David Matheson

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

Summary 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/m2) 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.

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.)

How well prepared are medical students for their first year as doctors? The views of consultants and specialist registrars in two teaching hospitals

Objective: To evaluate (1) the extent to which first year doctors (foundation year 1 doctors, F1s) in two teaching hospitals in the Trent Deanery were rated by specialist registrars (SpRs) and consultants as being well prepared for practice; (2) the importance ascribed by SpRs and consultants to the various items of core knowledge, skills and attitudes outlined in the publication of the General Medical Council, Tomorrow’s Doctors. Method: SpRs and consultants were asked to rate: how well prepared F1s were in a range of items of core knowledge, skills and attitudes that a new medical graduate must possess as outlined in Tomorrow’s Doctors; the importance for a new doctor of each item of core knowledge, skills and attitudes; and how well the medical school had prepared F1s in respect of key generic issues related to their practice. Results: In most of the items of core knowledge, skills and attitudes covering 8 of the 11 topic areas of Tomorrow’s Doctors, F1s were seen as not prepared for starting work, especially in regard to clinical and practical skills and the more challenging communication skills. They were best prepared in asking for help and in basic communication skills. Conclusions: Overall, F1s in the study were not well prepared either to perform the tasks that await them or in terms of most of the specific background knowledge and skills necessary for the successful execution of those tasks. The level of preparedness raises important issues about medical training and transition from medical graduate to first year doctor. Further research is needed to determine whether this situation exists in other regions of the UK.

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.

Lifelong Learning and Lifelong Education: a critique

It is suddenly fashionable in political circles in the United Kingdom (and elsewhere) to talk about lifelong learning and lifelong education. This seems to be the direct result of the present economic climate which has called into question many previous assumptions: job security has become an effective myth for most of those who can actually get work; long?term unemployment seems to have become structural and permanent. Consequently, the notions of lifelong learning and lifelong education have taken on dimensions far removed from the almost Utopian ideals of their supporters in the years following the publication of the report Learning to Be. Given the current economic gloom, the popularity of the terms with politicians and the fact of being in the European Year of Lifelong Learning, it is perhaps appropriate to take stock of the whole notion of lifelong learning and lifelong education and to see just what meaning (if any) lies behind these words and where they might take us in the future. This essay lays its foundations in the historical background to the ideas of lifelong learning and lifelong education before moving onto a critique of the post?Faure advocates of the principles. It discusses various problems inherent in the concepts (such as lifelong inadequacy) before concluding that, although many of the difficulties in the concepts are due to the confused nature of adult education itself (e.g. is it education or leisure?), there is a greater need than ever for sustained efforts in favour of lifelong education to help to restore the hope which seems to have become a rare commodity among an all too large section of society.

The views of doctors in their first year of medical practice on the lasting impact of a preparation for house officer course they undertook as final year medical students

BackgroundThe UK General Medical Council recommends that medical students have the opportunity of shadowing the outgoing new doctor whose post they will soon undertake. At the University of Nottingham the two-week shadowing period was preceded by two weeks of lectures/seminars wherein students followed sessions on topics such as common medical/surgical emergencies, contracts, time management, surviving the first two years of clinical practice, careers advice and so on.The present study aimed to gain a better knowledge and understanding of the lasting impact of a four-week preparation course for new Foundation Year 1 doctors [F1 s - interns]. The objectives chosen to achieve this aim were:1/ to determine the extent to which the lecture/seminar course and shadowing period achieved their stated aim of smoothing the transition from life as a medical student to work as a new doctor;2/ to evaluate perceptions of the importance of various forms of knowledge in easing the transition between medical student and new doctorMethodIn the spring of 2007, 90 graduates from Nottingham were randomly selected and then emailed a link to a short, online survey of quantitative and qualitative questions. Of these 76 responded. Analysis of quantitative data was carried out using SPSS 16.0 and employed McNemars test. Analysis of the qualitative data was carried out using the constant comparative method.ResultsOnly 31% of respondents strongly agreed or agreed that the lecture/seminar part of the course prepared them well for their first FY1 post; 14% agreed that during their first job they drew on the knowledge gained during the lecture/seminar course; 94% strongly agreed or agreed that the shadowing part of the course was more useful than the lecture/seminar part.Experiential knowledge gained in the shadowing was the most highly valued, followed by procedural knowledge with propositional knowledge coming far behind.ConclusionsOur study shows that new doctors retrospectively value most the knowledge they are able to transfer to the workplace and value least material which seems to repeat what they had learned for their final exams.

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.

New theory from an old technique: the Rolma matrices

Background:  Understanding the reasons behind non‐adherence to clinical practice guidelines is a complex process. Many explanatory models have been proposed that are grounded in qualitative theory. The 2 × 2 matrix has often been used to condense this potentially complex information into a format understandable to clinicians without educational or qualitative backgrounds.

Towards a conceptual framework demonstrating the effectiveness of audiovisual patient descriptions (patient video cases): a review of the current literature

BackgroundTechnological advances have enabled the widespread use of video cases via web-streaming and online download as an educational medium. The use of real subjects to demonstrate acute pathology should aid the education of health care professionals. However, the methodology by which this effect may be tested is not clear.MethodsWe undertook a literature review of major databases, found relevant articles relevant to using patient video cases as educational interventions, extracted the methodologies used and assessed these methods for internal and construct validity.ResultsA review of 2532 abstracts revealed 23 studies meeting the inclusion criteria and a final review of 18 of relevance. Medical students were the most commonly studied group (10 articles) with a spread of learner satisfaction, knowledge and behaviour tested. Only two of the studies fulfilled defined criteria on achieving internal and construct validity. The heterogeneity of articles meant it was not possible to perform any meta-analysis.ConclusionsPrevious studies have not well classified which facet of training or educational outcome the study is aiming to explore and had poor internal and construct validity. Future research should aim to validate a particular outcome measure, preferably by reproducing previous work rather than adopting new methods. In particular cognitive processing enhancement, demonstrated in a number of the medical student studies, should be tested at a postgraduate level.

Languages of Scotland: culture and the classroom

The indigenous languages of Scotland are in a precarious position faced with the massive presence of English. This essay examines the state and nature of the Scots and Gaelic languages. It places them in their historical context and traces how each has had its heyday in Scotland, in the case of Gaelic to be supplanted by Scots and in the case of Scots to be supplanted by English. Both have become marginalised in Scottish life and in the Scottish school. Both have been subject to various concerted campaigns aimed at their destruction. Gaelic, however, has at least had the consolation of being regarded as a language while Scots has not. The changing relationship between the school and these languages is examined in the context of the current revival of Scottish culture on a multiplicity of fronts.