Summary Background Bone metastases are a major cause of morbidity and mortality in men with prostate cancer. Preclinical studies suggest that osteoclast inhibition might prevent bone metastases. We ...assessed denosumab, a fully human anti-RANKL monoclonal antibody, for prevention of bone metastasis or death in non-metastatic castration-resistant prostate cancer. Methods In this phase 3, double-blind, randomised, placebo-controlled study, men with non-metastatic castration-resistant prostate cancer at high risk of bone metastasis (prostate-specific antigen PSA ≥8·0 μg/L or PSA doubling time ≤10·0 months, or both) were enrolled at 319 centres from 30 countries. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous denosumab 120 mg or subcutaneous placebo every 4 weeks. Randomisation was stratified by PSA eligibility criteria and previous or ongoing chemotherapy for prostate cancer. Patients, investigators, and all people involved in study conduct were masked to treatment allocation. The primary endpoint was bone-metastasis-free survival, a composite endpoint determined by time to first occurrence of bone metastasis (symptomatic or asymptomatic) or death from any cause. Efficacy analysis was by intention to treat. The masked treatment phase of the trial has been completed. This trial was registered at ClinicalTrials.gov , number NCT00286091. Findings 1432 patients were randomly assigned to treatment groups (716 denosumab, 716 placebo). Denosumab significantly increased bone-metastasis-free survival by a median of 4·2 months compared with placebo (median 29·5 95% CI 25·4–33·3 vs 25·2 22·2–29·5 months; hazard ratio HR 0·85, 95% CI 0·73–0·98, p=0·028). Denosumab also significantly delayed time to first bone metastasis (33·2 95% CI 29·5–38·0 vs 29·5 22·4–33·1 months; HR 0·84, 95% CI 0·71–0·98, p=0·032). Overall survival did not differ between groups (denosumab, 43·9 95% CI 40·1–not estimable months vs placebo, 44·8 40·1–not estimable months; HR 1·01, 95% CI 0·85–1·20, p=0·91). Rates of adverse events and serious adverse events were similar in both groups, except for osteonecrosis of the jaw and hypocalcaemia. 33 (5%) patients on denosumab developed osteonecrosis of the jaw versus none on placebo. Hypocalcaemia occurred in 12 (2%) patients on denosumab and two (<1%) on placebo. Interpretation This large randomised study shows that targeting of the bone microenvironment can delay bone metastasis in men with prostate cancer. Funding Amgen Inc.
Crisis resolution and home treatment teams (CRTs) offer an alternative to hospital admission for patients undergoing mental health crises in the UK. Few studies have been done to examine predictors ...of relapse and readmission after contact with CRTs.
We used the Clinical Record Interactive Search to identify all patients receiving care from CRTs in two National Health Service (NHS) mental health trusts in London: Camden and Islington NHS Foundation Trust and South London and Maudsley NHS Foundation Trust. We used Cox regression models to examine rates and predictors of admission to acute mental health services within 1 year of contact with CRTs. Sex, age, ethnicity, marital status, social deprivation, severity of psychopathology, duration of index CRT episode, first contact with services, and diagnosis were extracted and examined as predictors of admission.
Between Jan 1, 2008, and Aug 31, 2014, 17 666 patients were treated by CRTs-8759 patients in the Camden and Islington trust and 8907 patients in the South London and Maudsley trust. 53·9 patients per 100 person-years (95% CI 52·1-55·8) in Camden and Islington and 51·3 patients per 100 person-years (95% CI 49·6-53·1) in South London and Maudsley were admitted to acute services within 1 year of seeing the CRT. In both cohorts, non-affective psychotic disorders (adjusted hazard ratio HR 1·25, 95% CI 1·09-1·44 in Camden and Islington; 1·27, 1·17-1·38 in South London and Maudsley) and age older than 65 years (1·18, 1·01-1·37 in Camden and Islington; 1·32, 1·12-1·56 in South London and Maudsley) were associated with increased risk of admission, whereas first contact with services (0·57, 0·52-0·62 in Camden and Islington; 0·69, 0·63-0·75 in South London and Maudsley), anxiety disorders (0·81, 0·69-0·96 in Camden and Islington; 0·77, 0·67-0·87 in South London and Maudsley), and longer index CRT episodes (adjusted HR per day 0·996, 0·994-0·998 in Camden and Islington; 0·989, 0·987-0·991 in South London and Maudsley) were associated with reduced risk of admission.
Past use of mental health services and a diagnosis of non-affective psychosis, which are markers of severity of mental illness, and older age, which is a marker of chronicity, are all risk factors for future relapse after interactions with CRTs. These findings might help clinicians and policy makers to offer more targeted and cost-effective services to reduce relapse rates.
None.
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