Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy.

BACKGROUND: Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design. METHODS: We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostate-specific antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure-free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer). RESULTS: A total of 1917 patients underwent randomization from November 2011 through January 2014. The median age was 67 years, and the median PSA level was 53 ng per milliliter. A total of 52% of the patients had metastatic disease, 20% had node-positive or node-indeterminate nonmetastatic disease, and 28% had node-negative, nonmetastatic disease; 95% had newly diagnosed disease. The median follow-up was 40 months. There were 184 deaths in the combination group as compared with 262 in the ADT-alone group (hazard ratio, 0.63; 95% confidence interval [CI], 0.52 to 0.76; P<0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease. There were 248 treatment-failure events in the combination group as compared with 535 in the ADT-alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P<0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease. Grade 3 to 5 adverse events occurred in 47% of the patients in the combination group (with nine grade 5 events) and in 33% of the patients in the ADT-alone group (with three grade 5 events). CONCLUSIONS: Among men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure-free survival than ADT alone. (Funded by Cancer Research U.K. and others; STAMPEDE ClinicalTrials.gov number, NCT00268476 , and Current Controlled Trials number, ISRCTN78818544 .).

Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial.

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

Testing many treatments within a single protocol over 10 years at MRC Clinical Trials Unit at UCL: Multi-arm, multi-stage platform, umbrella and basket protocols.

There is real need to change how we do some of our clinical trials, as currently the testing and development process is too slow, too costly and too failure-prone often we find that a new treatment is no better than the current standard. Much of the focus on the development and testing pathway has been in improving the design of phase I and II trials. In this article, we present examples of new methods for improving the design of phase III trials (and the necessary lead up to them) as they are the most time-consuming and expensive part of the pathway. Key to all these methods is the aim to test many treatments and/or pose many therapeutic questions within one protocol.

Cost-effectiveness of classroom-based cognitive behaviour therapy in reducing symptoms of depression in adolescents: a trial-based analysis.

BACKGROUND: A substantial minority of adolescents suffer from depression and it is associated with increased risk of suicide, social and educational impairment, and mental health problems in adulthood. A recently conducted randomized controlled trial in England evaluated the effectiveness of a manualized universally delivered age-appropriate CBT programme in school classrooms. The cost-effectiveness of the programme for preventing low mood and depression for all participants from a health and social care sector perspective needs to be determined. METHODS: A trial-based cost-effectiveness analysis based on a cluster-randomized controlled trial (trial registration--ISRCTN 19083628) comparing classroom-based CBT with usual school provision of Personal Social and Health Education. Per-student cost of intervention was estimated from programme records. The study was undertaken in eight mixed-sex U.K. secondary schools, and included 3,357 school children aged 12 to 16 years (in the two trial arms evaluated in the cost-effectiveness analysis). The main outcome measures were individual self-reported data on care costs, Quality-Adjusted Life-Years (QALYs, based on the EQ-5D health-related quality-of-life instrument) and symptoms of depression (Short Mood and Feelings Questionnaire) at baseline, 6 and 12 months. RESULTS: Although there was lower quality-adjusted life-years over 12 months (-.05 QALYs per person, 95% confidence interval -.09 to -.005, p = .03) with CBT, this is a 'clinically' negligible difference, which was not found in the complete case analyses. There was little evidence of any between-arm differences in SMFQ scores (0.19, 95% CI -0.57 to 0.95, p = .62), or costs (£142, 95% CI -£132 to £415, p = .31) per person for CBT versus usual school provision. CONCLUSIONS: Our analysis suggests that the universal provision of classroom-based CBT is unlikely to be either more effective or less costly than usual school provision.

Service use in adolescents at risk of depression and self-harm: prospective longitudinal study.

PURPOSE: Although depression and self-harm are common mental health problems in adolescents, there are barriers to accessing help. Using a community-based sample, this study investigates predictors of service contacts for adolescents at high risk of depression and self-harm. METHODS: Three thousand seven hundred and forty-nine (3,749) 12- to 16-year-olds in UK secondary (high) schools provided baseline and 6 months' follow-up data on mood, self-harm and service contacts with a range of primary and secondary healthcare services. RESULTS: Although most adolescents at high risk of depression or self-harm had seen their general practitioner (GP) in the previous 6 months, less than one-third had used primary or secondary healthcare services for emotional problems. 5 % of adolescents who reported self-harm had seen specialist child and adolescent mental health services in the previous 6 months. In longitudinal analyses, after adjustment for confounders, both depression and self-harm predicted the use of any healthcare services [adjusted odds ratio (AOR) = 1.34 (95 % CI 1.09, 1.64); AOR = 1.38 (95 % CI 1.02, 1.86), respectively] and of specialist mental health services [AOR = 5.48 (95 % CI 2.27, 13.25); AOR = 2.58 (95 % CI 1.11, 6.00), respectively]. Amongst those with probable depression, 79 % had seen their GP and 5 % specialist mental health services in the preceding year. CONCLUSIONS: Most adolescents at high risk of depression or self-harm see their GP over a 6-month period although only a minority of them access specialist mental health services. Their consultations within primary care settings provide a potential opportunity for their identification and for signposting to appropriate specialist services.

Factors associated with the development of self-harm amongst a socio-economically deprived cohort of adolescents in Santiago, Chile.

PURPOSE: Studies carried out in the West indicate that the incidence of self-harm (SH) is particularly high amongst adolescents, but few studies have investigated its incidence and aetiology in low-income countries. The purpose of this study was to investigate risk factors associated with new onset episodes of SH, amongst Chilean adolescents from low socio-economic backgrounds. METHODS: Prospective cohort study nested within a cluster randomised controlled trial. A 6-month follow-up for 2,042 adolescents, median age 14 years, from socio-economically deprived areas of Santiago, Chile. RESULTS: The lifetime prevalence of SH was 23%. The incidence rate of SH at 6 months was 14% amongst those reporting no SH at baseline. In multivariable analyses, risk factors for incident SH include depressive symptoms, suicidal thoughts, poor problem-solving skills and cannabis misuse. CONCLUSIONS: The prevalence and incidence of SH in this socio-economically deprived sample differed highly according to gender. Poor problem-solving skills, suicidal thoughts, and cannabis misuse were associated with onset of SH.

Self-harm in young adolescents (12-16 years): onset and short-term continuation in a community sample.

BACKGROUND: To investigate the prevalence of self-harm in young adolescents and factors associated with onset and continuity over a one year period. METHOD: Prospective longitudinal study. Participants were young adolescents (n = 3964) aged 12-16 years attending 8 secondary schools in the Midlands and South West of England. RESULTS: Over a one year period 27% of young adolescents reported thoughts of self-harm and 15% reported at least one act of self-harm. Of those who self-harmed, less than one in five (18%) had sought help for psychological problems of anxiety or depression. Compared with boys, girls were at increased risk of developing thoughts (OR 1.61, 95% CI 1.26-2.06) and acts (OR 1.40, 95% CI 1.06-1.84) of self-harm, particularly amongst those girls in school year 9 (aged 13/14, thoughts adjusted Odds Ratio (aOR) 1.97, 95% CI 1.27-3.04; acts aOR 2.59, 95% CI 1.52-4.41). Of those reporting thoughts of self-harm at baseline, 60% also reported these thoughts at follow-up. Similarly 55% of those who reported an act of self-harm at baseline also reported that they had self-harmed at follow-up. Insecure peer relationships increased the likelihood that boys and girls would develop self-harming behaviours, as did being bullied for boys. Low mood was associated with the development of self-harming thoughts and behaviours for boys and girls, whilst a strong sense of school membership was associated with a reduced risk of developing thoughts of self-harm for boys and increased the likelihood of self-harming thoughts and behaviours ceasing for girls. CONCLUSION: Self harm in young adolescents is common with one in four reporting self-harming thoughts and one in six engaging in self-harming behaviour over a one year period. Self-harm is already established by 12/13 years of age and for over half of our sample, self-harming thoughts and behaviour persisted over the year. Secure peer and strong school relationships were associated with less self-harm. Few seek help for psychological problems, suggesting a need to increase awareness amongst all professionals who work with young adolescents about self-harm and associated risk factors.

Could a brief assessment of negative emotions and self-esteem identify adolescents at current and future risk of self-harm in the community? A prospective cohort analysis.

BACKGROUND: Self-harm is common in adolescents, but it is often unreported and undetected. Available screening tools typically ask directly about self-harm and suicidal ideation. Although in an ideal world, direct enquiry and open discussion around self-harm would be advocated, non-psychiatric professionals in community settings are often reluctant to ask about this directly and disclosure can be met with feeling of intense anxiety. Training non-specialist staff to directly ask about self-harm has limited effects suggesting that alternative approaches are required. This study investigated whether a targeted analysis of negative emotions and self-esteem could identify young adolescents at risk of self-harm in community settings. METHODS: Data were collected as part of a clinical trial from young people in school years 8-11 (aged 12-16) at eight UK secondary schools (N = 4503 at baseline, N = 3263 in prospective analysis). The Short Mood and Feelings Questionnaire, Revised Child Anxiety and Depression Scale, Rosenberg Self-Esteem Scale, personal failure (Children's Automatic Thoughts Scale), and two items on self-harm were completed at baseline, 6 and 12 months. RESULTS: Following a process of Principal Components Analysis, item reduction, and logistic regression analysis, three internally reliable factors were identified from the original measures that were independently associated with current and future self-harm; personal failure (3 items), physical symptoms of depression/anxiety (6 items), positive self-esteem (5 items). The summed score of these 14 items had good accuracy in identifying current self-harm (AUC 0.87 girls, 0.81 boys) and at six months for girls (0.81), and fair accuracy at six months for boys (AUC 0.74) and 12 months for girls (AUC 0.77). CONCLUSIONS: A brief and targeted assessment of negative emotions and self-esteem, focusing on factors that are strongly associated with current and future self-harm, could potentially be used to help identify adolescents who are at risk in community settings. Further research should assess the psychometric properties of the items identified and test this approach in more diverse community contexts.

School connectedness, peer attachment, and self-esteem as predictors of adolescent depression.

Recent literature suggests that school connectedness (SC) may be a key determinant of adolescent mental health. Specifically, SC has been found to have a negative relationship with adolescent depression. In the current, cross sectional study, we examine whether the relationship between SC and symptoms of low mood is dampened or moderated by self-esteem (SE) and peer attachment style. Participants were 5022 adolescents (aged 11-16) who completed a battery of questionnaires in school, including measures of low mood, SC, SE, and peer attachment style. The relationship between SC and low mood was reduced by the inclusion of SE and peer attachment style. Peer attachment style was the largest predictor of low mood. The relationship between SC and low mood was not moderated by SE or peer attachment style. Interventions for adolescent depression may be most effective by focussing on increasing SE and fostering secure attachments, rather than solely focussing on increasing SC.

Self-management of fatigue in rheumatoid arthritis: a randomised controlled trial of group cognitive-behavioural therapy.

OBJECTIVES: To investigate the effect of group cognitive behavioural therapy (CBT) for fatigue self-management, compared with groups receiving fatigue information alone, on fatigue impact among people with rheumatoid arthritis (RA). METHODS: Two-arm, parallel randomised controlled trial in adults with RA, fatigue ≥ 6/10 (Visual Analogue Scale (VAS) 0-10, high bad) and no recent change in RA medication. Group CBT for fatigue self-management comprised six (weekly) 2 h sessions, and consolidation session (week 14). Control participants received fatigue self-management information in a 1 h didactic group session. Primary outcome at 18 weeks was the impact of fatigue measured using two methods (Multi-dimensional Assessment of Fatigue (MAF) 0-50; VAS 0-10), analysed using intention-to-treat analysis of covariance with multivariable regression models. RESULTS: Of 168 participants randomised, 41 withdrew before entry and 127 participated. There were no major baseline differences between the 65 CBT and 62 control participants. At 18 weeks CBT participants reported better scores than control participants for fatigue impact: MAF 28.99 versus 23.99 (adjusted difference -5.48, 95% CI -9.50 to -1.46, p=0.008); VAS 5.99 versus 4.26 (adjusted difference -1.95, 95% CI -2.99 to -0.90, p<0.001). Standardised effect sizes for fatigue impact were MAF 0.59 (95% CI 0.15 to 1.03) and VAS 0.77 (95% CI 0.33 to 1.21), both in favour of CBT. Secondary outcomes of perceived fatigue severity, coping, disability, depression, helplessness, self-efficacy and sleep were also better in CBT participants. CONCLUSIONS: Group CBT for fatigue self-management in RA improves fatigue impact, coping and perceived severity, and well-being. TRIAL REGISTRATION: ISRCTN 32195100.

Adding abiraterone to androgen deprivation therapy in men with metastatic hormone-sensitive prostate cancer: A systematic review and meta-analysis.

BACKGROUND: There is a need to synthesise the results of numerous randomised controlled trials evaluating the addition of therapies to androgen deprivation therapy (ADT) for men with metastatic hormone-sensitive prostate cancer (mHSPC). This systematic review aims to assess the effects of adding abiraterone acetate plus prednisone/prednisolone (AAP) to ADT. METHODS: Using our framework for adaptive meta-analysis (FAME), we started the review process before trials had been reported and worked collaboratively with trial investigators to anticipate when eligible trial results would emerge. Thus, we could determine the earliest opportunity for reliable meta-analysis and take account of unavailable trials in interpreting results. We searched multiple sources for trials comparing AAP plus ADT versus ADT in men with mHSPC. We obtained results for the primary outcome of overall survival (OS), secondary outcomes of clinical/radiological progression-free survival (PFS) and grade III-IV and grade V toxicity direct from trial teams. Hazard ratios (HRs) for the effects of AAP plus ADT on OS and PFS, Peto Odds Ratios (Peto ORs) for the effects on acute toxicity and interaction HRs for the effects on OS by patient subgroups were combined across trials using fixed-effect meta-analysis. FINDINGS: We identified three eligible trials, one of which was still recruiting (PEACE-1 (NCT01957436)). Results from the two remaining trials (LATITUDE (NCT01715285) and STAMPEDE (NCT00268476)), representing 82% of all men randomised to AAP plus ADT versus ADT (without docetaxel in either arm), showed a highly significant 38% reduction in the risk of death with AAP plus ADT (HR = 0.62, 95% confidence interval [CI] = 0.53-0.71, p = 0.55 × 10-10), that translates into a 14% absolute improvement in 3-year OS. Despite differences in PFS definitions across trials, we also observed a consistent and highly significant 55% reduction in the risk of clinical/radiological PFS (HR = 0.45, 95% CI = 0.40-0.51, p = 0.66 × 10-36) with the addition of AAP, that translates to a 28% absolute improvement at 3 years. There was no evidence of a difference in the OS benefit by Gleason sum score, performance status or nodal status, but the size of the benefit may vary by age. There were more grade III-IV acute cardiac, vascular and hepatic toxicities with AAP plus ADT but no excess of other toxicities or death. INTERPRETATION: Adding AAP to ADT is a clinically effective treatment option for men with mHSPC, offering an alternative to docetaxel for men who are starting treatment for the first time. Future research will need to address which of these two agents or whether their combination is most effective, and for whom.

Adding Celecoxib With or Without Zoledronic Acid for Hormone-Naïve Prostate Cancer: Long-Term Survival Results From an Adaptive, Multiarm, Multistage, Platform, Randomized Controlled Trial.

Purpose Systemic Therapy for Advanced or Metastatic Prostate Cancer: Evaluation of Drug Efficacy is a randomized controlled trial using a multiarm, multistage, platform design. It recruits men with high-risk, locally advanced or metastatic prostate cancer who were initiating long-term hormone therapy. We report survival data for two celecoxib (Cel)-containing comparisons, which stopped accrual early at interim analysis on the basis of failure-free survival. Patients and Methods Standard of care (SOC) was hormone therapy continuously (metastatic) or for ≥ 2 years (nonmetastatic); prostate (± pelvic node) radiotherapy was encouraged for men without metastases. Cel 400 mg was administered twice a day for 1 year. Zoledronic acid (ZA) 4 mg was administered for six 3-weekly cycles, then 4-weekly for 2 years. Stratified random assignment allocated patients 2:1:1 to SOC (control), SOC + Cel, or SOC + ZA + Cel. The primary outcome measure was all-cause mortality. Results were analyzed with Cox proportional hazards and flexible parametric models adjusted for stratification factors. Results A total of 1,245 men were randomly assigned (Oct 2005 to April 2011). Groups were balanced: median age, 65 years; 61% metastatic, 14% N+/X M0, 25% N0M0; 94% newly diagnosed; median prostate-specific antigen, 66 ng/mL. Median follow-up was 69 months. Grade 3 to 5 adverse events were seen in 36% SOC-only, 33% SOC + Cel, and 32% SOC + ZA + Cel patients. There were 303 control arm deaths (83% prostate cancer), and median survival was 66 months. Compared with SOC, the adjusted hazard ratio was 0.98 (95% CI, 0.80 to 1.20; P = .847; median survival, 70 months) for SOC + Cel and 0.86 (95% CI, 0.70 to 1.05; P =.130; median survival, 76 months) for SOC + ZA + Cel. Preplanned subgroup analyses in men with metastatic disease showed a hazard ratio of 0.78 (95% CI, 0.62 to 0.98; P = .033) for SOC + ZA + Cel. Conclusion These data show no overall evidence of improved survival with Cel. Preplanned subgroup analyses provide hypotheses for future studies.

Failure-Free Survival and Radiotherapy in Patients With Newly Diagnosed Nonmetastatic Prostate Cancer: Data From Patients in the Control Arm of the STAMPEDE Trial.

IMPORTANCE: The natural history of patients with newly diagnosed high-risk nonmetastatic (M0) prostate cancer receiving hormone therapy (HT) either alone or with standard-of-care radiotherapy (RT) is not well documented. Furthermore, no clinical trial has assessed the role of RT in patients with node-positive (N+) M0 disease. The STAMPEDE Trial includes such individuals, allowing an exploratory multivariate analysis of the impact of radical RT. OBJECTIVE: To describe survival and the impact on failure-free survival of RT by nodal involvement in these patients. DESIGN, SETTING, AND PARTICIPANTS: Cohort study using data collected for patients allocated to the control arm (standard-of-care only) of the STAMPEDE Trial between October 5, 2005, and May 1, 2014. Outcomes are presented as hazard ratios (HRs) with 95% CIs derived from adjusted Cox models; survival estimates are reported at 2 and 5 years. Participants were high-risk, hormone-naive patients with newly diagnosed M0 prostate cancer starting long-term HT for the first time. Radiotherapy is encouraged in this group, but mandated for patients with node-negative (N0) M0 disease only since November 2011. EXPOSURES: Long-term HT either alone or with RT, as per local standard. Planned RT use was recorded at entry. MAIN OUTCOMES AND MEASURES: Failure-free survival (FFS) and overall survival. RESULTS: A total of 721 men with newly diagnosed M0 disease were included: median age at entry, 66 (interquartile range [IQR], 61-72) years, median (IQR) prostate-specific antigen level of 43 (18-88) ng/mL. There were 40 deaths (31 owing to prostate cancer) with 17 months' median follow-up. Two-year survival was 96% (95% CI, 93%-97%) and 2-year FFS, 77% (95% CI, 73%-81%). Median (IQR) FFS was 63 (26 to not reached) months. Time to FFS was worse in patients with N+ disease (HR, 2.02 [95% CI, 1.46-2.81]) than in those with N0 disease. Failure-free survival outcomes favored planned use of RT for patients with both N0M0 (HR, 0.33 [95% CI, 0.18-0.61]) and N+M0 disease (HR, 0.48 [95% CI, 0.29-0.79]). CONCLUSIONS AND RELEVANCE: Survival for men entering the cohort with high-risk M0 disease was higher than anticipated at study inception. These nonrandomized data were consistent with previous trials that support routine use of RT with HT in patients with N0M0 disease. Additionally, the data suggest that the benefits of RT extend to men with N+M0 disease. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00268476; ISRCTN78818544.

Survival with Newly Diagnosed Metastatic Prostate Cancer in the "Docetaxel Era": Data from 917 Patients in the Control Arm of the STAMPEDE Trial (MRC PR08, CRUK/06/019).

BACKGROUND: Prostate cancer (PCa) is the second most common disease among men worldwide. It is important to know survival outcomes and prognostic factors for this disease. Recruitment for the largest therapeutic randomised controlled trial in PCa--the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy: A Multi-Stage Multi-Arm Randomised Controlled Trial (STAMPEDE)--includes men with newly diagnosed metastatic PCa who are commencing long-term androgen deprivation therapy (ADT); the control arm provides valuable data for a prospective cohort. OBJECTIVE: Describe survival outcomes, along with current treatment standards and factors associated with prognosis, to inform future trial design in this patient group. DESIGN, SETTING, AND PARTICIPANTS: STAMPEDE trial control arm comprising men newly diagnosed with M1 disease who were recruited between October 2005 and January 2014. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS) and failure-free survival (FFS) were reported by primary disease characteristics using Kaplan-Meier methods. Hazard ratios and 95% confidence intervals (CIs) were derived from multivariate Cox models. RESULTS AND LIMITATIONS: A cohort of 917 men with newly diagnosed M1 disease was recruited to the control arm in the specified interval. Median follow-up was 20 mo. Median age at randomisation was 66 yr (interquartile range [IQR]: 61-71), and median prostate-specific antigen level was 112 ng/ml (IQR: 34-373). Most men (n=574; 62%) had bone-only metastases, whereas 237 (26%) had both bone and soft tissue metastases; soft tissue metastasis was found mainly in distant lymph nodes. There were 238 deaths, 202 (85%) from PCa. Median FFS was 11 mo; 2-yr FFS was 29% (95% CI, 25-33). Median OS was 42 mo; 2-yr OS was 72% (95% CI, 68-76). Survival time was influenced by performance status, age, Gleason score, and metastases distribution. Median survival after FFS event was 22 mo. Trial eligibility criteria meant men were younger and fitter than general PCa population. CONCLUSIONS: Survival remains disappointing in men presenting with M1 disease who are started on only long-term ADT, despite active treatments being available at first failure of ADT. Importantly, men with M1 disease now spend the majority of their remaining life in a state of castration-resistant relapse. PATIENT SUMMARY: Results from this control arm cohort found survival is relatively short and highly influenced by patient age, fitness, and where prostate cancer has spread in the body.

Combining enzalutamide with abiraterone, prednisone, and androgen deprivation therapy in the STAMPEDE trial.

There are compelling reasons to study the addition of both enzalutamide and abiraterone, in combination, to standard-of-care for hormone-naïve prostate cancer. Through a protocol amendment, this will be assessed in the STAMPEDE trial, with overall survival as primary outcome measure.

Aortic pulse wave velocity improves cardiovascular event prediction: an individual participant meta-analysis of prospective observational data from 17,635 subjects.

OBJECTIVES: The goal of this study was to determine whether aortic pulse wave velocity (aPWV) improves prediction of cardiovascular disease (CVD) events beyond conventional risk factors. BACKGROUND: Several studies have shown that aPWV may be a useful risk factor for predicting CVD, but they have been underpowered to examine whether this is true for different subgroups. METHODS: We undertook a systematic review and obtained individual participant data from 16 studies. Study-specific associations of aPWV with CVD outcomes were determined using Cox proportional hazard models and random effect models to estimate pooled effects. RESULTS: Of 17,635 participants, a total of 1,785 (10%) had a CVD event. The pooled age- and sex-adjusted hazard ratios (HRs) per 1-SD change in loge aPWV were 1.35 (95% confidence interval [CI]: 1.22 to 1.50; p < 0.001) for coronary heart disease, 1.54 (95% CI: 1.34 to 1.78; p < 0.001) for stroke, and 1.45 (95% CI: 1.30 to 1.61; p < 0.001) for CVD. Associations stratified according to sex, diabetes, and hypertension were similar but decreased with age (1.89, 1.77, 1.36, and 1.23 for age ≤50, 51 to 60, 61 to 70, and >70 years, respectively; pinteraction <0.001). After adjusting for conventional risk factors, aPWV remained a predictor of coronary heart disease (HR: 1.23 [95% CI: 1.11 to 1.35]; p < 0.001), stroke (HR: 1.28 [95% CI: 1.16 to 1.42]; p < 0.001), and CVD events (HR: 1.30 [95% CI: 1.18 to 1.43]; p < 0.001). Reclassification indices showed that the addition of aPWV improved risk prediction (13% for 10-year CVD risk for intermediate risk) for some subgroups. CONCLUSIONS: Consideration of aPWV improves model fit and reclassifies risk for future CVD events in models that include standard risk factors. aPWV may enable better identification of high-risk populations that might benefit from more aggressive CVD risk factor management.

School intervention to improve mental health of students in Santiago, Chile: a randomized clinical trial.

IMPORTANCE: Depression can have devastating effects unless prevented or treated early and effectively. Schools offer an excellent opportunity to intervene with adolescents presenting emotional problems. There are very few universal school-based depression interventions conducted in low- and middle-income countries. OBJECTIVE: To assess the effectiveness of a school-based, universal psychological intervention to reduce depressive symptoms among adolescents from low-income families. DESIGN, SETTING, AND PARTICIPANTS: A 2-arm, parallel, cluster, randomized clinical trial was conducted in secondary schools in deprived socioeconomic areas of Santiago, Chile. Almost all students registered in the selected schools consented to take part in the study. A total of 2512 secondary school students from 22 schools and 66 classes participated. INTERVENTIONS: Students in the intervention arm attended 11 one-hour weekly and 2 booster classroom sessions of an intervention based on cognitive-behavioral models. The intervention was delivered by trained nonspecialists. Schools in the control arm received the standard school curriculum. MAIN OUTCOMES AND MEASURES: Scores on the self-administered Beck Depression Inventory-II at 3 months (primary) and 12 months (secondary) after completing the intervention. RESULTS: There were 1291 participants in the control arm and 1221 in the intervention arm. Primary outcome data were available for 82.1% of the participants. There was no evidence of any clinically important difference in mean depression scores between the groups (adjusted difference in mean, -0.19; 95% CI, -1.22 to 0.84) or for any of the other outcomes 3 months after completion of the intervention. No significant differences were found in any of the outcomes at 12 months. CONCLUSIONS AND RELEVANCE: A well-designed and implemented school-based intervention did not reduce depressive symptoms among socioeconomically deprived adolescents in Santiago, Chile. There is growing evidence that universal school interventions may not be sufficiently effective to reduce or prevent depressive symptoms. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN19466209.

Action 3:30: protocol for a randomized feasibility trial of a teaching assistant led extracurricular physical activity intervention.

BACKGROUND: Many children do not meet physical activity (PA) guidelines. Extracurricular programmes could provide a mechanism to increase the PA levels of primary-school-aged children. Teaching assistants (TAs) are a valuable resource in all UK primary schools and could be trained to delivery after-school PA programmes. The aim of this feasibility study is to examine whether the Action 3:30 PA intervention, which is delivered by TAs, could be effective in increasing the PA of Year 5 and 6 children. METHODS/DESIGN: A feasibility trial will be conducted in 20 primary schools. Schools will be randomly assigned to intervention or control arms. Intervention schools will receive a 25-hour TA training programme for two TAs, a first-aid certificate course for two TAs; ongoing TA support; 40 one-hour session plans that can be delivered by TAs; Action 3:30 clubs that run twice a week for 20 weeks; and ten sets of parent information sheets that are distributed biweekly.All measures will be assessed at baseline (Time 0), at the end of the intervention period (Time 1) and four months after the intervention has ended (Time 2). As this is a feasibility study, our primary interest is in estimating the recruitment of schools and children, adherence to the intervention, and completeness of data collection for outcomes and costs.As the most likely primary outcome measure in a future definitive trial will be accelerometer-determined minutes of moderate-to-vigorous PA (MVPA) per day, participants will wear accelerometers for five days (including two weekend days). Several psychosocial variables that could act as mediators in a future trial will be assessed via a questionnaire. Process evaluations of the session attendance, perceived enjoyment and perceived exertion will be assessed during the intervention. At the end of the intervention period, qualitative assessments will be conducted to identify how the programme could be improved before proceeding to a larger trial. DISCUSSION: The goal of the feasibility trial is to assess the potential of this innovative intervention approach and provide all the information necessary to design a cluster randomized controlled trial. TRIAL REGISTRATION: ISRCTN, ISRCTN58502739.

Classroom based cognitive behavioural therapy in reducing symptoms of depression in high risk adolescents: pragmatic cluster randomised controlled trial.

OBJECTIVE: To compare the effectiveness of classroom based cognitive behavioural therapy with attention control and usual school provision for adolescents at high risk of depression. DESIGN: Three arm parallel cluster randomised controlled trial. SETTING: Eight UK secondary schools. PARTICIPANTS: Adolescents (n=5030) aged 12-16 years in school year groups 8-11. Year groups were randomly assigned on a 1:1:1 ratio to cognitive behavioural therapy, attention control, or usual school provision. Allocation was balanced by school, year, number of students and classes, frequency of lessons, and timetabling. Participants were not blinded to treatment allocation. INTERVENTIONS: Cognitive behavioural therapy, attention control, and usual school provision provided in classes to all eligible participants. MAIN OUTCOME MEASURES: Outcomes were collected by self completed questionnaire administered by researchers. The primary outcome was symptoms of depression assessed at 12 months by the short mood and feelings questionnaire among those identified at baseline as being at high risk of depression. Secondary outcomes included negative thinking, self worth, and anxiety. Analyses were undertaken on an intention to treat basis and accounted for the clustered nature of the design. RESULTS: 1064 (21.2%) adolescents were identified at high risk of depression: 392 in the classroom based cognitive behavioural therapy arm, 374 in the attention control arm, and 298 in the usual school provision arm. At 12 months adjusted mean scores on the short mood and feelings questionnaire did not differ for cognitive behavioural therapy versus attention control (-0.63, 95% confidence interval -1.85 to 0.58, P=0.41) or for cognitive behavioural therapy versus usual school provision (0.97, -0.20 to 2.15, P=0.12). CONCLUSION: In adolescents with depressive symptoms, outcomes were similar for attention control, usual school provision, and cognitive behavioural therapy. Classroom based cognitive behavioural therapy programmes may result in increased self awareness and reporting of depressive symptoms but should not be undertaken without further evaluation and research. TRIAL REGISTRATION: Current Controlled Trials ISRCTN19083628.