Feasibility, pitfalls and results of a structured concept-development phase for a randomized controlled phase III trial on radiotherapy in primary prostate cancer patients.

OBJECTIVE: Failure rate in randomized controlled trials (RCTs) is > 50%, includes safety-problems, underpowered statistics, lack of efficacy, lack of funding or insufficient patient recruitment and is even more pronounced in oncology trials. We present results of a structured concept-development phase (CDP) for a phase III RCT on personalized radiotherapy (RT) in primary prostate cancer (PCa) patients implementing prostate specific membrane antigen targeting positron emission tomography (PSMA-PET). MATERIALS AND METHODS: The 1 yr process of the CDP contained five main working packages: (i) literature search and scoping review, (ii) involvement of individual patients, patients' representatives and patients' self-help groups addressing the patients' willingness to participate in the preparation process and the conduct of RCTs as well as the patient informed consent (PIC), (iii) involvement of national and international experts and expert panels (iv) a phase II pilot study investigating the safety of implementation of PSMA-PET for focal dose escalation RT and (v) in-silico RT planning studies assessing feasibility of envisaged dose regimens and effects of urethral sparing in focal dose escalation. RESULTS: (i) Systematic literature searches confirmed the high clinical relevance for more evidence on advanced RT approaches, in particular stereotactic body RT, in high-risk PCa patients. (ii) Involvement of patients, patient representatives and randomly selected males relevantly changed the PIC and initiated a patient empowerment project for training of bladder preparation. (iii) Discussion with national and international experts led to adaptions of inclusion and exclusion criteria. (iv) Fifty patients were treated in the pilot trial and in- and exclusion criteria as well as enrollment calculations were adapted accordingly. Parallel conduction of the pilot trial revealed pitfalls on practicability and broadened the horizon for translational projects. (v) In-silico planning studies confirmed feasibility of envisaged dose prescription. Despite large prostate- and boost-volumes of up to 66% of the prostate, adherence to stringent anorectal dose constraints was feasible. Urethral sparing increased the therapeutic ratio. CONCLUSION: The dynamic framework of interdisciplinary working programs in CDPs enhances robustness of RCT protocols and may be associated with decreased failure rates. Structured recommendations are warranted to further define the process of such CDPs in radiation oncology trials.

Inequalities in tuberculosis mortality: long-term trends in 11 European countries.

SETTING: Previous studies in many countries have shown that mortality due to tuberculosis (TB) is higher among people of lower socio-economic status. OBJECTIVE: To assess the magnitude and direction of trends in educational inequalities in TB mortality in 11 European countries. DESIGN: Data on TB mortality between 1980 and 2011 were collected among persons aged 35-79 years. Age-standardised mortality rates by educational level were calculated. Inequalities were estimated using the relative and slope indices of inequality. RESULTS: In the first decade of the twenty-first century, educational inequalities in TB mortality occurred in all countries in this study. The largest absolute inequalities were observed in Lithuania, and the smallest in Denmark. In most countries, relative inequalities have remained stable since the 1980s or 1990s, while absolute inequalities remained stable or went down. In Lithuania and Estonia, however, absolute inequalities increased substantially. CONCLUSION: The reduction in absolute inequalities in TB mortality, as seen in many European countries, is a major achievement; however, inequalities persist and are still a major cause for concern in the twenty-first century. Interventions aimed at preventing TB disease and reducing TB case fatality in lower socio-economic groups should be intensified, especially in the Baltic countries.