Fifteen-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer.

BACKGROUND: Between 1999 and 2009 in the United Kingdom, 82,429 men between 50 and 69 years of age received a prostate-specific antigen (PSA) test. Localized prostate cancer was diagnosed in 2664 men. Of these men, 1643 were enrolled in a trial to evaluate the effectiveness of treatments, with 545 randomly assigned to receive active monitoring, 553 to undergo prostatectomy, and 545 to undergo radiotherapy. METHODS: At a median follow-up of 15 years (range, 11 to 21), we compared the results in this population with respect to death from prostate cancer (the primary outcome) and death from any cause, metastases, disease progression, and initiation of long-term androgen-deprivation therapy (secondary outcomes). RESULTS: Follow-up was complete for 1610 patients (98%). A risk-stratification analysis showed that more than one third of the men had intermediate or high-risk disease at diagnosis. Death from prostate cancer occurred in 45 men (2.7%): 17 (3.1%) in the active-monitoring group, 12 (2.2%) in the prostatectomy group, and 16 (2.9%) in the radiotherapy group (P = 0.53 for the overall comparison). Death from any cause occurred in 356 men (21.7%), with similar numbers in all three groups. Metastases developed in 51 men (9.4%) in the active-monitoring group, in 26 (4.7%) in the prostatectomy group, and in 27 (5.0%) in the radiotherapy group. Long-term androgen-deprivation therapy was initiated in 69 men (12.7%), 40 (7.2%), and 42 (7.7%), respectively; clinical progression occurred in 141 men (25.9%), 58 (10.5%), and 60 (11.0%), respectively. In the active-monitoring group, 133 men (24.4%) were alive without any prostate cancer treatment at the end of follow-up. No differential effects on cancer-specific mortality were noted in relation to the baseline PSA level, tumor stage or grade, or risk-stratification score. No treatment complications were reported after the 10-year analysis. CONCLUSIONS: After 15 years of follow-up, prostate cancer-specific mortality was low regardless of the treatment assigned. Thus, the choice of therapy involves weighing trade-offs between benefits and harms associated with treatments for localized prostate cancer. (Funded by the National Institute for Health and Care Research; ProtecT Current Controlled Trials number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.).

Prostate-Specific Antigen Screening and 15-Year Prostate Cancer Mortality: A Secondary Analysis of the CAP Randomized Clinical Trial.

Importance: The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) reported no effect of prostate-specific antigen (PSA) screening on prostate cancer mortality at a median 10-year follow-up (primary outcome), but the long-term effects of PSA screening on prostate cancer mortality remain unclear. Objective: To evaluate the effect of a single invitation for PSA screening on prostate cancer-specific mortality at a median 15-year follow-up compared with no invitation for screening. Design, Setting, and Participants: This secondary analysis of the CAP randomized clinical trial included men aged 50 to 69 years identified at 573 primary care practices in England and Wales. Primary care practices were randomized between September 25, 2001, and August 24, 2007, and men were enrolled between January 8, 2002, and January 20, 2009. Follow-up was completed on March 31, 2021. Intervention: Men received a single invitation for a PSA screening test with subsequent diagnostic tests if the PSA level was 3.0 ng/mL or higher. The control group received standard practice (no invitation). Main Outcomes and Measures: The primary outcome was reported previously. Of 8 prespecified secondary outcomes, results of 4 were reported previously. The 4 remaining prespecified secondary outcomes at 15-year follow-up were prostate cancer-specific mortality, all-cause mortality, and prostate cancer stage and Gleason grade at diagnosis. Results: Of 415 357 eligible men (mean [SD] age, 59.0 [5.6] years), 98% were included in these analyses. Overall, 12 013 and 12 958 men with a prostate cancer diagnosis were in the intervention and control groups, respectively (15-year cumulative risk, 7.08% [95% CI, 6.95%-7.21%] and 6.94% [95% CI, 6.82%-7.06%], respectively). At a median 15-year follow-up, 1199 men in the intervention group (0.69% [95% CI, 0.65%-0.73%]) and 1451 men in the control group (0.78% [95% CI, 0.73%-0.82%]) died of prostate cancer (rate ratio [RR], 0.92 [95% CI, 0.85-0.99]; P = .03). Compared with the control, the PSA screening intervention increased detection of low-grade (Gleason score [GS] ≤6: 2.2% vs 1.6%; P < .001) and localized (T1/T2: 3.6% vs 3.1%; P < .001) disease but not intermediate (GS of 7), high-grade (GS ≥8), locally advanced (T3), or distally advanced (T4/N1/M1) tumors. There were 45 084 all-cause deaths in the intervention group (23.2% [95% CI, 23.0%-23.4%]) and 50 336 deaths in the control group (23.3% [95% CI, 23.1%-23.5%]) (RR, 0.97 [95% CI, 0.94-1.01]; P = .11). Eight of the prostate cancer deaths in the intervention group (0.7%) and 7 deaths in the control group (0.5%) were related to a diagnostic biopsy or prostate cancer treatment. Conclusions and Relevance: In this secondary analysis of a randomized clinical trial, a single invitation for PSA screening compared with standard practice without routine screening reduced prostate cancer deaths at a median follow-up of 15 years. However, the absolute reduction in deaths was small. Trial Registration: isrctn.org Identifier: ISRCTN92187251.

Thulium laser transurethral vaporesection of the prostate versus transurethral resection of the prostate for men with lower urinary tract symptoms or urinary retention (UNBLOCS): a randomised controlled trial.

BACKGROUND: Transurethral resection of the prostate (TURP) is the standard operation for benign prostatic obstruction. Thulium laser transurethral vaporesection of the prostate (ThuVARP) is a technique with suggested advantages over TURP, including reduced complications and hospital stay. We aimed to investigate TURP versus ThuVARP in men with lower urinary tract symptoms or urinary retention secondary to benign prostatic obstruction. METHODS: In this randomised, blinded, parallel-group, pragmatic equivalence trial, men in seven UK hospitals with bothersome lower urinary tract symptoms or urinary retention secondary to benign prostatic obstruction were randomly assigned (1:1) at the point of surgery to receive ThuVARP or TURP. Patients were masked until follow-up completion. Centres used their usual TURP procedure (monopolar or bipolar). All trial surgeons underwent training on the ThuVARP technique. Co-primary outcomes were maximum urinary flow rate (Qmax) and International Prostate Symptom Score (IPSS) at 12-months post-surgery. Equivalence was defined as a difference of 2·5 points or less for IPSS and 4 mL per s or less for Qmax. Analysis was done according to the intention-to-treat principle. The trial is registered with the ISRCTN Registry, ISRCTN00788389. FINDINGS: Between July 23, 2014, and Dec 30, 2016, 410 men were randomly assigned to ThuVARP or TURP, 205 per study group. TURP was superior for Qmax (mean 23·2 mL per s for TURP and 20·2 mL per s for ThuVARP; adjusted difference in means -3·12, 95% CI -5·79 to -0·45). Equivalence was shown for IPSS (mean 6·3 for TURP and 6·4 for ThuVARP; adjusted difference in means 0·28, -0·92 to 1·49). Mean hospital stay was 48 h in both study groups. 91 (45%) of 204 patients in the TURP group and 96 (47%) of 203 patients in the ThuVARP group had at least one complication. INTERPRETATION: TURP and ThuVARP were equivalent for urinary symptom improvement (IPSS) 12-months post-surgery, and TURP was superior for Qmax. Anticipated laser benefits for ThuVARP of reduced hospital stay and complications were not observed. FUNDING: UK National Institute for Health Research Health Technology Assessment Programme.

The ProtecT randomised trial cost-effectiveness analysis comparing active monitoring, surgery, or radiotherapy for prostate cancer.

BACKGROUND: There is limited evidence relating to the cost-effectiveness of treatments for localised prostate cancer. METHODS: The cost-effectiveness of active monitoring, surgery, and radiotherapy was evaluated within the Prostate Testing for Cancer and Treatment (ProtecT) randomised controlled trial from a UK NHS perspective at 10 years' median follow-up. Prostate cancer resource-use collected from hospital records and trial participants was valued using UK reference-costs. QALYs (quality-adjusted-life-years) were calculated from patient-reported EQ-5D-3L measurements. Adjusted mean costs, QALYs, and incremental cost-effectiveness ratios were calculated; cost-effectiveness acceptability curves and sensitivity analyses addressed uncertainty; subgroup analyses considered age and disease-risk. RESULTS: Adjusted mean QALYs were similar between groups: 6.89 (active monitoring), 7.09 (radiotherapy), and 6.91 (surgery). Active monitoring had lower adjusted mean costs (£5913) than radiotherapy (£7361) and surgery (£7519). Radiotherapy was the most likely (58% probability) cost-effective option at the UK NICE willingness-to-pay threshold (£20,000 per QALY). Subgroup analyses confirmed radiotherapy was cost-effective for older men and intermediate/high-risk disease groups; active monitoring was more likely to be the cost-effective option for younger men and low-risk groups. CONCLUSIONS: Longer follow-up and modelling are required to determine the most cost-effective treatment for localised prostate cancer over a man's lifetime. TRIAL REGISTRATION: Current Controlled Trials number, ISRCTN20141297: http://isrctn.org (14/10/2002); ClinicalTrials.gov number, NCT02044172: http://www.clinicaltrials.gov (23/01/2014).

Systematic review and meta-analysis of the associations between body mass index, prostate cancer, advanced prostate cancer, and prostate-specific antigen.

PURPOSE: The relationship between body mass index (BMI) and prostate cancer remains unclear. However, there is an inverse association between BMI and prostate-specific antigen (PSA), used for prostate cancer screening. We conducted this review to estimate the associations between BMI and (1) prostate cancer, (2) advanced prostate cancer, and (3) PSA. METHODS: We searched PubMed and Embase for studies until 02 October 2017 and obtained individual participant data from four studies. In total, 78 studies were identified for the association between BMI and prostate cancer, 21 for BMI and advanced prostate cancer, and 35 for BMI and PSA. We performed random-effects meta-analysis of linear associations of log-PSA and prostate cancer with BMI and, to examine potential non-linearity, of associations between categories of BMI and each outcome. RESULTS: In the meta-analyses with continuous BMI, a 5 kg/m2 increase in BMI was associated with a percentage change in PSA of - 5.88% (95% CI - 6.87 to - 4.87). Using BMI categories, compared to normal weight men the PSA levels of overweight men were 3.43% lower (95% CI - 5.57 to - 1.23), and obese men were 12.9% lower (95% CI - 15.2 to - 10.7). Prostate cancer and advanced prostate cancer analyses showed little or no evidence associations. CONCLUSION: There is little or no evidence of an association between BMI and risk of prostate cancer or advanced prostate cancer, and strong evidence of an inverse and non-linear association between BMI and PSA. The association between BMI and prostate cancer is likely biased if missed diagnoses are not considered.

Grading Severity and Bother Using the International Prostate Symptom Score and International Consultation on Incontinence Questionnaire Male Lower Urinary Tract Symptoms Score in Men Seeking Lower Urinary Tract Symptoms Therapy.

PURPOSE: We established severity banding ranges, bother assessment and key item content in principal patient reported outcomes measures in men seeking therapy for lower urinary tract symptoms. MATERIALS AND METHODS: Data for International Prostate Symptom Score (I-PSS) and International Consultation on Incontinence Questionnaire Male Lower Urinary Tract Symptoms (ICIQ-MLUTS) were derived from a study evaluating 820 men at 26 United Kingdom hospitals. ROC curves were used to establish severity bandings. RESULTS: Classification tree showed that thresholds between mild-moderate and moderate-severe severity bands were 15 and 27 for I-PSS, 16 and 26 for ICIQ-MLUTS/severity, and 22 and 81 for ICIQ-MLUTS/bother, respectively. Highest area under the ROC curve and lowest Akaike's information criteria of univariate logistic regression indicated that ICIQ-MLUTS/bother was more related to global quality of life than were I-PSS and ICIQ-MLUTS/severity. The symptoms affecting I-PSS-quality of life (QoL) were only fully identified by ICIQ-MLUTS, because 2 key symptoms (urinary incontinence and post-micturition dribble) are not measured by I-PSS. ICIQ-MLUTS demonstrated that bother of some lower urinary tract symptoms is disproportionate to severity, and that persisting high bother levels following surgery are more likely due to storage (18% to 25%) and post-voiding (18% to 28%) lower urinary tract symptoms than voiding lower urinary tract symptoms (5% to 13%). Symptom improvement after surgery was uncertain if baseline I-PSS-QoL score was less than 3. CONCLUSIONS: The severity threshold scores were measured for the 2 key lower urinary tract symptoms patient reported outcomes measures, and the results indicate suitable categories of symptom severity for use in men referred for urological care. The ICIQ-MLUTS measures all the lower urinary tract symptoms affecting quality of life and includes individual symptom bother scores.

Quality control of uroflowmetry and urodynamic data from two large multicenter studies of male lower urinary tract symptoms.

AIM: The International Continence Society (ICS) has standardized quality control and interpretation of uroflowmetry and urodynamics. We evaluated traces from two large studies of male lower urinary tract symptoms (UPSTREAM and UNBLOCS) against ICS standards of urodynamic equipment and practice. METHODS: Ten percent of uroflowmetry and urodynamics traces were selected at random from hospital sites. A data capture template was designed from the ICS Fundamentals of Urodynamic Practice checklist. Two pretrained blinded assessors extracted the data, with a third assessor to arbitrate. Departmental records of calibration checks and equipment maintenance were scrutinized. RESULTS: Seven out of twenty-five (28%) departments reported no calibration checks. Four sites (16%) could not provide annual service records. In 32 out of 296 (10.8%) uroflowmetry traces, findings were affected by artifact. One hundred ten urodynamic study traces were reviewed; in 11 records (10%), key pressure traces were incompletely displayed. In 30 (27.2%), reference zero was not set to atmospheric pressure. Resting pressures were outside the expected range for 36 (32.7%). Pressure drift was seen in 18 traces (16.4%). At pressure-flow study commencement, permission to void was omitted in 15 (13.6%). Cough testing after voiding was done in 71.2%, but the resulting cough spikes were significantly different in 16.5%. Erroneous diagnosis of bladder outlet obstruction (BOO) was identified in six cases (5.5%). CONCLUSIONS: Erroneous diagnosis of BOO is a serious error of interpretation, as it could lead to unnecessary surgery. Other errors of standardization, testing, and interpretation were identified with lower risk of adverse implications. Inconsistent documentation of service records mean equipment accuracy is uncertain.

A third trial oversight committee: Functions, benefits and issues.

BACKGROUND/AIMS: Clinical trial oversight is central to the safety of participants and production of robust data. The United Kingdom Medical Research Council originally set out an oversight structure comprising three committees in 1998. The first committee, led by the trial team, is hands-on with trial conduct/operations ('Trial Management Group') and essential. The second committee (Data Monitoring Committee), usually completely independent of the trial, reviews accumulating trial evidence and is used by most later phase trials. The Independent Data Monitoring Committee makes recommendations to the third oversight committee. The third committee, ('Trial Steering Committee'), facilitates in-depth interactions of independent and non-independent trial members and gives broader oversight (blinded to comparative analysis). We investigated the roles and functioning of the third oversight committee with multiple research methods. We reflect upon these findings to standardise the committee's remit and operation and to potentially increase its usage. METHODS: We utilised findings from our recent published suite of research on the third oversight committee to inform guideline revision. In brief, we conducted a survey of 38 United Kingdom-registered Clinical Trials Units, reviewed a cohort of 264 published trials, observed 8 third oversight committee meetings and interviewed 52 trialists. We convened an expert panel to discuss third oversight committees. Subsequently, we interviewed nine patient/lay third committee members and eight committee Chairs. RESULTS: In the survey, most Clinical Trials Units required a third committee for all their trials (27/38, 71%) with independent members (ranging from 1 to 6). In the survey and interviews, the independence of the third committee was valued to make unbiased consideration of Independent Data Monitoring Committee recommendations and to advise on trial progress, protocol changes and recruitment issues in conjunction with the trial leadership. The third committee also advised funders and sponsors about trial continuation and represented patients and the public by including lay members. Of the cohort of 264 published trials, 144 reported a 'steering' committee (55%), but the independence of these members was not described so these may have been internal Trial Management Groups. Around two thirds of papers (60%) reported having an Independent Data Monitoring Committee and 26.9% neither a steering nor an Independent Data Monitoring Committee. However, before revising the third committee charter (Terms of Reference), greater standardisation is needed around defining member independence, composition, primacy of decision-making, interactions with other committees and the lifespan. CONCLUSION: A third oversight committee has benefits for trial oversight and conduct, and a revised charter will facilitate greater standardisation and wider adoption.

The associations of anthropometric, behavioural and sociodemographic factors with circulating concentrations of IGF-I, IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 in a pooled analysis of 16,024 men from 22 studies.

Insulin-like growth factors (IGFs) and insulin-like growth factor binding proteins (IGFBPs) have been implicated in the aetiology of several cancers. To better understand whether anthropometric, behavioural and sociodemographic factors may play a role in cancer risk via IGF signalling, we examined the cross-sectional associations of these exposures with circulating concentrations of IGFs (IGF-I and IGF-II) and IGFBPs (IGFBP-1, IGFBP-2 and IGFBP-3). The Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset includes individual participant data from 16,024 male controls (i.e. without prostate cancer) aged 22-89 years from 22 prospective studies. Geometric means of protein concentrations were estimated using analysis of variance, adjusted for relevant covariates. Older age was associated with higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGF-I, IGF-II and IGFBP-3. Higher body mass index was associated with lower concentrations of IGFBP-1 and IGFBP-2. Taller height was associated with higher concentrations of IGF-I and IGFBP-3 and lower concentrations of IGFBP-1. Smokers had higher concentrations of IGFBP-1 and IGFBP-2 and lower concentrations of IGFBP-3 than nonsmokers. Higher alcohol consumption was associated with higher concentrations of IGF-II and lower concentrations of IGF-I and IGFBP-2. African Americans had lower concentrations of IGF-II, IGFBP-1, IGFBP-2 and IGFBP-3 and Hispanics had lower IGF-I, IGF-II and IGFBP-3 than non-Hispanic whites. These findings indicate that a range of anthropometric, behavioural and sociodemographic factors are associated with circulating concentrations of IGFs and IGFBPs in men, which will lead to a greater understanding of the mechanisms through which these factors influence cancer risk.

10-Year Outcomes after Monitoring, Surgery, or Radiotherapy for Localized Prostate Cancer.

BACKGROUND: The comparative effectiveness of treatments for prostate cancer that is detected by prostate-specific antigen (PSA) testing remains uncertain. METHODS: We compared active monitoring, radical prostatectomy, and external-beam radiotherapy for the treatment of clinically localized prostate cancer. Between 1999 and 2009, a total of 82,429 men 50 to 69 years of age received a PSA test; 2664 received a diagnosis of localized prostate cancer, and 1643 agreed to undergo randomization to active monitoring (545 men), surgery (553), or radiotherapy (545). The primary outcome was prostate-cancer mortality at a median of 10 years of follow-up. Secondary outcomes included the rates of disease progression, metastases, and all-cause deaths. RESULTS: There were 17 prostate-cancer-specific deaths overall: 8 in the active-monitoring group (1.5 deaths per 1000 person-years; 95% confidence interval [CI], 0.7 to 3.0), 5 in the surgery group (0.9 per 1000 person-years; 95% CI, 0.4 to 2.2), and 4 in the radiotherapy group (0.7 per 1000 person-years; 95% CI, 0.3 to 2.0); the difference among the groups was not significant (P=0.48 for the overall comparison). In addition, no significant difference was seen among the groups in the number of deaths from any cause (169 deaths overall; P=0.87 for the comparison among the three groups). Metastases developed in more men in the active-monitoring group (33 men; 6.3 events per 1000 person-years; 95% CI, 4.5 to 8.8) than in the surgery group (13 men; 2.4 per 1000 person-years; 95% CI, 1.4 to 4.2) or the radiotherapy group (16 men; 3.0 per 1000 person-years; 95% CI, 1.9 to 4.9) (P=0.004 for the overall comparison). Higher rates of disease progression were seen in the active-monitoring group (112 men; 22.9 events per 1000 person-years; 95% CI, 19.0 to 27.5) than in the surgery group (46 men; 8.9 events per 1000 person-years; 95% CI, 6.7 to 11.9) or the radiotherapy group (46 men; 9.0 events per 1000 person-years; 95% CI, 6.7 to 12.0) (P<0.001 for the overall comparison). CONCLUSIONS: At a median of 10 years, prostate-cancer-specific mortality was low irrespective of the treatment assigned, with no significant difference among treatments. Surgery and radiotherapy were associated with lower incidences of disease progression and metastases than was active monitoring. (Funded by the National Institute for Health Research; ProtecT Current Controlled Trials number, ISRCTN20141297 ; ClinicalTrials.gov number, NCT02044172 .).

Developing new age-specific prostate-specific antigen thresholds for testing for prostate cancer.

PURPOSE: To examine whether age-related reference ranges for "normal" prostate-specific antigen (PSA) change (determined in men without prostate cancer) can be used to identify men at high risk of having prostate cancer. METHODS: Subjects were men aged 50-69 years with PSA < 10 ng/mL from the UK-based Prostate Testing for cancer and Treatment (ProtecT) study. Men with prostate cancer were categorized as high or low risk of progression (Low risk: Gleason score ≤ 6 and stage T1-T2a; High risk: Gleason score 7-10 or stage T2C). Men without prostate cancer were those with no histological confirmation of prostate cancer. Previously developed longitudinal reference ranges for normal age-related PSA change were used to calculate an age-specific PSA threshold. We compared the ability of our age-specific PSA threshold to discriminate between high- and no/low-risk prostate cancer with that of two existing thresholds: (i) threshold of PSA = 3 ng/ml for all ages; (ii) National Institute of Clinical Excellence (NICE) guidelines dependent on age-group thresholds (age 50-59: PSA = 3 ng/mL; age 60-70: PSA = 4 ng/mL; age ≥ 70: PSA = 5 ng/mL). RESULTS: We included 823 men with high-risk prostate cancer and 80,721 men with no/low-risk prostate cancer. A threshold of PSA = 3 ng/ml for all ages identified more high-risk prostate cancers, recommending biopsy in 9.8% of men, of which 10.3% (n = 823) had high-risk prostate cancer. Using the NICE guidelines as the threshold for biopsy, 6.9% men were recommended for biopsy, of which 11.9% (n = 668) had high-risk prostate cancer. Using the new age-specific threshold for biopsy, 2.3% men were recommended for biopsy, of which 15.2% (n = 290) had high-risk prostate cancer. The age-specific threshold identified fewer high-risk prostate cancers, but fewer men received unnecessary biopsy. CONCLUSION: There is no benefit to using reference ranges for "normal" PSA that change with age nor the age-specific thresholds suggested by the NICE guidelines. While the age-varying thresholds are more discriminatory, too many high-risk cancers are missed.

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.

The provision of dietary and physical activity advice for men diagnosed with prostate cancer: a qualitative study of the experiences and views of health care professionals, patients and partners.

PURPOSE: To explore the views and experiences of health care professionals (HCPs), men diagnosed with localised prostate cancer and their partners about the provision of advice on diet and physical activity after diagnosis and treatment for localised prostate cancer. METHODS: Semi-structured in-depth interviews with ten HCPs (Consultant Urological Surgeons, Uro-Oncology Clinical Nurse Specialists and Allied Health Professionals: see Table 1) and sixteen men diagnosed with localised prostate cancer and seven of their partners. Data from interviews were thematically analysed using the Framework Approach. RESULTS: The men and their partners provided differing accounts to the HCPs and sometimes to each other concerning the provision of advice on diet and physical activity. Some men were unable to recall receiving such advice from HCPs. Factors impacting upon advice-giving included the perceived lack of an evidence base to support dietary and physical activity advice and the credibility of advice providers. The timing of advice provision was a contentious issue as some HCPs believed that patients might not be willing to receive dietary and physical activity advice at the time of diagnosis, whilst others viewed this an opportune time to provide behaviour change information. Patients concurred with the latter opinion. CONCLUSIONS: Men and their partners would value nutritional and physical activity advice from their HCP, after a localised prostate cancer diagnosis. Men would prefer to receive this advice at an early stage in their cancer journey and may implement behaviour change if the received advice is clear and evidence-based. HCPs should receive suitable training regarding what information to provide to men and how best to deliver this information.

Post-diagnosis serum insulin-like growth factors in relation to dietary and lifestyle changes in the Prostate testing for cancer and Treatment (ProtecT) trial.

PURPOSE: The insulin-like growth factor (IGF) system is modifiable by diet and lifestyle, and has been linked to prostate cancer development and progression. METHODS: We conducted a prospective cohort study of 621 men diagnosed with localized prostate cancer to investigate the associations of dietary and lifestyle changes with post-diagnosis circulating levels of IGF-I and IGFBP-3. We used analysis of covariance to estimate the associations, controlling for baseline IGF-I or IGFBP-3, respectively. RESULTS: Mean IGF-I levels were 6.5% (95% CI -12.8, -0.3%, p = 0.04) lower in men who decreased their protein intake after diagnosis compared to men who did not change. Men who changed their fruit and vegetable intake had lower IGF-I levels compared to non-changers [Decreased intake: -10.1%, 95% CI -18.4, -1.8%, p = 0.02; Increased intake: -12.0%, 95% CI -18.4, -1.8%, p = 0.002]. IGFBP-3 was 14.6% (95% CI -24.5, -4.8%, p = 0.004) lower in men who achieved a healthy body mass index after diagnosis. Men who became inactive had 9.5% higher average IGF-I levels (95% CI 0.1, 18.9%, p = 0.05). CONCLUSIONS: Decreased protein intake and body mass index, and increased physical activity and fruit and vegetable intake, following a prostate cancer diagnosis were associated with reduced post-diagnosis serum IGF-I and IGFBP-3. Counterintuitively, reduced fruit and vegetable intake was also associated with reduced IGF-I, but with weak statistical support, possibly implicating chance. If confirmed in other studies, our findings may inform potential lifestyle interventions in prostate cancer. ProtecT was registered at International Standard Randomised Controlled Trial Registry, http://isrctn.org as ISRCTN20141297.

Acceptability of dietary and physical activity lifestyle modification for men following radiotherapy or radical prostatectomy for localised prostate cancer: a qualitative investigation.

BACKGROUND: The experience and acceptability of lifestyle interventions for men with localised prostate cancer are not well understood, yet lifestyle interventions are increasingly promoted for cancer survivors. We explored the opinions, experiences and perceived acceptability of taking part in nutritional and physical activity interventions amongst men with prostate cancer and their partners; with the ultimate plan to use such information to inform the development of nutritional and physical activity interventions for men with prostate cancer. METHODS: Semi-structured interviews with 16 men, and seven partners, undergoing curative surgery or radiotherapy for prostate cancer. Interviews explored experiences of lifestyle interventions, acceptable changes participants would make and perceived barriers and facilitators to change. Interviews were thematically analysed using the framework approach. RESULTS: Men were frequently open to lifestyle modification and family support was considered vital to facilitate change. Health beneficial, clinician endorsed, understandable, enjoyable interventions were perceived as attractive. Barriers included 'modern' digital technology, poor weather, competing commitments or physical limitations, most notably incontinence following radical prostatectomy. Men were keen to participate in research, with few negative aspects identified. CONCLUSIONS: Men are willing to change behaviour but this needs to be supported by clinicians and health professionals facilitating lifestyle change. An 'intention-behaviour gap', when an intended behaviour does not materialise, may exist. Digital technology for data collection and lifestyle measurement may not be suitable for all, and post-surgery urinary incontinence is a barrier to physical activity. These novel findings should be incorporated into lifestyle intervention development, and implemented clinically.

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.

Investigating the prostate specific antigen, body mass index and age relationship: is an age-BMI-adjusted PSA model clinically useful?

PURPOSE: Previous studies indicate a possible inverse relationship between prostate-specific antigen (PSA) and body mass index (BMI), and a positive relationship between PSA and age. We investigated the associations between age, BMI, PSA, and screen-detected prostate cancer to determine whether an age-BMI-adjusted PSA model would be clinically useful for detecting prostate cancer. METHODS: Cross-sectional analysis nested within the UK ProtecT trial of treatments for localized cancer. Of 18,238 men aged 50-69 years, 9,457 men without screen-detected prostate cancer (controls) and 1,836 men with prostate cancer (cases) met inclusion criteria: no history of prostate cancer or diabetes; PSA < 10 ng/ml; BMI between 15 and 50 kg/m2. Multivariable linear regression models were used to investigate the relationship between log-PSA, age, and BMI in all men, controlling for prostate cancer status. RESULTS: In the 11,293 included men, the median PSA was 1.2 ng/ml (IQR: 0.7-2.6); mean age 61.7 years (SD 4.9); and mean BMI 26.8 kg/m2 (SD 3.7). There were a 5.1% decrease in PSA per 5 kg/m2 increase in BMI (95% CI 3.4-6.8) and a 13.6% increase in PSA per 5-year increase in age (95% CI 12.0-15.1). Interaction tests showed no evidence for different associations between age, BMI, and PSA in men above and below 3.0 ng/ml (all p for interaction >0.2). The age-BMI-adjusted PSA model performed as well as an age-adjusted model based on National Institute for Health and Care Excellence (NICE) guidelines at detecting prostate cancer. CONCLUSIONS: Age and BMI were associated with small changes in PSA. An age-BMI-adjusted PSA model is no more clinically useful for detecting prostate cancer than current NICE guidelines. Future studies looking at the effect of different variables on PSA, independent of their effect on prostate cancer, may improve the discrimination of PSA for prostate cancer.

Physical activity, alcohol consumption, BMI and smoking status before and after prostate cancer diagnosis in the ProtecT trial: opportunities for lifestyle modification.

Associations between certain lifestyle characteristics and prostate cancer risk have been reported, and continuation post-diagnosis can adversely affect prognosis. We explored whether men make spontaneous changes to their physical activity and alcohol intake, body mass index (BMI) and smoking status, following a diagnosis of localised prostate cancer. A detailed diet, health and lifestyle questionnaire was completed by 511 participants within the Prostate Testing for Cancer and Treatment (ProtecT) randomised controlled trial, both before and 9 months after a diagnosis of prostate cancer. Of 177 men who were insufficiently active before their diagnosis (median 0 activity units/week; IQR 0-9), 40.7% had increased their activity by a median of 22 U week(-1) (IQR 15-35) 9 months later, and there was weak evidence that men were more active after diagnosis than before (p = 0.07). Men categorised as "working" occupational social class and who were insufficiently active before diagnosis were 2.03 (95%, CI = 1.03-3.99, p = 0.04) times more likely to have increased their physical activity levels compared to men classified as "managerial or professional." Similarly, men who were insufficiently active pre-diagnosis and with T-stage 2 compared with T-stage 1 prostate cancer were 2.47 (95%, CI = 1.29-4.71, p = 0.006) times more likely to be sufficiently active post-diagnosis. Following diagnosis, there was an overall reduction in alcohol intake (p = 0.03) and the proportion of current smokers (p = 0.09), but no overall change in BMI. We conclude that some men spontaneously change certain lifestyle behaviours on receiving a diagnosis of prostate cancer. For many men, however, additional support through lifestyle interventions is probably required to facilitate and maintain these changes.

A systematic review of dietary, nutritional, and physical activity interventions for the prevention of prostate cancer progression and mortality.

PURPOSE: Given the long-term, although potentially fatal, nature of prostate cancer, there is increasing observational evidence for the reduction in disease progression and mortality through changes in lifestyle factors. METHODS: We systematically reviewed dietary, nutritional, and physical activity randomized interventions aimed at modifying prostate cancer progression and disease-specific mortality, including a detailed assessment of risk of bias and methodological quality. RESULTS: Forty-four randomized controlled trials of lifestyle interventions, with prostate cancer progression or mortality outcomes, were identified. Substantial heterogeneity of the data prevented a meta-analysis. The included trials involved 3,418 prostate cancer patients, median 64 men per trial, from 13 countries. A trial of a nutritional supplement of pomegranate seed, green tea, broccoli, and turmeric; a trial comparing flaxseed, low-fat diet, flaxseed, and low-fat diet versus usual diet; and a trial supplementing soy, lycopene, selenium, and coenzyme Q10, all demonstrated beneficial effects. These trials were also assessed as having low risk of bias and high methodological quality (as were seven other trials with no evidence of benefit). The remaining trials were either underpowered, at high or unclear risk of bias, inadequately reported, of short duration or measured surrogate outcomes of unproven relationship to mortality or disease progression, which precluded any benefits reported being reliable. CONCLUSION: Large, well-designed randomized trials with clinical endpoints are recommended for lifestyle modification interventions.

Associations of vitamin D pathway genes with circulating 25-hydroxyvitamin-D, 1,25-dihydroxyvitamin-D, and prostate cancer: a nested case-control study.

PURPOSE: Vitamin D pathway single nucleotide polymorphisms (SNPs) are potentially useful proxies for investigating whether circulating vitamin D metabolites [total 25-hydroxyvitamin-D, 25(OH)D; 1,25-dihydroxyvitamin, 1,25(OH)2D] are causally related to prostate cancer. We investigated associations of sixteen SNPs across seven genes with prostate-specific antigen-detected prostate cancer. METHODS: In a nested case-control study (within the ProtecT trial), we estimated odds ratios and 95 % confidence intervals (CIs) quantifying associations between SNPs and prostate cancer. Subgroup analyses investigated whether associations were stronger in men who had high/low sun exposure [a proxy for 25(OH)D]. We quantified associations of SNPs with stage (T1-T2/T3-T4) and grade (<7/≥7). Multiple variant scores included SNPs encoding proteins involved in 25(OH)D synthesis and metabolism. RESULTS: We included 1,275 prostate cancer cases (141 locally advanced, 385 high grades) and 2,062 healthy controls. Vitamin D-binding protein SNPs were associated with prostate cancer (rs4588-A: OR 1.20, CI 1.01, 1.41, p = 0.04; rs7041-T: OR 1.19, CI 1.02, 1.38, p = 0.03). Low 25(OH)D metabolism score was associated with high (vs low) grade (OR 0.76, CI 0.63, 0.93, p = 0.01); there was a similar association of its component variants: rs6013897-A in CYP24A1 (OR 0.78, CI 0.60, 1.01, p = 0.06) and rs10877012-T in CYP27B1 (OR 0.80, CI 0.63, 1.02, p = 0.07). There was no evidence that associations differed by level of sun exposure. CONCLUSION: We found some evidence that vitamin D pathway SNPs were associated with prostate cancer risk and grade, but not stage. There was no evidence of an association in men with deficient vitamin D (measured by having low sun exposure).