Long-Term Follow-Up of a Large Active Surveillance Cohort of Patients With Prostate Cancer

PURPOSE: Active surveillance is increasingly accepted as a treatment option for favorable-risk prostate cancer. Long-term follow-up has been lacking. In this study, we report the long-term outcome of a large active surveillance protocol in men with favorable-risk prostate cancer.

PATIENTS AND METHODS: In a prospective single-arm cohort study carried out at a single academic health sciences center, 993 men with favorable- or intermediate-risk prostate cancer were managed with an initial expectant approach. Intervention was offered for a prostate-specific antigen (PSA) doubling time of less than 3 years, Gleason score progression, or unequivocal clinical progression. Main outcome measures were overall and disease-specific survival, rate of treatment, and PSA failure rate in the treated patients.

RESULTS: Among the 819 survivors, the median follow-up time from the first biopsy is 6.4 years (range, 0.2 to 19.8 years). One hundred forty-nine (15%) of 993 patients died, and 844 patients are alive (censored rate, 85.0%). There were 15 deaths (1.5%) from prostate cancer. The 10- and 15-year actuarial cause-specific survival rates were 98.1% and 94.3%, respectively. An additional 13 patients (1.3%) developed metastatic disease and are alive with confirmed metastases (n = 9) or have died of other causes (n = 4). At 5, 10, and 15 years, 75.7%, 63.5%, and 55.0% of patients remained untreated and on surveillance. The cumulative hazard ratio for nonprostate-to-prostate cancer mortality was 9.2:1.

CONCLUSION: Active surveillance for favorable-risk prostate cancer is feasible and seems safe in the 15-year time frame. In our cohort, 2.8% of patients have developed metastatic disease, and 1.5% have died of prostate cancer. This mortality rate is consistent with expected mortality in favorable-risk patients managed with initial definitive intervention.

Physical activity and sport participation for people with long-term illness

Purpose:Physical activity is recommended for optimal prevention of cardiovascular disease(CVD) and participation in sport is associated with improved well-being. However, people with long-standing illness/disability are less likely to participate in sport than others. Evidence of factors associated with their participation is limited and the best approach to encourage participation is unknown. This study aimed to identify sport participation levels and their correlates, among adults with long standing illness/disability in Northern Ireland, where CVD prevalence is high. Method:Using routinely collected data in annual surveys of population samples from 2007 to 2011, descriptive statistics were derived. Chi-squared tests were used to compare characteristics of those with a long-term illness/disability and those without long-term health problems. Uni-variate binary regression analysis for the whole sample and those with a long-standing illness/disability, using sport participation as the dependent variable, was performed and variables with a p-value of 0.1 or less were taken into a multi-variate analysis. Results:The sample included 13,683 adults; 3550(26%) reported having long-term illness/disability. Fewer of those with, than without, long-term illness/disability reported sport participation in the previous year (868/3550(24.5%) v 5615/10133(55.6%)). Multi-variate analysis showed that, for those with long-standing illness/disability, being single and less socio-economically deprived correlated positively with sport participation. For both those with long-standing illness/disability and the full sample, sport participation correlated positively with being male, aged <56 years, access to a household car/van, sports club membership, health ‘fairly good’ or ‘good’ in the previous year, doing paid/unpaid work, and living in an urban location. For the full sample but not those with long-standing illness/disability, sport participation correlated positively with being a non-smoker, higher educational status and personal internet access. Of note, personal internet access was less for those with, than without, long-term illness/disability (41% v 70%). Conclusions:Efforts to promote physical activity in sport for those with long-standing illness/disability should target older people, married females, those who live rurally, and those who are socio-economically deprived and report their health as ‘not good’. Implementation of initiatives should not rely on the internet, to which these people may not have ready access, to help support their sport participation and physical activity in optimal CVD prevention.

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.

Development of a new welfare assessment protocol for practical application in long-term dog shelters

In many European shelters, dogs may spend many years confined. A poor environment and inappropriate management may lead to a low quality of life. The absence of harmonised European regulatory frameworks defining the minimum requirements for shelter facilities makes the definition of welfare standards for kennelled dogs challenging. Here, a new protocol was developed and tested to help identify the main welfare issues for shelter dogs. Twenty-six indicators were identified including management, resource and animal based measures. Accuracy and interobserver reliability were checked between four assessors. The protocol was applied in 29 shelters (n=1308 dogs) in six European countries. Overall prevalence of poor health conditions was below 10%. Test-retest reliability and validity of the protocol were investigated with encouraging results. A logistic regression was carried out to assess the potential of the protocol as a tool to identify welfare hazards in shelter environments. Inappropriate space allowance, for example, was found to be a risk factor potentially affecting the animal's cleanliness, skin condition and body condition. The protocol was designed to be concise and easy to implement. Systematic data collection could help identify welfare problems that are likely to arise in certain shelter designs and thus determine improvement in animal care standards.

Long-term statin therapy in patients with systolic heart failure and normal cholesterol:effects on elevated serum markers of collagen turnover, inflammation, and B-type natriuretic peptide

BACKGROUND: The role of statin therapy in heart failure (HF) is unclear. The amino-terminal propeptide of procollagen type III (PIIINP) predicts outcome in HF, and yet there are conflicting reports of statin therapy effects on PIIINP.

OBJECTIVES: This study determined whether there was an increase in serum markers of inflammation, fibrosis (including PIIINP), and B-type natriuretic peptide (BNP) in patients with systolic HF and normal total cholesterol and determined the effects of long-term treatment with atorvastatin on these markers.

METHODS: Fifty-six white patients with systolic HF and normal cholesterol levels (age 72 [13] years; 68% male; body mass index 27.0 [7.3] kg/m(2); ejection fraction 35 [13]%; 46% with history of smoking) were randomly allocated to atorvastatin treatment for 6 months, titrated to 40 mg/d (A group) or not (C group). Age- and/or sex-matched subjects without HF (N group) were also recruited. Biomarkers were measured at baseline (all groups) and 6 months (A and C groups).

RESULTS: Serum markers of collagen turnover, inflammation, and BNP were significantly elevated in HF patients compared with normal participants (all P < 0.05). There were correlations between these markers in HF patients but not in normal subjects. Atorvastatin treatment for 6 months caused a significant reduction in the following biomarkers compared with baseline: BNP, from median (interquartile range) 268 (190-441) pg/mL to 185 (144-344) pg/mL; high-sensitivity C-reactive protein (hs-CRP), from 5.26 (1.95 -9.29) mg/L to 3.70 (2.34-6.81) mg/L; and PIIINP, from 4.65 (1.86) to 4.09 (1.25) pg/mL (all P < 0.05 baseline vs 6 months). Between-group differences were significant for PIIINP only (P = 0.027). There was a positive interaction between atorvastatin effects and baseline hs-CRP and PIIINP (P < 0.01).

CONCLUSIONS: Long-term statin therapy reduced PIIINP in this small, selected HF population with elevated baseline levels. Further evaluation of statin therapy in the management of HF patients with elevated PIIINP is warranted.

Path-Dependency, Stocks, Switching Points, Flows: Reflections on Long-term Global Change and Local Opportunities

This paper examines the possibilities for peripheral localities to achieve upward mobility in the world-system by “hooking on” to larger processes of world-system accumulation. In particular, is it possible for economies that are dependent on foreign investment to receive a flow of investments that is high enough to overcome the negative impacts of a high stock of foreign investment, thus enabling them to cross a threshold and achieve upward mobility in the world-system? An analysis of therecent experience of the southern Irish “Celtic Tiger” economy during 1990-2000 indicates that such an upward movement is possible on the basis of massive foreign investment inflows. On closer examination, however, the Irish-type model appears to be highly deficient, because a high proportion of growth is illusionary and also on grounds of social desirability and lack of generalizability.