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Active monitoring, radical prostatectomy, or radiotherapy for localised prostate cancer: study design and diagnostic and baseline results of the ProtecT randomised phase 3 trial

BACKGROUND Prostate cancer is a major public health problem with considerable uncertainties about the effectiveness of population screening and treatment options. We report the study design, participant sociodemographic and clinical characteristics, and the initial results of the testing and diagnostic phase of the Prostate testing for cancer and Treatment (ProtecT) trial, which aims to investigate the effectiveness of treatments for localised prostate cancer. METHODS In this randomised phase 3 trial, men aged 50-69 years registered at 337 primary care centres in nine UK cities were invited to attend a specialist nurse appointment for a serum prostate-specific antigen (PSA) test. Prostate biopsies were offered to men with a PSA concentration of 3·0 μg/L or higher. Consenting participants with clinically localised prostate cancer were randomly assigned to active monitoring (surveillance strategy), radical prostatectomy, or three-dimensional conformal external-beam radiotherapy by a computer-generated allocation system. Randomisation was stratified by site (minimised for differences in participant age, PSA results, and Gleason score). The primary endpoint is prostate cancer mortality at a median 10-year follow-up, ascertained by an independent committee, which will be analysed by intention to treat in 2016. This trial is registered with ClinicalTrials.gov, number NCT02044172, and as an International Standard Randomised Controlled Trial, number ISRCTN20141297. FINDINGS Between Oct 1, 2001, and Jan 20, 2009, 228,966 men were invited to attend an appointment with a specialist nurse. Of the invited men, 100,444 (44%) attended their initial appointment and 82,429 (82%) of attenders had a PSA test. PSA concentration was below the biopsy threshold in 73,538 (89%) men. Of the 8566 men with a PSA concentration of 3·0-19·9 μg/L, 7414 (87%) underwent biopsies. 2896 men were diagnosed with prostate cancer (4% of tested men and 39% of those who had a biopsy), of whom 2417 (83%) had clinically localised disease (mostly T1c, Gleason score 6). With the addition of 247 pilot study participants recruited between 1999 and 2001, 2664 men were eligible for the treatment trial and 1643 (62%) agreed to be randomly assigned (545 to active monitoring, 545 to radiotherapy, and 553 to radical prostatectomy). Clinical and sociodemographic characteristics of randomly assigned participants were balanced across treatment groups. INTERPRETATION The ProtecT trial randomly assigned 1643 men with localised prostate cancer to active monitoring, radiotherapy, or surgery. Participant clinicopathological features are more consistent with contemporary patient characteristics than in previous prostate cancer treatment trials. FUNDING UK National Institute for Health Research Health Technology Assessment Programme.

Impact of prostate cancer testing: an evaluation of the emotional consequences of a negative biopsy result

Background:When testing for prostate cancer, as many as 75% of men with a raised prostate-specific antigen (PSA) have a benign biopsy result. Little is known about the psychological effect of this result for these men.Methods:In all, 330 men participating in the prostate testing for cancer and treatment (ProtecT) study were studied; aged 50–69 years with a PSA level of ⩾3 ng ml−1 and a negative biopsy result. Distress and negative mood were measured at four time-points: two during diagnostic testing and two after a negative biopsy result.Results:The majority of men were not greatly affected by testing or a negative biopsy result. The impact on psychological health was highest at the time of the biopsy, with around 20% reporting high distress (33 out of 171) and tense/anxious moods (35 out of 180). Longitudinal analysis on 195 men showed a significant increase in distress at the time of the biopsy compared with levels at the PSA test (difference in Impact of Events Scale (IES) score: 9.47; 95% confidence interval (CI) (6.97, 12.12); P<0.001). These levels remained elevated immediately after the negative biopsy result (difference in score: 7.32; 95% CI (5.51, 9.52); P<0.001) and 12 weeks later (difference in score: 2.42; 95% CI (0.50, 1.15); P=0.009). Psychological mood at the time of PSA testing predicted high levels of distress and anxiety at subsequent time-points.Conclusions:Most men coped well with the testing process, although a minority experienced elevated distress at the time of biopsy and after a negative result. Men should be informed of the risk of distress relating to diagnostic uncertainty before they consent to PSA testing.

Associations of aspirin, nonsteroidal anti-inflammatory drug and paracetamol use with PSA-detected prostate cancer: findings from a large, population-based, case-control study (the ProtecT study).

Evidence from laboratory studies suggests that chronic inflammation plays an important role in prostate cancer aetiology. This has resulted in speculation that nonsteroidal anti‐inflammatory drugs may protect against prostate cancer development. We analysed data from a cross‐sectional case–control study (ncases= 1,016; ncontrols= 5,043), nested within a UK‐wide population‐based study that used prostate specific antigen (PSA) testing for identification of asymptomatic prostate cancers, to investigate the relationship of aspirin, nonsteroidal anti‐inflammatory drug (NSAID) and paracetamol use with prostate cancer. In conditional logistic regression models accounting for stratum matching on age (5‐year age bands) and recruitment centre, use of non‐aspirin NSAIDs [odds ratio (OR) = 1.32; 95% confidence interval (CI): 1.04–1.67] or all NSAIDs (OR = 1.25; 95% CI = 1.07–1.47) were positively associated with prostate cancer. There were weaker, not conventionally statistically significant, positive associations of aspirin (OR = 1.13; 95% CI = 0.94–1.36) and paracetamol (OR = 1.20; 95% CI = 0.90–1.60) with prostate cancer. Mutual adjustment for aspirin, non‐aspirin NSAIDs or paracetamol made little difference to these results. There was no evidence of confounding by age, family history of prostate cancer, body mass index or self‐reported diabetes. Aspirin, NSAID and paracetamol use were associated with reduced serum PSA concentrations amongst controls. Our findings do not support the hypothesis that NSAIDs reduce the risk of PSA‐detected prostate cancer. Our conclusions are unlikely to be influenced by PSA detection bias because the inverse associations of aspirin, NSAID and paracetamol use with serum PSA would have attenuated (not generated) the observed positive associations.

Design and preliminary recruitment results of the Cluster randomised triAl of PSA testing for Prostate cancer (CAP)

Background:Screening for prostate cancer continues to generate controversy because of concerns about over-diagnosis and unnecessary treatment. We describe the rationale, design and recruitment of the Cluster randomised triAl of PSA testing for Prostate cancer (CAP) trial, a UK-wide cluster randomised controlled trial investigating the effectiveness and cost-effectiveness of prostate-specific antigen (PSA) testing.Methods:Seven hundred and eighty-five general practitioner (GP) practices in England and Wales were randomised to a population-based PSA testing or standard care and then approached for consent to participate. In the intervention arm, men aged 50–69 years were invited to undergo PSA testing, and those diagnosed with localised prostate cancer were invited into a treatment trial. Control arm practices undertook standard UK management. All men were flagged with the Health and Social Care Information Centre for deaths and cancer registrations. The primary outcome is prostate cancer mortality at a median 10-year-follow-up.Results:Among randomised practices, 271 (68%) in the intervention arm (198 114 men) and 302 (78%) in the control arm (221 929 men) consented to participate, meeting pre-specified power requirements. There was little evidence of differences between trial arms in measured baseline characteristics of the consenting GP practices (or men within those practices).Conclusions:The CAP trial successfully met its recruitment targets and will make an important contribution to international understanding of PSA-based prostate cancer screening.

Do the risk factors of age, family history of prostate cancer or a higher prostate specific antigen level raise anxiety at prostate biopsy?

To date, little is known of the impact knowledge of personal risk factors has on anxiety in men undergoing biopsy tests for prostate cancer. This analysis explores anxiety scores of men at higher risk due to age, family history of prostate cancer and a higher prostate specific antigen (PSA) level when proceeding from PSA test to prostate biopsy. A prospective cohort of 4198 men aged 50-69 years with a PSA result of >3ng/ml was studied, recruited for the Prostate testing for cancer and Treatment study (ProtecT). Anxiety scores at the time of biopsy were lower in older men (p<0.001). No age group showed an increase in anxiety as the men proceeded from PSA testing to biopsy, although older men did not show the same level of decrease in anxiety as younger men (p=0.035). There was no difference in anxiety scores at biopsy between men with or without a family history of prostate cancer (p=0.68), or between those with a raised PSA of 10-<20ng/ml compared to a PSA result of 3-<10ng/ml (p=0.46). Change in scores since the initial PSA test appeared unaffected by family history (p=0.995) or by PSA result (p=0.76). Within the context of a research study, the increased risk of prostate cancer through older age, having a family history of prostate cancer, or having a significantly elevated PSA level appears to have no detrimental effect on mens anxiety level when proceeding to biopsy.

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.

Detection of prostate cancer in unselected young men: prospective cohort nested within a randomised controlled trial

Objective To investigate the feasibility of testing for prostate cancer and the prevalence and characteristics of the disease in unselected young men. Design Prospective cohort nested within a randomised controlled trial, with two years of follow-up. Setting Eight general practices in a UK city. Participants 1299 unselected men aged 45-49. Intervention Prostate biopsies for participants with a prostate specific antigen level of 1.5 ng/ml or more and the possibility of randomisation to three treatments for those with localised prostate cancer. Main outcome measures Uptake of testing for prostate specific antigen; positive predictive value of prostate specific antigen; and prevalence of prostate cancer, TNM disease stage, and histological grade (Gleason score). Results 442 of 1299 men agreed to be tested for prostate specific antigen (34%) and 54 (12%) had a raised level. The positive predictive value for prostate specific antigen was 21.3%. Ten cases of prostate cancer were detected (2.3%) with eight having at least two positive results in biopsy cores and three showing perineural invasion. One tumour was of high volume (cT2c), Gleason score 7, with a positive result on digital rectal examination; nine tumours were cT1c, Gleason score 6, and eight had a negative result on digital rectal examination. Five of the nine eligible participants (55%) agreed to be randomised. No biochemical disease progression in the form of a rising prostate specific antigen level occurred in two years of follow-up. Conclusions Men younger than 50 will accept testing for prostate cancer but at a much lower rate than older men. Using an age based threshold of 1.5 ng/ml, the prevalence of prostate cancer was similar to that in older men (3.0 ng/ml threshold) and some cancers of potential clinical significance were found. Trial registration Current Controlled Trials ISRCTN20141297

Validating the use of Hospital Episode Statistics data and comparison of costing methodologies for economic evaluation: an end-of-life case study from the Cluster randomised triAl of PSA testing for Prostate cancer (CAP)

Objectives To evaluate the accuracy of routine data for costing inpatient resource use in a large clinical trial and to investigate costing methodologies. Design Final-year inpatient cost profiles were derived using (1) data extracted from medical records mapped to the National Health Service (NHS) reference costs via service codes and (2) Hospital Episode Statistics (HES) data using NHS reference costs. Trust finance departments were consulted to obtain costs for comparison purposes. Setting 7 UK secondary care centres. Population A subsample of 292 men identified as having died at least a year after being diagnosed with prostate cancer in Cluster randomised triAl of PSA testing for Prostate cancer (CAP), a long-running trial to evaluate the effectiveness and cost-effectiveness of prostate-specific antigen (PSA) testing. Results Both inpatient cost profiles showed a rise in costs in the months leading up to death, and were broadly similar. The difference in mean inpatient costs was £899, with HES data yielding ∼8% lower costs than medical record data (differences compatible with chance, p=0.3). Events were missing from both data sets. 11 men (3.8%) had events identified in HES that were all missing from medical record review, while 7 men (2.4%) had events identified in medical record review that were all missing from HES. The response from finance departments to requests for cost data was poor: only 3 of 7 departments returned adequate data sets within 6 months. Conclusions Using HES routine data coupled with NHS reference costs resulted in mean annual inpatient costs that were very similar to those derived via medical record review; therefore, routinely available data can be used as the primary method of costing resource use in large clinical trials. Neither HES nor medical record review represent gold standards of data collection. Requesting cost data from finance departments is impractical for large clinical trials. Trial registration number ISRCTN92187251; Pre-results.

A Peer Review Intervention for Monitoring and Evaluating sites (PRIME) that improved randomized controlled trial conduct and performance

OBJECTIVE Good clinical practice (GCP) guidelines emphasize trial site monitoring, although the implementation is unspecified and evidence for benefit is sparse. We aimed to develop a site monitoring process using peer reviewers to improve staff training, site performance, data collection, and GCP compliance. STUDY DESIGN AND SETTING The Peer Review Intervention for Monitoring and Evaluating sites (PRIME) team observed and gave feedback on trial recruitment and follow-up appointments, held staff meetings, and examined documentation during annual 2-day site visits. The intervention was evaluated in the ProtecT trial, a UK randomized controlled trial of localized prostate cancer treatments (ISRCTN20141297). The ProtecT coordinator and senior nurses conducted three monitoring rounds at eight sites (2004-2007). The process evaluation used PRIME report findings, trial databases, resource use, and a site nurse survey. RESULTS Adverse findings decreased across all sites from 44 in round 1 to 19 in round 3. Most findings related to protocol adherence or site organizational issues, including improvements in eligibility criteria application and data collection. Staff found site monitoring acceptable and made changes after reviews. CONCLUSION The PRIME process used observation by peer reviewers to improve protocol adherence and train site staff, which increased trial performance and consistency.

Contemporary accuracy of death certificates for coding prostate cancer as a cause of death: Is reliance on death certification good enough? A comparison with blinded review by an independent cause of death evaluation committee

Background:Accurate cause of death assignment is crucial for prostate cancer epidemiology and trials reporting prostate cancer-specific mortality outcomes.Methods:We compared death certificate information with independent cause of death evaluation by an expert committee within a prostate cancer trial (2002–2015).Results:Of 1236 deaths assessed, expert committee evaluation attributed 523 (42%) to prostate cancer, agreeing with death certificate cause of death in 1134 cases (92%, 95% CI: 90%, 93%). The sensitivity of death certificates in identifying prostate cancer deaths as classified by the committee was 91% (95% CI: 89%, 94%); specificity was 92% (95% CI: 90%, 94%). Sensitivity and specificity were lower where death occurred within 1 year of diagnosis, and where there was another primary cancer diagnosis.Conclusions:UK death certificates accurately identify cause of death in men with prostate cancer, supporting their use in routine statistics. Possible differential misattribution by trial arm supports independent evaluation in randomised trials.