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.).

Functional and quality of life outcomes of localised prostate cancer treatments (Prostate Testing for Cancer and Treatment [ProtecT] study).

OBJECTIVE: To investigate the functional and quality of life (QoL) outcomes of treatments for localised prostate cancer and inform treatment decision-making. PATIENTS AND METHODS: Men aged 50-69 years diagnosed with localised prostate cancer by prostate-specific antigen testing and biopsies at nine UK centres in the Prostate Testing for Cancer and Treatment (ProtecT) trial were randomised to, or chose one of, three treatments. Of 2565 participants, 1135 men received active monitoring (AM), 750 a radical prostatectomy (RP), 603 external-beam radiotherapy (EBRT) with concurrent androgen-deprivation therapy (ADT) and 77 low-dose-rate brachytherapy (BT, not a randomised treatment). Patient-reported outcome measures (PROMs) completed annually for 6 years were analysed by initial treatment and censored for subsequent treatments. Mixed effects models were adjusted for baseline characteristics using propensity scores. RESULTS: Treatment-received analyses revealed different impacts of treatments over 6 years. Men remaining on AM experienced gradual declines in sexual and urinary function with age (e.g., increases in erectile dysfunction from 35% of men at baseline to 53% at 6 years and nocturia similarly from 20% to 38%). Radical treatment impacts were immediate and continued over 6 years. After RP, 95% of men reported erectile dysfunction persisting for 85% at 6 years, and after EBRT this was reported by 69% and 74%, respectively (P < 0.001 compared with AM). After RP, 36% of men reported urinary leakage requiring at least 1 pad/day, persisting for 20% at 6 years, compared with no change in men receiving EBRT or AM (P < 0.001). Worse bowel function and bother (e.g., bloody stools 6% at 6 years and faecal incontinence 10%) was experienced by men after EBRT than after RP or AM (P < 0.001) with lesser effects after BT. No treatment affected mental or physical QoL. CONCLUSION: Treatment decision-making for localised prostate cancer can be informed by these 6-year functional and QoL outcomes.

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).

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 .).

Four-year outcomes from a multiparametric magnetic resonance imaging (MRI)-based active surveillance programme: PSA dynamics and serial MRI scans allow omission of protocol biopsies.

OBJECTIVES: To report outcomes from a multiparametric (mp) magnetic resonance imaging (MRI)-based active surveillance programme that did not include performing protocol biopsies after the first confirmatory biopsy. PATIENTS AND METHODS: All patients diagnosed with Gleason 3 + 3 prostate cancer because of a raised PSA level who underwent mpMRI after diagnosis were included. Patients were recorded in a prospective clinical database and followed up with PSA monitoring and repeat MRI. In patients who remained on active surveillance after the first MRI (with or without confirmatory biopsy), we investigated PSA dynamics for association with subsequent progression. Comparison between first and second MRI scans was undertaken. Outcomes assessed were: progression to radical therapy at first MRI/confirmatory biopsy and progression to radical therapy in those who remained on active surveillance after first MRI. RESULTS: A total of 211 patients were included, with a median of 4.2 years of follow-up. The rate of progression to radical therapy was significantly greater at all stages among patients with visible lesions than in those with initially negative MRI (47/125 (37.6%) vs 11/86 (12.8%); odds ratio 4.1 (95% CI 2.0-8.5), P < 0.001). Only 1/56 patients (1.8%) with negative initial MRI scans who underwent a confirmatory systematic biopsy had upgrading to Gleason 3 + 4 disease. PSA velocity was significantly associated with subsequent progression in patients with negative initial MRI (area under the curve 0.85 [95% CI 0.75-0.94]; P <0.001). Patients with high-risk visible lesions on first MRI who remained on active surveillance had a high risk of subsequent progression 19/76 (25.0%) vs 9/84 (10.7%) for patients with no visible lesions, despite reassuring targeted and systematic confirmatory biopsies and regardless of PSA dynamics. CONCLUSION: Men with low-risk Gleason 3 + 3 prostate cancer on active surveillance can forgo protocol biopsies in favour of MRI and PSA monitoring with selective re-biopsy.

Couple-Based Psychosexual Support Following Prostate Cancer Surgery: Results of a Feasibility Pilot Randomized Control Trial.

INTRODUCTION: Surgery for prostate cancer can result in distressing side effects such as sexual difficulties, which are associated with lower levels of dyadic functioning. The study developed and tested an intervention to address sexual, relational, and emotional aspects of the relationship after prostate cancer by incorporating elements of family systems theory and sex therapy. AIMS: To develop and test the feasibility and acceptability of relational psychosexual treatment for couples with prostate cancer, determine whether a relational-psychosexual intervention is feasible and acceptable for couples affected by prostate cancer, and determine the parameters for a full-scale trial. METHODS: Forty-three couples were recruited for this pilot randomized controlled trial and received a six-session manual-based psychosexual intervention or usual care. Outcomes were measured before, after, and 6 months after the intervention. Acceptability and feasibility were established from recruitment and retention rates and adherence to the manual. MAIN OUTCOME MEASURES: The primary outcome measurement was the sexual bother subdomain of the Expanded Prostate Cancer Index Composite. The Hospital Anxiety and Depression Scale and the 15-item Systemic Clinical Outcome and Routine Evaluation (SCORE-15) were used to measure emotional and relational functioning, respectively. RESULTS: The intervention was feasible and acceptable. The trial achieved adequate recruitment (38%) and retention (74%) rates. The intervention had a clinically and statistically significant effect on sexual bother immediately after the intervention. Small decreases in anxiety and depression were observed for the intervention couples, although these were not statistically significant. Practitioners reported high levels of adherence to the manual. CONCLUSION: The clinically significant impact on sexual bother and positive feedback on the study's feasibility and acceptability indicate that the intervention should be tested in a multicenter trial. The SCORE-15 lacked specificity for this intervention, and future trials would benefit from a couple-focused measurement.

Midterm oncological outcome and clinicopathological characteristics of anterior prostate cancers treated by endoscopic extraperitoneal radical prostatectomy.

PURPOSE: The purpose of the study is to characterise the clinicopathological characteristics of anterior prostate cancer (APC) compared to posterior prostate cancer (PPC)s and to determine the midterm oncological outcomes of patients with APCs undergoing endoscopic extraperitoneal radical prostatectomy (EERPE). METHODS: A retrospective review was carried out on all EERPEs performed in 2009. Pathology reports (transrectal ultrasound biopsy and surgical specimen), specimen photographs, demographic details and oncological outcome data from a prospectively maintained database were reviewed. Unpaired t test, chi-squared test and Kaplan-Meier curves were used for the analysis. RESULTS: Of 139 patients identified, 53 were APCs (38 %) and 86 were PPCs (62 %). Significantly, greater number of repeat biopsies were required to diagnose APCs (p = 0.02) and they had significantly fewer positive biopsy cores (p = 0.0005). The APC group had a significantly higher PSA density (PSAd) with (<5 and 5-25 %) tumour involvement in positive cores compared to PPCs (p = 0.036 and 0.024, respectively). APCs had higher positive surgical margin (PSM) rates (p = ns), the apical margin more likely positive than PPCs (p = 0.0006). Biochemical recurrence-free survival (BRFS) for APCs at 1, 2 and 3 years was lower than PPCs, although not statistically significant (p = 0.16). CONCLUSION: In our study, APCs proved more difficult to diagnose and stage, had a higher PSM rate and a trend towards a worse bRFS than PPCs. Additionally, the use of PSAd low core involvement biopsies might aide clinicians to investigate this cohort of patients more thoroughly before advising active surveillance.

Patient-Reported Outcomes 12 Years after Localized Prostate Cancer Treatment.

BACKGROUND: Long-term patient-reported outcomes are needed to inform treatment decisions for localized prostate cancer. METHODS: Patient-reported outcomes of 1643 randomly assigned participants in the ProtecT (Prostate Testing for Cancer and Treatment) trial were evaluated to assess the functional and quality-of-life impacts of prostatectomy, radiotherapy with neoadjuvant androgen deprivation, and active monitoring. This article focuses on the outcomes of the randomly assigned participants from 7 to 12 years using mixed effects linear and logistic models. RESULTS: Response rates exceeded 80% for most measures. Among the randomized groups over 7 to 12 years, generic quality-of-life scores were similar. Among those in the prostatectomy group, urinary leakage requiring pads occurred in 18 to 24% of patients over 7 to 12 years, compared with 9 to 11% in the active monitoring group and 3 to 8% in the radiotherapy group. In the prostatectomy group, 18% reported erections sufficient for intercourse at 7 years, compared with 30% in the active monitoring and 27% in the radiotherapy groups; all converged to low levels of potency by year 12. Nocturia (voiding at least twice per night) occurred in 34% in the prostatectomy group compared with 48% in the radiotherapy group and 47% in the active monitoring group at 12 years. Fecal leakage affected 12% in the radiotherapy group compared with 6% in the other groups by year 12. The active monitoring group experienced gradual age-related declines in sexual and urinary function, avoiding radical treatment effects unless they changed management. CONCLUSIONS: ProtecT provides robust evidence about continued impacts of treatments in the long term. These data allow patients newly diagnosed with localized prostate cancer and their clinicians to assess the trade-offs between treatment harms and benefits and enable better informed and prudent treatment decisions. (Funded by the UK National Institute for Health and Care Research Health Technology Assessment Programme projects 96/20/06 and 96/20/99; ISRCTN number, ISRCTN20141297; ClinicalTrials.gov number, NCT02044172.)

Endoscopic extraperitoneal radical prostatectomy: critical analysis of outcomes and learning curve.

OBJECTIVE: To assess the outcomes and learning curve of extraperitoneal endoscopic radical prostatectomy (EERP) using cumulative summation charts from a single tertiary referral centre. PATIENTS AND METHODS: The data from 300 consecutive men with localized prostate cancer who underwent EERP at Western General Hospital, Edinburgh, UK, between February 2006 and July 2009 were prospectively maintained in a database. The data collected included demographic details, perioperative outcomes, complications and follow-up for functional and oncology outcomes. The learning curve was analysed using generalized linear models for complication rate, operative time and blood loss, using procedure experience. RESULTS: The mean (sd, range) operative duration was 160.52 (40.84, 100-310) min, and the intraoperative blood loss was 229.3 (172, 20-1000) mL. There was no conversion to open surgery and no patient required intraoperative blood transfusion. Only one of 250 (0.3%) patients required a blood transfusion after EERP. The median (range) hospital stay was 3 (2-20) days and the median catheterization time before cystography was 9 days. There was evidence that the complication rate reduced as experience was gained (odds ratio 0.98, 95% confidence interval, CI, 0.97-0.99; P= 0.002), with the estimated probability of a complication decreasing from 29% for the first to <1% for the 250th procedure. Also there was evidence of a decrease in operative duration (-0.0020 rate parameter on log scale; 95% CI -0.0024 to -0.0017; P < 0.001) and blood loss (-0.01 rate parameter on log scale; 95% CI -0.003 to -0.0002; P= 0.021). The positive surgical margin rate in pT2 disease decreased from 27% in the first 50 to 14.7% in the last 50 operated cases. The continence rate and biochemical recurrence-free rate at a minimum follow-up of 1 year for the first 100 patients was 89% and 94%, respectively. CONCLUSION: The results from this series suggest that the benefits of minimally invasive surgery for localized prostate cancer (EERP) can be replicated after mentored fellowship training of a surgeon. The complication rate reduced substantially as experience was gained, suggesting a continuous surgical learning curve.

Could prostate biopsies be avoided in men older than 75 years with raised PSA?

OBJECTIVES: Our purpose was to review current practice regarding the use of prostate biopsies in men older than 75 years with raised PSA by presenting the results of a retrospective audit and to identify these older men who really benefit from prostate biopsies. METHODS: A high-volume tertiary center's prospectively maintained prostate biopsy database of contemporary biopsies was reviewed. Men were stratified by age and PSA. Logistic regression analysis, Mantel-Haenszel and Fisher's exact tests were used for statistical analysis. RESULTS: Overall, 1,593 men underwent prostate biopsies between April 2004 and August 2006. Of these, 293 patients (18.4%) with a mean age of 82.62 years and mean PSA of 30.37 ng/ml were eligible for the study with an overall incidence of prostate cancer of 73.7%. Elderly men with PSA >20 ng/ml had a prostate cancer detection rate of 91%. They were more likely to have-high grade disease (OR = 5.4, 95% CI = 2.8-10.8, p < 0.0001) and receive hormone deprivation therapy (RR = 3.0, 95% CI = 2.1-4.3, p < 0.0001). Elderly men with PSA <20 ng/ml had a 3-fold risk of being placed on active monitoring. Almost 20% of them had 1 complication following biopsy, of whom 12 (4.1%) needed hospitalization. CONCLUSIONS: Given the high probability of detecting prostate cancer and receiving conservative treatment, prostate biopsies can be omitted in men >75 years with PSA >20 ng/ml. However, they are still useful in fit men >75 and <80 years with PSA <20 ng/ml who can be the potential candidates for treatment with curative intent.

Strategies adopted by men to deal with uncertainty and anxiety when following an active surveillance/monitoring protocol for localised prostate cancer and implications for care: a longitudinal qualitative study embedded within the ProtecT trial.

OBJECTIVES: Active surveillance (AS) enables men with low risk, localised prostate cancer (PCa) to avoid radical treatment unless progression occurs; lack of reliable AS protocols to determine progression leaves uncertainties for men and clinicians. This study investigated men's strategies for coping with the uncertainties of active monitoring (AM, a surveillance strategy within the Prostate testing for cancer and Treatment, ProtecT trial) over the longer term and implications for optimising supportive care. DESIGN: Longitudinal serial in-depth qualitative interviews every 2-3 years for a median 7 (range 6-14) years following diagnosis. SETTING: Four centres within the UK Protect trial. PARTICIPANTS: Purposive sample of 20 men with localised PCa: median age at diagnosis 64 years (range 52-68); 15 (75%) had low-risk PCa; 12 randomly allocated to, 8 choosing AM. Eleven men continued with AM throughout the study period (median 7 years). Nine received radical treatment after a median 4 years (range 0.8-13.8 years). INTERVENTION: AM: 3-monthly serum prostate-specific antigen (PSA)-level assessment (year 1), 6-12 monthly thereafter; increase in PSA ≥50% during previous 12 months or patient/clinician concern triggered review. MAIN OUTCOMES: Thematic analysis of 73 interviews identified strategies to accommodate uncertainty and anxiety of living with untreated cancer; implications for patient care. RESULTS: Men sought clarity, control or reassurance, with contextual factors mediating individual responses. Trust in the clinical team was critical for men in balancing anxiety and facilitating successful management change/continued monitoring. Only men from ProtecT were included; men outside ProtecT may have different experiences. CONCLUSION: Men looked to clinicians for clarity, control and reassurance. Where provided, men felt comfortable continuing AM or having radical treatments when indicated. Clinicians build patient trust by clearly describing uncertainties, allowing patients control wherever possible and being aware of how context influences individual responses. Insights indicate need for supportive services to build trust and patient engagement over the long term. TRIAL REGISTRATION NUMBER: ISRCTN20141297; Pre-results.

Ten-year Mortality, Disease Progression, and Treatment-related Side Effects in Men with Localised Prostate Cancer from the ProtecT Randomised Controlled Trial According to Treatment Received.

BACKGROUND: The ProtecT trial reported intention-to-treat analysis of men with localised prostate cancer (PCa) randomly allocated to active monitoring (AM), radical prostatectomy, and external beam radiotherapy. OBJECTIVE: To determine report outcomes according to treatment received in men in randomised and treatment choice cohorts. DESIGN, SETTING, AND PARTICIPANTS: This study focuses on secondary care. Men with clinically localised prostate cancer at one of nine UK centres were invited to participate in the treatment trial comparing AM, radical prostatectomy, and radiotherapy. INTERVENTION: Two cohorts included 1643 men who agreed to be randomised; 997 declined randomisation and chose treatment. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Health-related quality of life impacts on urinary, bowel, and sexual function were assessed using patient-reported outcome measures. Analysis was carried out based on treatment received for each cohort and on pooled estimates using meta-analysis. Differences were estimated with adjustment for known prognostic factors using propensity scores. RESULTS AND LIMITATIONS: According to treatment received, more men receiving AM died of PCa (AM 1.85%, surgery 0.67%, radiotherapy 0.73%), whilst this difference remained consistent with chance in the randomised cohort (p=0.08); stronger evidence was found in the exploratory analyses (randomised plus choice cohort) when AM was compared with the combined radical treatment group (p=0.003). There was also strong evidence that metastasis (AM 5.6%, surgery 2.4%, radiotherapy 2.7%) and disease progression (AM 20.35%, surgery 5.87%, radiotherapy 6.62%) were more common in the AM group. Compared with AM, there were higher risks of sexual dysfunction (95% at 6mo) and urinary incontinence (55% at 6mo) after surgery, and of sexual dysfunction (88% at 6mo) and bowel dysfunction (5% at 6mo) after radiotherapy. The key limitations are the potential for bias when comparing groups defined by treatment received and outdating of the interventions being evaluated during the lengthy follow-up required in trials of screen-detected PCa. CONCLUSIONS: Analyses according to treatment received showed increased rates of disease-related events and lower rates of patient-reported harms in men managed by AM compared with men managed by radical treatment, and stronger evidence of greater PCa mortality in the AM group. PATIENT SUMMARY: More than 90 out of every 100 men with localised prostate cancer do not die of prostate cancer within 10yr, irrespective of whether treatment is by means of monitoring, surgery, or radiotherapy. Side effects on sexual and bladder function are much better after active monitoring, but the risks of spreading of prostate cancer are more common.

Active monitoring, radical prostatectomy and radical radiotherapy in PSA-detected clinically localised prostate cancer: the ProtecT three-arm RCT.

BACKGROUND: Prostate cancer is the most common cancer among men in the UK. Prostate-specific antigen testing followed by biopsy leads to overdetection, overtreatment as well as undertreatment of the disease. Evidence of treatment effectiveness has lacked because of the paucity of randomised controlled trials comparing conventional treatments. OBJECTIVES: To evaluate the effectiveness of conventional treatments for localised prostate cancer (active monitoring, radical prostatectomy and radical radiotherapy) in men aged 50-69 years. DESIGN: A prospective, multicentre prostate-specific antigen testing programme followed by a randomised trial of treatment, with a comprehensive cohort follow-up. SETTING: Prostate-specific antigen testing in primary care and treatment in nine urology departments in the UK. PARTICIPANTS: Between 2001 and 2009, 228,966 men aged 50-69 years received an invitation to attend an appointment for information about the Prostate testing for cancer and Treatment (ProtecT) study and a prostate-specific antigen test; 82,429 men were tested, 2664 were diagnosed with localised prostate cancer, 1643 agreed to randomisation to active monitoring (n = 545), radical prostatectomy (n = 553) or radical radiotherapy (n = 545) and 997 chose a treatment. INTERVENTIONS: The interventions were active monitoring, radical prostatectomy and radical radiotherapy. TRIAL PRIMARY OUTCOME MEASURE: Definite or probable disease-specific mortality at the 10-year median follow-up in randomised participants. SECONDARY OUTCOME MEASURES: Overall mortality, metastases, disease progression, treatment complications, resource utilisation and patient-reported outcomes. RESULTS: There were no statistically significant differences between the groups for 17 prostate cancer-specific (p = 0.48) and 169 all-cause (p = 0.87) deaths. Eight men died of prostate cancer in the active monitoring group (1.5 per 1000 person-years, 95% confidence interval 0.7 to 3.0); five died of prostate cancer in the radical prostatectomy group (0.9 per 1000 person-years, 95% confidence interval 0.4 to 2.2 per 1000 person years) and four died of prostate cancer in the radical radiotherapy group (0.7 per 1000 person-years, 95% confidence interval 0.3 to 2.0 per 1000 person years). More men developed metastases in the active monitoring group than in the radical prostatectomy and radical radiotherapy groups: active monitoring, n = 33 (6.3 per 1000 person-years, 95% confidence interval 4.5 to 8.8); radical prostatectomy, n = 13 (2.4 per 1000 person-years, 95% confidence interval 1.4 to 4.2 per 1000 person years); and radical radiotherapy, n = 16 (3.0 per 1000 person-years, 95% confidence interval 1.9 to 4.9 per 1000 person-years; p = 0.004). There were higher rates of disease progression in the active monitoring group than in the radical prostatectomy and radical radiotherapy groups: active monitoring (n = 112; 22.9 per 1000 person-years, 95% confidence interval 19.0 to 27.5 per 1000 person years); radical prostatectomy (n = 46; 8.9 per 1000 person-years, 95% confidence interval 6.7 to 11.9 per 1000 person-years); and radical radiotherapy (n = 46; 9.0 per 1000 person-years, 95% confidence interval 6.7 to 12.0 per 1000 person years; p < 0.001). Radical prostatectomy had the greatest impact on sexual function/urinary continence and remained worse than radical radiotherapy and active monitoring. Radical radiotherapy's impact on sexual function was greatest at 6 months, but recovered somewhat in the majority of participants. Sexual and urinary function gradually declined in the active monitoring group. Bowel function was worse with radical radiotherapy at 6 months, but it recovered with the exception of bloody stools. Urinary voiding and nocturia worsened in the radical radiotherapy group at 6 months but recovered. Condition-specific quality-of-life effects mirrored functional changes. No differences in anxiety/depression or generic or cancer-related quality of life were found. At the National Institute for Health and Care Excellence threshold of £20,000 per quality-adjusted life-year, the probabilities that each arm was the most cost-effective option were 58% (radical radiotherapy), 32% (active monitoring) and 10% (radical prostatectomy). LIMITATIONS: A single prostate-specific antigen test and transrectal ultrasound biopsies were used. There were very few non-white men in the trial. The majority of men had low- and intermediate-risk disease. Longer follow-up is needed. CONCLUSIONS: At a median follow-up point of 10 years, prostate cancer-specific mortality was low, irrespective of the assigned treatment. Radical prostatectomy and radical radiotherapy reduced disease progression and metastases, but with side effects. Further work is needed to follow up participants at a median of 15 years. TRIAL REGISTRATION: Current Controlled Trials ISRCTN20141297. FUNDING: This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 37. See the National Institute for Health Research Journals Library website for further project information.

Prostate cancer is the most common cancer in men and is often found through a blood test called a prostate-specific antigen test and through biopsies of the prostate. Over the years, these tests led to the detection of many small cancers that do not cause harm. Some prostate cancers are harmful, but it is difficult to recognise them early. When cancer is still inside the prostate, the conventional treatments are surgery or radiotherapy, which carry side effects including leaking urine and difficulty getting an erection, so another option is repeat investigations at regular intervals (active monitoring), with treatments given if the cancer progresses. These options needed to be compared in a study called a 'randomised trial' in which men agree to be allocated to one of the three treatments. In the Prostate testing for cancer and Treatment (ProtecT) study, 200,000 men aged 50­69 years were invited to have a prostate-specific antigen test. Of the 82,849 men who agreed to be tested, 1643 of whom had prostate cancer that was still contained in the prostate agreed to be allocated to one of the three treatments. After an average of 10 years of follow-up, 99% of men were alive in each of the treatment groups. However, when compared with active monitoring, surgery and radiotherapy reduced the risk of disease spreading outside the prostate by half. Patients reported that urinary leakage and sexual function were worst with surgery, and sexual and bowel functions were affected by radiotherapy. Men on active monitoring had a gradual decline in their urinary and sexual function, particularly as around half of them later had surgery or radiotherapy. Radiotherapy was the treatment that seemed to be the best value for money. The findings from the Prostate testing for cancer and Treatment (ProtecT) study can help men make decisions about being tested and which treatment to have if they are found to have cancer within the prostate. We now need to find out the longer-term effects of these treatments on how long men live and their quality of life.

Mortality Among Men with Advanced Prostate Cancer Excluded from the ProtecT Trial.

BACKGROUND: Early detection and treatment of asymptomatic men with advanced and high-risk prostate cancer (PCa) may improve survival rates. OBJECTIVE: To determine outcomes for men diagnosed with advanced PCa following prostate-specific antigen (PSA) testing who were excluded from the ProtecT randomised trial. DESIGN, SETTING, AND PARTICIPANTS: Mortality was compared for 492 men followed up for a median of 7.4 yr to a contemporaneous cohort of men from the UK Anglia Cancer Network (ACN) and with a matched subset from the ACN. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PCa-specific and all-cause mortality were compared using Kaplan-Meier analysis and Cox's proportional hazards regression. RESULTS AND LIMITATIONS: Of the 492 men excluded from the ProtecT cohort, 37 (8%) had metastases (N1, M0=5, M1=32) and 305 had locally advanced disease (62%). The median PSA was 17µg/l. Treatments included radical prostatectomy (RP; n=54; 11%), radiotherapy (RT; n=245; 50%), androgen deprivation therapy (ADT; n=122; 25%), other treatments (n=11; 2%), and unknown (n=60; 12%). There were 49 PCa-specific deaths (10%), of whom 14 men had received radical treatment (5%); and 129 all-cause deaths (26%). In matched ProtecT and ACN cohorts, 37 (9%) and 64 (16%), respectively, died of PCa, while 89 (22%) and 103 (26%) died of all causes. ProtecT men had a 45% lower risk of death from PCa compared to matched cases (hazard ratio 0.55, 95% confidence interval 0.38-0.83; p=0.0037), but mortality was similar in those treated radically. The nonrandomised design is a limitation. CONCLUSIONS: Men with PSA-detected advanced PCa excluded from ProtecT and treated radically had low rates of PCa death at 7.4-yr follow-up. Among men who underwent nonradical treatment, the ProtecT group had a lower rate of PCa death. Early detection through PSA testing, leadtime bias, and group heterogeneity are possible factors in this finding. PATIENT SUMMARY: Prostate cancer that has spread outside the prostate gland without causing symptoms can be detected via prostate-specific antigen testing and treated, leading to low rates of death from this disease.

The loss of 5alpha-reductase type I and type II mRNA expression in metastatic prostate cancer to bone and lymph node metastasis.

PURPOSE: Considerable evidence has accumulated demonstrating that the 5alpha-reduction of testosterone to dihydrotestosterone occurs more efficiently in the normal and benign hyperplastic prostate than in prostate cancer tissues. Efforts have also been channeled into investigating the distribution of 5alpha-reductase isoenzymes in primary prostate tissues and in "in vitro" cell models of the human prostate. However, no one has, thus far, examined the expression of these isoenzymes in prostate cancer metastasis, although such studies might shed some light on the mechanism(s) responsible for the loss of hormone sensitivity in those tumors. The present report addresses this issue in the hope that this might help to identify the steps leading to the development of prostate cancer metastasis. EXPERIMENTAL DESIGN: In the present study we used in situ mRNA hybridization of sections from archival paraffin-embedded material to investigate the expression of 5alpha-reductase type I (5alphaR-I) and type II (5alphaR-II) mRNAs in prostate cancer bony (n = 9) and lymph node (n = 13) metastasis, and compared the mRNA distributions with those observed in sections from primary prostate tumors (n = 12). In parallel, sections were investigated for androgen receptor (AR) mRNA expression, and immunostained for AR and prostate-specific antigen. RESULTS: Neither 5alphaR-I nor 5alphaR-II mRNA expression was detected in any of the prostate metastatic lesions, although the same metastatic sites expressed AR mRNA, and stained for cytoplasmic prostate-specific antigen and nuclear AR. In contrast, primary prostate tumors displayed intense staining for 5alphaR-I and 5alphaR-II. CONCLUSION: These findings suggest that the loss of 5alpha-reductase mRNA expression in bone and lymph node metastasis may be associated, in part, with the progression of these tumors to androgen insensitivity.

CYP7B generates a selective estrogen receptor beta agonist in human prostate.

In human prostate, dehydroepiandrosterone (DHEA) is a substrate for two major metabolic pathways that produce functionally opposing sex steroids. In one pathway, DHEA is converted into potent androgens such as testosterone and 5alpha-dihydrotestosterone. In the other, DHEA is metabolized to 7alpha-hydroxy-DHEA (7HD). Recently, CYP7B, a novel P450 enzyme originally characterized in mouse brain and expressed in rodent prostate, has been found to be responsible for all extrahepatic 7alpha-hydroxylase activity. In this study, we have investigated the expression and function of this novel enzyme in human prostate. We have used reverse transcription combined with PCR and mRNA in situ hybridization to determine and localize the expression of CYP7B mRNA in human benign prostatic hyperplasia. High levels of CYP7B mRNA were localized in the epithelial cells together with estrogen receptor beta (ERbeta). 7alpha-Hydroxylation was the major metabolic fate of DHEA in human prostate. Furthermore, we have shown that human prostate epithelial cells in primary culture maintain a high level of 7alpha-hydroxylase activity, which was enhanced by coculture with stroma cells. To investigate the functional relevance of CYP7B expression to sex-steroid action in prostate, we used transient transfections and ligand binding assay to determine the ability of 7HD to bind and activate the sex-steroid receptors: androgen receptor, ERalpha, and ERbeta. 7HD specifically activates ERbeta-mediated transcription, mimicking the effects of 17beta-estradiol, but has no impact on ERalpha and androgen receptor. Given that DHEA, and its sulfate, circulate at micromolar concentrations, there is a clear possibility that CYP7B generates sufficient 7HD to activate ERbeta over and above that achieved with very low concentrations of intraprostatic 17beta-estradiol. In conclusion, our study suggests that CYP7B catalyzes oxysterol 7alpha-hydroxylation within the human prostate epithelium. By this reaction, an ERbeta-specific agonist, 7HD, is produced. Therefore, CYP7B may be a novel regulator of the androgens/estrogenic balance within the prostate.

Exploring the feasibility and acceptability of couple-based psychosexual support following prostate cancer surgery: study protocol for a pilot randomised controlled trial.

BACKGROUND: Men who undergo surgery for prostate cancer frequently experience significant side-effects including urinary and sexual dysfunction. These difficulties can lead to anxiety, depression and reduced quality of life. Many partners also experience psychological distress. An additional impact can be on the couple relationship, with changes to intimacy, and unmet psychosexual supportive needs in relation to sexual recovery and rehabilitation. The aim of this exploratory randomised controlled trial pilot study is to determine the feasibility and acceptability of a novel family-relational-psychosexual intervention to support intimacy and reduce distress among couples following prostate cancer surgery and to estimate the efficacy of this intervention. METHODS/DESIGN: The intervention will comprise six sessions of psychosexual and relationship support delivered by experienced couple-support practitioners. Specialist training in delivering the intervention will be provided to practitioners and they will be guided by a detailed treatment manual based on systemic principles. Sixty-eight couples will be randomised to receive either the intervention or standard care (comprising usual follow-up hospital appointments). A pre-test, post-test design will be used to test the feasibility of the intervention (baseline, end of intervention and six-month follow-up) and its acceptability to couples and healthcare professionals (qualitative interviews). Both individual and relational outcome measures will assess sexual functioning, anxiety and depression, couple relationship, use of health services and erectile dysfunction medication/technologies. An economic analysis will estimate population costs of the intervention, compared to usual care, using simple modelling to evaluate the affordability of the intervention. DISCUSSION: Given the increasing incidence and survival of post-operative men with prostate cancer, it is timely and appropriate to determine the feasibility of a definitive trial through a pilot randomised controlled trial of a family-relational-psychosexual intervention for couples. The study will provide evidence about the components of a couple-based intervention, its acceptability to patients and healthcare professionals, and its influence on sexual and relational functioning. Data from this study will be used to calculate sample sizes required for any definitive trial. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01842438.Registration date: 24 April 2013; Randomisation of first patient: 13 May 2013.

Improving medical work experience for students.

BACKGROUND: This exploratory piece details the development of the programme Medic Insight, which was established in 2007 in Lothian. This is an aptly-named unique organisation that provides an insight into life as a doctor for school students. CONTEXT: We believe that the provision of work experience needs to be improved for both students and doctors. Securing work experience in medicine has historically been biased: individuals that have family or friends who work as doctors are able to organise shadowing placements with greater ease. Shadowing experiences are of questionable value, and frequently offer exposure to only one field, and administrators struggle to match doctors' working schedules with those of students. INNOVATION: Medic Insight has been developed to address these key problems. It provides a free, application-based shadowing experience for 15-16-year olds, in addition to interactive seminars for younger students. Over the course of the 5-day shadowing experience (Medic Insight Week), students rotate through a variety of specialties, meeting doctors of all grades. Doctors agree to act as mentors prior to the shadowing weeks and post their availability online. IMPLICATIONS: Data from our pilot in 2008 has been encouraging. All students who answered our questionnaire found the experience to be either useful or very useful, and ongoing data collection is proving this to be an enjoyable and effective programme. We are confident that Medic Insight will help all suitably enthusiastic and able school students make informed decisions to apply to study medicine.