fact, this contribution is not really about the mechanics of sports betting or match fixing at all; rather it is about the sometimes under explained reason why match fixing has reportedly become increasingly attractive as of late to international crime syndicates. That reason relates to the fact that given the traditional liquidity of gambling markets, sports betting can, and has long been, an attractively accessible conduit for criminal syndicates to launder the proceeds of crime. Accordingly, the term “winnings”, noted in part (c) of the above equation, takes on an altogether more nefarious meaning.

This essay’s attempt to review the possible links between match fixing in sport, gambling-related “winnings” and money laundering is presented in four parts.

First, some context will be given to what is meant by money laundering, how it is currently policed internationally and, most importantly, how the growth of online gambling presents a unique set of vulnerabilities and opportunities to launder the proceeds of crime. The globalisation of organised crime, sports betting and transnational financial services now means that money laundering opportunities have moved well beyond a flutter on the horses at your local racetrack or at the roulette table of your nearest casino. The growth of online gambling platforms means that at a click it is possible for the proceeds of crime in one jurisdiction to be placed on a betting market in another jurisdiction with the winnings drawn down and laundered in a third jurisdiction and thus the internationalisation of gambling-related money laundering threatens the integrity of sport globally.

Second, and referring back to the infamous hearings of the US Senate Special Committee to Investigate Organised Crime in Interstate Commerce of the early 1950s, (“the Kefauver Committee”), this article will begin by illustrating the long standing interest of organised crime gangs – in this instance, various Mafia families in the United States – in money laundering via sports gambling-related means.

Third, and using the seminal 2009 report “Money Laundering through the Football Sector” by the Financial Action Task Force (FATF, an inter-governmental body established in 1989 to promote effective implementation of legal, regulatory and operational measures for combating money laundering, terrorist financing and other related threats to the integrity of the international financial system), this essay seeks to assess the vulnerabilities of international sport to match fixing, as motivated in part by the associated secondary criminality of tax evasion and transnational economic crime.

The fourth and concluding parts of the essay spin from problems to possible solutions. The underlying premise here is that heretofore there has been an insularity to the way that sports organisations have both conceptualised and sought to address the match fixing threat e.g., if we (in sport) initiate player education programmes; establish integrity units; enforce codes of conduct and sanctions strictly; then our integrity or brand should be protected. This essay argues that, although these initiatives are important, the source and process of match fixing is beyond sport’s current capacity, as are the possible solutions.

The Impact of Colleague Peer Review on the Radiotherapy Treatment Planning Process in the Radical Treatment of Lung Cancer

AIMS: Modern radiotherapy uses techniques to reliably identify tumour and reduce target volume margins. However, this can potentially lead to an increased risk of geographic miss. One source of error is the accuracy of target volume delineation (TVD). Colleague peer review (CPR) of all curative-intent lung cancer plans has been mandatory in our institution since May 2013. At least two clinical oncologists review plans, checking treatment paradigm, TVD, prescription dose tumour and critical organ tolerances. We report the impact of CPR in our institution.

MATERIALS AND METHODS: Radiotherapy treatment plans of all patients receiving radical radiotherapy were presented at weekly CPR meetings after their target volumes were reviewed and signed off by the treating consultant. All cases and any resultant change to TVD (including organs at risk) or treatment intent were recorded in our prospective CPR database. The impact of CPR over a 13 month period from May 2013 to June 2014 is reported.

RESULTS: One hundred and twenty-two patients (63% non-small cell lung carcinoma, 17% small cell lung carcinoma and 20% 'clinical diagnosis') were analysed. On average, 3.2 cases were discussed per meeting (range 1-8). CPR resulted in a change in treatment paradigm in 3% (one patient proceeded to induction chemotherapy, two patients had high-dose palliative radiotherapy). Twenty-one (17%) had a change in TVD and one (1%) patient had a change in dose prescription. In total, 6% of patients had plan adjustment after review of dose volume histogram.

CONCLUSION: The introduction of CPR in our centre has resulted in a change in a component of the treatment plan for 27% of patients receiving curative-intent lung radiotherapy. We recommend CPR as a mandatory quality assurance step in the planning process of all radical lung plans.

Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial

BACKGROUND: Bone metastases frequently cause skeletal events in patients with metastatic castration-resistant prostate cancer. Radium-223 dichloride (radium-223) selectively targets bone metastases with high-energy, short-range α-particles. We assessed the effect of radium-223 compared with placebo in patients with castration-resistant prostate cancer and bone metastases.

METHODS: In this phase 3, double-blind, randomised ALSYMPCA trial, we enrolled patients who had symptomatic castration-resistant prostate cancer with two or more bone metastases and no known visceral metastases, who were receiving best standard of care, and had previously either received or were unsuitable for docetaxel. Patients were stratified by previous docetaxel use, baseline total alkaline phosphatase level, and current bisphosphonate use, then randomly assigned (2:1) to receive either six intravenous injections of radium-223 (50 kBq/kg) or matching placebo; one injection was given every 4 weeks. Randomisation was done with an interactive voice response system, taking into account trial stratification factors. Participants and investigators were masked to treatment assignment. The primary endpoint was overall survival, which has been reported previously. Here we report on time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-verterbal), or occurence of spinal cord compression, or tumour-related orthopeadic surgical intervention. All events were required to be clinically apparent and were not assessed by periodic radiological review. Statistical analyses of symptomatic skeletal events were based on the intention-to-treat population. The study has been completed and is registered with ClinicalTrials.gov, number NCT00699751.

FINDINGS: Between June 12, 2008, and Feb 1, 2011, 921 patients were enrolled, of whom 614 (67%) were randomly assigned to receive radium-223 and 307 (33%) placebo. Symptomatic skeletal events occurred in 202 (33%) of 614 patients in the radium-223 group and 116 (38%) of 307 patients in the placebo group. Time to first symptomatic skeletal event was longer with radium-223 than with placebo (median 15·6 months [95% CI 13·5-18·0] vs 9·8 months [7·3-23·7]; hazard ratio [HR]=0·66, 95% CI 0·52-0·83; p=0·00037). The risks of external beam radiation therapy for bone pain (HR 0·67, 95% CI 0·53-0·85) and spinal cord compression (HR=0·52, 95% CI 0·29-0·93) were reduced with radium-233 compared with placebo. Radium-223 treatment did not seem to significantly reduce the risk of symptomatic pathological bone fracture (HR 0·62, 95% CI 0·35-1·09), or the need for tumour-related orthopaedic surgical intervention (HR 0·72, 95% CI 0·28-1·82).

INTERPRETATION: Radium-223 should be considered as a treatment option for patients with castration-resistant prostate cancer and symptomatic bone metastases.

FUNDING: Algeta and Bayer HealthCare Pharmaceuticals.