Grace Young

Effect of a low-intensity psa-based screening intervention on prostate cancer mortality : The CAP randomized clinical trial

Importance Prostate cancer screening remains controversial because potential mortality or quality-of-life benefits may be outweighed by harms from overdetection and overtreatment. Objective To evaluate the effect of a single prostate-specific antigen (PSA) screening intervention and standardized diagnostic pathway on prostate cancer–specific mortality. Design, Setting, and Participants The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) included 419 582 men aged 50 to 69 years and was conducted at 573 primary care practices across the United Kingdom. Randomization and recruitment of the practices occurred between 2001 and 2009; patient follow-up ended on March 31, 2016. Intervention An invitation to attend a PSA testing clinic and receive a single PSA test vs standard (unscreened) practice. Main Outcomes and Measures Primary outcome: prostate cancer–specific mortality at a median follow-up of 10 years. Prespecified secondary outcomes: diagnostic cancer stage and Gleason grade (range, 2-10; higher scores indicate a poorer prognosis) of prostate cancers identified, all-cause mortality, and an instrumental variable analysis estimating the causal effect of attending the PSA screening clinic. Results Among 415 357 randomized men (mean [SD] age, 59.0 [5.6] years), 189 386 in the intervention group and 219 439 in the control group were included in the analysis (n = 408 825; 98%). In the intervention group, 75 707 (40%) attended the PSA testing clinic and 67 313 (36%) underwent PSA testing. Of 64 436 with a valid PSA test result, 6857 (11%) had a PSA level between 3 ng/mL and 19.9 ng/mL, of whom 5850 (85%) had a prostate biopsy. After a median follow-up of 10 years, 549 (0.30 per 1000 person-years) died of prostate cancer in the intervention group vs 647 (0.31 per 1000 person-years) in the control group (rate difference, −0.013 per 1000 person-years [95% CI, −0.047 to 0.022]; rate ratio [RR], 0.96 [95% CI, 0.85 to 1.08]; P = .50). The number diagnosed with prostate cancer was higher in the intervention group (n = 8054; 4.3%) than in the control group (n = 7853; 3.6%) (RR, 1.19 [95% CI, 1.14 to 1.25]; P < .001). More prostate cancer tumors with a Gleason grade of 6 or lower were identified in the intervention group (n = 3263/189 386 [1.7%]) than in the control group (n = 2440/219 439 [1.1%]) (difference per 1000 men, 6.11 [95% CI, 5.38 to 6.84]; P < .001). In the analysis of all-cause mortality, there were 25 459 deaths in the intervention group vs 28 306 deaths in the control group (RR, 0.99 [95% CI, 0.94 to 1.03]; P = .49). In the instrumental variable analysis for prostate cancer mortality, the adherence-adjusted causal RR was 0.93 (95% CI, 0.67 to 1.29; P = .66). Conclusions and Relevance Among practices randomized to a single PSA screening intervention vs standard practice without screening, there was no significant difference in prostate cancer mortality after a median follow-up of 10 years but the detection of low-risk prostate cancer cases increased. Although longer-term follow-up is under way, the findings do not support single PSA testing for population-based screening. Trial Registration ISRCTN Identifier: ISRCTN92187251

Patient-reported outcomes in the ProtecT randomized trial of clinically localized prostate cancer treatments: study design, and baseline urinary, bowel and sexual function and quality of life

To present the baseline patient‐reported outcome measures (PROMs) in the Prostate Testing for Cancer and Treatment (ProtecT) randomized trial comparing active monitoring, radical prostatectomy and external‐beam conformal radiotherapy for localized prostate cancer and to compare results with other populations.

Urodynamics for Prostate Surgery Trial; Randomised Evaluation of Assessment Methods (UPSTREAM) for diagnosis and management of bladder outlet obstruction in men: study protocol for a randomised controlled trial

BackgroundLower urinary tract symptoms (LUTS) comprise storage symptoms, voiding symptoms and post-voiding symptoms. Prevalence and severity of LUTS increase with age and the progressive increase in the aged population group has emphasised the importance to our society of appropriate and effective management of male LUTS. Identification of causal mechanisms is needed to optimise treatment and uroflowmetry is the simplest non-invasive test of voiding function. Invasive urodynamics can evaluate storage function and voiding function; however, there is currently insufficient evidence to support urodynamics becoming part of routine practice in the clinical evaluation of male LUTS.DesignA 2-arm trial, set in urology departments of at least 26 National Health Service (NHS) hospitals in the United Kingdom (UK), randomising men with bothersome LUTS for whom surgeons would consider offering surgery, between a care pathway based on urodynamic tests with invasive multichannel cystometry and a care pathway based on non-invasive routine tests. The aim of the trial is to determine whether a care pathway not including invasive urodynamics is no worse for men in terms of symptom outcome than one in which it is included, at 18 months after randomisation. This primary clinical outcome will be measured with the International Prostate Symptom Score (IPSS). We will also establish whether inclusion of invasive urodynamics reduces rates of bladder outlet surgery as a main secondary outcome.DiscussionThe general population has an increased life-expectancy and, as men get older, their prostates enlarge and potentially cause benign prostatic obstruction (BPO) which often requires surgery. Furthermore, voiding symptoms become increasingly prevalent, some of which may not be due to BPO. Therefore, as the population ages, more operations will be considered to relieve BPO, some of which may not actually be appropriate. Hence, there is sustained interest in the diagnostic pathway and this trial could improve the chances of an accurate diagnosis and reduce overall numbers of surgical interventions for BPO in the NHS. The morbidity, and therapy costs, of testing must be weighed against the cost saving of surgery reduction.Trial registrationControlled-trials.com - ISRCTN56164274 (confirmed registration: 8 April 2014).

Prostate-specific antigen (PSA) testing of men in UK general practice: a 10-year longitudinal cohort study

Objectives Cross-sectional studies suggest that around 6% of men undergo prostate-specific antigen (PSA) testing each year in UK general practice (GP). This longitudinal study aims to determine the cumulative testing pattern of men over a 10-year period and whether this testing can be considered equivalent to screening for prostate cancer (PCa). Setting, participants and outcome measures Patient-level data on PSA tests, biopsies and PCa diagnoses were obtained from the UK Clinical Practice Research Datalink (CPRD) for the years 2002 to 2011. The cumulative risks of PSA testing and of being diagnosed with PCa were estimated for the 10-year study period. Associations of a man’s age, region and index of multiple deprivation with the cumulative risk of PSA testing and PCa diagnosis were investigated. Rates of biopsy and diagnosis, following a high test result, were compared with those from the programme of PSA testing in the Prostate Testing for Cancer and Treatment (ProtecT) study. Results The 10-year risk of exposure to at least one PSA test in men aged 45 to 69 years in UK GP was 39.2% (95% CI 39.0 to 39.4%). The age-specific risks ranged from 25.2% for men aged 45–49 years to 53.0% for men aged 65–69 years (p for trend <0.001). For those with a PSA level ≥3, a test in UK GP was less likely to result in a biopsy (6%) and/or diagnosis of PCa (15%) compared with ProtecT study participants (85% and 34%, respectively). Conclusion A high proportion of men aged 45–69 years undergo PSA tests in UK GP: 39% over a 10-year period. A high proportion of these tests appear to be for the investigation of lower urinary tract symptoms and not screening for PCa. Trial registration number ISRCTN20141297, NCT02044172.

Informed consent in randomised controlled trials: Development and preliminary evaluation of a measure of Participatory and Informed Consent (PIC)

BackgroundInformed consent (IC) is an ethical and legal prerequisite for trial participation, yet current approaches evaluating participant understanding for IC during recruitment lack consistency. No validated measure has been identified that evaluates participant understanding for IC based on their contributions during consent interactions. This paper outlines the development and formative evaluation of the Participatory and Informed Consent (PIC) measure for application to recorded recruitment appointments. The PIC allows the evaluation of recruiter information provision and evidence of participant understanding.MethodsPublished guidelines for IC were reviewed to identify potential items for inclusion. Seventeen purposively sampled trial recruitment appointments from three diverse trials were reviewed to identify the presence of items relevant to IC. A developmental version of the measure (DevPICv1) was drafted and applied to six further recruitment appointments from three further diverse trials to evaluate feasibility, validity, stability and inter-rater reliability. Findings guided revision of the measure (DevPICv2) which was applied to six further recruitment appointments as above.ResultsDevPICv1 assessed recruiter information provision (detail and clarity assessed separately) and participant talk (detail and understanding assessed separately) over 20 parameters (or 23 parameters for three-arm trials). Initial application of the measure to six diverse recruitment appointments demonstrated promising stability and inter-rater reliability but a need to simplify the measure to shorten time for completion. The revised measure (DevPICv2) combined assessment of detail and clarity of recruiter information and detail and evidence of participant understanding into two single scales for application to 22 parameters or 25 parameters for three-arm trials. Application of DevPICv2 to six further diverse recruitment appointments showed considerable improvements in feasibility (e.g. time to complete) with good levels of stability (i.e. test-retest reliability) and inter-rater reliability maintained.ConclusionsThe DevPICv2 provides a measure for application to trial recruitment appointments to evaluate quality of recruiter information provision and evidence of patient understanding and participation during IC discussions. Initial evaluation shows promising feasibility, validity, reliability and ability to discriminate across a range of recruiter practice and evidence of participant understanding. More validation work is needed in new clinical trials to evaluate and refine the measure further.

Effect of Oral Prednisolone on Symptom Duration and Severity in Nonasthmatic Adults With Acute Lower Respiratory Tract Infection: A Randomized Clinical Trial

Importance Acute lower respiratory tract infection is common and often treated inappropriately in primary care with antibiotics. Corticosteroids are increasingly used but without sufficient evidence. Objective To assess the effects of oral corticosteroids for acute lower respiratory tract infection in adults without asthma. Design, Setting, and Participants Multicenter, placebo-controlled, randomized trial (July 2013 to final follow-up October 2014) conducted in 54 family practices in England among 401 adults with acute cough and at least 1 lower respiratory tract symptom not requiring immediate antibiotic treatment and with no history of chronic pulmonary disease or use of asthma medication in the past 5 years. Interventions Two 20-mg prednisolone tablets (n = 199) or matched placebo (n = 202) once daily for 5 days. Main Outcomes and Measures The primary outcomes were duration of moderately bad or worse cough (0 to 28 days; minimal clinically important difference, 3.79 days) and mean severity of symptoms on days 2 to 4 (scored from 0 [not affected] to 6 [as bad as it could be]; minimal clinically important difference, 1.66 units). Secondary outcomes were duration and severity of acute lower respiratory tract infection symptoms, duration of abnormal peak flow, antibiotic use, and adverse events. Results Among 401 randomized patients, 2 withdrew immediately after randomization, and 1 duplicate patient was identified. Among the 398 patients with baseline data (mean age, 47 [SD, 16.0] years; 63% women; 17% smokers; 77% phlegm; 70% shortness of breath; 47% wheezing; 46% chest pain; 42% abnormal peak flow), 334 (84%) provided cough duration and 369 (93%) symptom severity data. Median cough duration was 5 days (interquartile range [IQR], 3-8 days) in the prednisolone group and 5 days (IQR, 3-10 days) in the placebo group (adjusted hazard ratio, 1.11; 95% CI, 0.89-1.39; P = .36 at an &agr; = .05). Mean symptom severity was 1.99 points in the prednisolone group and 2.16 points in the placebo group (adjusted difference, −0.20; 95% CI, −0.40 to 0.00; P = .05 at an &agr; = .001). No significant treatment effects were observed for duration or severity of other acute lower respiratory tract infection symptoms, duration of abnormal peak flow, antibiotic use, or nonserious adverse events. There were no serious adverse events. Conclusions and Relevance Oral corticosteroids should not be used for acute lower respiratory tract infection symptoms in adults without asthma because they do not reduce symptom duration or severity. Trial Registration ISRCTN.com Identifier: ISRCTN57309858

Do people who choose their treatment in a large randomised trial with parallel preference groups differ at baseline from those who agree to random treatment allocation? Results from the protect study

Background Many patients decline participation in randomised trials due to treatment preferences. It is not known whether it is possible to combine evidence from those choosing treatment and those randomised in RCTs with parallel non-randomised preference groups without compromising external validity. This study explored whether people who chose their treatment within an RCT in which recruiters were trained to explore treatment preferences were different at baseline from those who agreed to randomisation.

A prospective cohort and extended comprehensive-cohort design provided insights about the generalizability of a pragmatic trial: the ProtecT prostate cancer trial

Objectives Randomized controlled trials (RCTs) deliver robust internally valid evidence but generalizability is often neglected. Design features built into the Prostate testing for cancer and Treatment (ProtecT) RCT of treatments for localized prostate cancer (PCa) provided insights into its generalizability. Study Design and Setting Population-based cluster randomization created a prospective study of prostate-specific antigen (PSA) testing and a comprehensive-cohort study including groups choosing treatment or excluded from the RCT, as well as those randomized. Baseline information assessed selection and response during RCT conduct. Results The prospective study (82,430 PSA-tested men) represented healthy men likely to respond to a screening invitation. The extended comprehensive cohort comprised 1,643 randomized, 997 choosing treatment, and 557 excluded with advanced cancer/comorbidities. Men choosing treatment were very similar to randomized men except for having more professional/managerial occupations. Excluded men were similar to the randomized socio-demographically but different clinically, representing less healthy men with more advanced PCa. Conclusion The design features of the ProtecT RCT provided data to assess the representativeness of the prospective cohort and generalizability of the findings of the RCT. Greater attention to collecting data at the design stage of pragmatic trials would better support later judgments by clinicians/policy-makers about the generalizability of RCT findings in clinical practice.

Cross-sectional study evaluating data quality of the National Cancer Registration and Analysis Service (NCRAS) prostate cancer registry data using the Cluster randomised trial of PSA testing for Prostate cancer (CAP)

Objectives To compare the completeness and agreement of prostate cancer data recorded by the National Cancer Registration and Analysis Service (NCRAS) with research-level data specifically abstracted from medical records from the Cluster randomised triAl of prostate specific antigen (PSA) testing for Prostate cancer (CAP) trial. Design Cross-sectional comparison study. Participants We included 1356 men from the CAP trial cohort who were linked to the NCRAS registry. Primary and secondary outcome measures Completeness of prostate cancer data in NCRAS and CAP and agreement for tumour, node, metastases (TNM) stage (T1/T2; T3; T4/N1/M1) and Gleason grade (4–6; 7; 8–10), measured by differences in proportions and Cohen’s kappa statistic. Data were also stratified by year and pre-2010 versus post-2010, when NCRAS reporting standards changed. Results Compared with CAP, completeness was lower in NCRAS for Gleason grade (41.2% vs 76.7%, difference 35.5, 95% CI 32.1 to 39.0) and TNM stage (29.9% vs 67.6%, difference 37.6, 95% CI 34.1 to 41.1). NCRAS completeness for Gleason grade (pre-2010 vs post-2010 31.69% vs 64%; difference 32.31, 95% CI 26.76 to 37.87) and TNM stage (19.31% vs 55.50%; difference 36.19, 95% CI 30.72 to 41.67) improved over time. Agreement for Gleason grade was high (Cohen’s kappa, κ=0.90, 95% CI 0.88 to 0.93), but lower for TNM stage (κ=0.41, 95% CI 0.37 to 0.51) overall. There was a trend towards improved agreement on Gleason grade, but not TNM stage, when comparing pre-2010 and post-2010 data. Conclusion NCRAS case identification was very high; however, data on prostate cancer grade was less complete than CAP, and agreement for TNM stage was modest. Although the completeness of NCRAS data has improved since 2010, the higher completeness rate in CAP demonstrates that gains could potentially be achieved in routine registry data. This study’s findings highlight a need for improved recording of stage and grade data in the source medical records.

Validation of the National Cancer Registration and Analysis Service prostate cancer registry with data from the CAP study

Abstract Background Prostate cancer is the second most common cancer in the UK, with 39 741 cases diagnosed in 2014. The National Cancer Registration and Analysis Service (NCRAS) collects data about cancer (including prostate cancer) in England. The CAP study is a cluster-randomised controlled trial investigating the effectiveness and cost-effectiveness of prostate-specific antigen (PSA) testing. The value of cancer registries is high if they receive and process quality data, which can be evaluated in various domains, including completeness and validity. This study aimed to compare the completeness and accuracy of the NCRAS registry with data from the CAP study. Methods We compared the percentage completeness and agreement of prostate cancer diagnosis by Union Internationale Contre le Cancer (UICC) TNM stage and Gleason grade in the NCRAS cancer registry with information collected via independent medical record review on participants in CAP. CAP study participants were matched to NCRAS registry entries by their National Health Service number. Agreement was assessed with Cohens κ. Findings 1356 men were included in this study (mean age 75·1 years, SD 5·1). Both the NCRAS registry (97·9%) and CAP study (98·5%) had high levels of completeness for date of diagnosis. Agreement was high for combined Gleason score (κ=0·90, 95% CI 0·89–092) and low for American Joint Committee on Cancer (AJCC) group (0·48, 0·43–0·53) overall. TNM staging agreement was 0·35 (0·31–0·37) for T, 0·51 (0·45–0·57) for N, and 0·58 (0·51–0·66) for M stage. Agreement was moderate when considering local (T1–3N0M0) versus metastatic disease (T4NxMx/TxN1Mx/TxNxM1) (0·54, 0·44–0·64). Interpretation The NCRAS prostate cancer registry has a high level of completeness for case registration, and strong accuracy for Gleason grade. Agreement of exact TNM staging and AJCC group seems low, which could be explained if staging data were collected from different sources (ie, pathological vs imaging staging methods), and needs to be explored further. Prostate cancer stage and accuracy of grade data for the NCRAS registry need repeated assessment to drive improvements in data quality. Funding None.