Opportunistic prostate-specific antigen testing in Norwegian men: a public health challenge.

OBJECTIVE: To describe age-specific prostate-specific antigen (PSA) distributions and resulting prostate cancer diagnoses that arise from population-wide opportunistic PSA testing. PATIENTS AND METHODS: Over 8 million PSA tests were performed on >1.4 million Norwegian men from 2000 to 2020. During this period 43 486 men were diagnosed with localised prostate cancer. Most of the PSA testing reflected opportunistic testing. Age-specific PSA value distributions were constructed for men aged 45-75 years with and without prostate cancer. RESULTS: The distributions of PSA values in men with and without prostate cancer widened with age and overlapped extensively from 3 to 7 ng/mL. Localised prostate cancer diagnoses increased 10-fold from the age of 45 to 75 years. PSA testing identified intermediate- or high-grade cancers in 21% (95% confidence interval [CI] 19-23%) of men aged 50-54 years and 42% (95% CI 41-43%) of men aged 70-74 years. Grade group (GG)1, GG2, GG3 and ≥GG4 constituted 49%, 31%, 10% and 10% of cancers identified at age 50-54 years and 26%, 26%, 18%, and 30% of cancers identified at age 70-74 years. CONCLUSION: Opportunistic PSA testing increases with ageing and often generates values that cannot discriminate benign prostate enlargement from prostate cancer. A clinical cascade using additional imaging or serum tests is necessary to avoid negative biopsies and the overdiagnosis of indolent disease. The declining specificity of PSA testing with ageing poses a significant public health challenge especially among older men aged ≥70 years.

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.

Prostate cancer screening and treatment: where have we come from and where are we going?

OBJECTIVE: To evaluate the current prostate cancer screening and treatment paradigm in light of recently published long-term results of major screening and treatment trials. METHODS: Historical review of the evolution of the diagnosis and treatment of prostate cancer followed by a detailed summary of the findings and differences among the three major screening trials and the three major treatment trials. RESULTS: Prostate-specific antigen (PSA) testing can identify clinically significant prostate cancer and has produced a significant stage shift and is the likely explanation for the decline in prostate cancer mortality. Unfortunately, PSA testing predominantly identifies low-grade disease that is unlikely to progress during a patient's lifetime leading to substantial diagnosis of indolent disease. Treatment with radical prostatectomy (RP) appears to benefit primarily younger men (aged <65 years) with intermediate-grade disease. Too few men with low-grade disease benefit from RP to justify intervening in all. Unfortunately, high-grade prostate cancer often progresses despite surgery and radiation. CONCLUSION: The primary PSA testing paradigm is wrong. Rather than attempting to identify all prostate cancers as early as possible, testing objectives should shift towards identifying men likely to harbour clinically significant disease. These are the men who appear to benefit from early diagnosis and intervention, including the earlier use of antiandrogen therapy prior to widespread metastases.

Tamsulosin and the risk of dementia in older men with benign prostatic hyperplasia.

PURPOSE: Clinicians use tamsulosin, an α1-adrenoceptor antagonist, to manage symptomatic benign prostatic hyperplasia (BPH). Because α1-adrenoceptors are also present in the brain, the potential exists for adverse effects on cognitive functions. We explored the association between tamsulosin use and dementia risk. METHODS: We used Medicare data (2006-2012) to conduct a cohort study among patients aged ≥65 years and diagnosed with BPH. Men taking tamsulosin (n = 253 136) were matched at a 1:1 ratio using propensity-scores to each of 6 comparison cohorts: patients who used no BPH-medication (n = 180 926), and patients who used the following alternative-BPH-medications: doxazosin (n = 28 581), terazosin (n = 23 858), alfuzosin (n = 17 934), dutasteride (n = 34 027), and finasteride (n = 38 767). Assessment began following the first fill of BPH-medication to identify incident dementia by ICD-9 diagnosis codes. We estimated hazard ratios (HR) and 95% confidence intervals (CI) for dementia using Cox proportional hazard regression for each of the 6 propensity-score-matched cohort-pairs. RESULTS: The median follow-up period for all cohorts was 19.8 months. After propensity-score matching, the tamsulosin cohort had an incidence of dementia of 31.3/1000 person-years compared with only 25.9/1000 person-years in the no-BPH-medication cohort. The risk of dementia was significantly higher in the tamsulosin cohort, when compared with the no-BPH-medication cohort (HR [95% CI]: 1.17 [1.14, 1.21]) and each of the alternative-BPH-medication cohorts: doxazosin (1.20 [1.12, 1.28]), terazosin (1.11 [1.04, 1.19]), alfuzosin (1.12 [1.03, 1.22]), dutasteride (1.26 [1.19, 1.34]), and finasteride (1.13 [1.07, 1.19]). The significance of these findings persisted in sensitivity analyses. CONCLUSION: Tamsulosin may increase the risk of dementia in older men with BPH.

Is Tamsulosin Linked to Dementia in the Elderly?

PURPOSE OF REVIEW: Lower urinary tract symptoms (LUTS) result from age-related changes in detrusor function and prostatic growth that are driven by alterations in the ratio of circulating androgens and estrogens. Alpha-adrenergic receptor blockers are commonly used to treat LUTS because they influence urethral tone and intra-urethral pressure. Molecular cloning studies have identified three α1-adrenergic receptor subtypes (α1A, α1B, and α1D). The α1A subtype is predominant in the human prostate but is also present in many parts of the brain that direct cognitive function. Tamsulosin is the most widely used α1-adrenergic receptor antagonist with 12.6 million prescriptions filled in 2010 alone. When compared to the other common types of α1-adrenergic receptor antagonists (i.e., terazosin, doxazosin, and alfuzosin), tamsulosin is 10- to 38-fold more selective for the α1A versus the α1B subtype. RECENT FINDINGS: Duan et al. have recently shown that men taking tamsulosin have a higher risk of developing dementia when compared to men taking other α-adrenergic antagonists or no α-adrenergic antagonists at all (HR 1.17; 95% CI 1.14-1.21). Based upon this retrospective analysis, we believe that tamsulosin, because of its unique affinity for α1A-adrenergic receptors, may increase the risk of developing dementia when used for an extended period of time. If these findings are confirmed, they carry significant public health implications for an aging society.

Long-term functional outcomes after treatment for localized prostate cancer.

BACKGROUND: The purpose of this analysis was to compare long-term urinary, bowel, and sexual function after radical prostatectomy or external-beam radiation therapy. METHODS: The Prostate Cancer Outcomes Study (PCOS) enrolled 3533 men in whom prostate cancer had been diagnosed in 1994 or 1995. The current cohort comprised 1655 men in whom localized prostate cancer had been diagnosed between the ages of 55 and 74 years and who had undergone either surgery (1164 men) or radiotherapy (491 men). Functional status was assessed at baseline and at 2, 5, and 15 years after diagnosis. We used multivariable propensity scoring to compare functional outcomes according to treatment. RESULTS: Patients undergoing prostatectomy were more likely to have urinary incontinence than were those undergoing radiotherapy at 2 years (odds ratio, 6.22; 95% confidence interval [CI], 1.92 to 20.29) and 5 years (odds ratio, 5.10; 95% CI, 2.29 to 11.36). However, no significant between-group difference in the odds of urinary incontinence was noted at 15 years. Similarly, although patients undergoing prostatectomy were more likely to have erectile dysfunction at 2 years (odds ratio, 3.46; 95% CI, 1.93 to 6.17) and 5 years (odds ratio, 1.96; 95% CI, 1.05 to 3.63), no significant between-group difference was noted at 15 years. Patients undergoing prostatectomy were less likely to have bowel urgency at 2 years (odds ratio, 0.39; 95% CI, 0.22 to 0.68) and 5 years (odds ratio, 0.47; 95% CI, 0.26 to 0.84), again with no significant between-group difference in the odds of bowel urgency at 15 years. CONCLUSIONS: At 15 years, no significant relative differences in disease-specific functional outcomes were observed among men undergoing prostatectomy or radiotherapy. Nonetheless, men treated for localized prostate cancer commonly had declines in all functional domains during 15 years of follow-up. (Funded by the National Cancer Institute.).

Successful external validation of a model to predict other cause mortality in localized prostate cancer.

BACKGROUND: Although life expectancy estimation is vital to decision making for localized prostate cancer, there are few, if any, valid and usable tools. Our goal was to create and validate a prediction model for other cause mortality in localized prostate cancer patients that could aid clinician's initial treatment decisions at the point of care. METHODS: We combined an adjusted Social Security Administration table with a subset of comorbidities from a UK actuarial life expectancy model. Life tables were adjusted on the basis of survival data from a cohort of almost 10,000 radical prostatectomy patients treated at four major US academic institutions. Comorbidity-specific odds ratios were calculated and incorporated with baseline risk of mortality. We externally validated the model on 2898 patients from the Prostate Cancer Outcomes Study, which included men diagnosed with prostate cancer in six SEER cancer registries. These men had sufficient follow-up for our endpoints of 10- and 15-year mortality and also had self-reported comorbidity data. RESULTS: Life expectancy for prostate cancer patients were close to that of a typical US man who was 3 years younger. On external validation, 10- and 15-year concordance indexes were 0.724 and 0.726, respectively. Our model exhibited excellent calibration. Taking into account differences between how comorbidities are used in the model versus how they were recorded in the validation cohort, calibration would improve for most patients, but there would be overestimation of the risk of death in the oldest and sickest patients. CONCLUSIONS: We successfully created and externally validated a new life expectancy prediction model that, while imperfect, has clear advantages to any alternative. We urge consideration of its use in counseling patients with localized prostate cancer.

The Comparative Harms of Open and Robotic Prostatectomy in Population Based Samples.

PURPOSE: Robotic assisted radical prostatectomy has largely replaced open radical prostatectomy for the surgical management of prostate cancer despite conflicting evidence of superiority with respect to disease control or functional sequelae. Using population cohort data, in this study we examined sexual and urinary function in men undergoing open radical prostatectomy vs those undergoing robotic assisted radical prostatectomy. MATERIALS AND METHODS: Subjects surgically treated for prostate cancer were selected from 2 large population based prospective cohort studies, the Prostate Cancer Outcomes Study (enrolled 1994 to 1995) and the Comparative Effectiveness Analysis of Surgery and Radiation (enrolled 2011 to 2012). Subjects completed baseline, 6-month and 12-month standardized patient reported outcome measures. Main outcomes were between-group differences in functional outcome scores at 6 and 12 months using linear regression, and adjusting for baseline function, sociodemographic and clinical characteristics. Sensitivity analyses were used to evaluate outcomes between patients undergoing open radical prostatectomy and robotic assisted radical prostatectomy within and across CEASAR and PCOS. RESULTS: The combined cohort consisted of 2,438 men, 1,505 of whom underwent open radical prostatectomy and 933 of whom underwent robotic assisted radical prostatectomy. Men treated with robotic assisted radical prostatectomy reported better urinary function at 6 months (mean difference 3.77 points, 95% CI 1.09-6.44) but not at 12 months (1.19, -1.32-3.71). Subjects treated with robotic assisted radical prostatectomy also reported superior sexual function at 6 months (8.31, 6.02-10.56) and at 12 months (7.64, 5.25-10.03). Sensitivity analyses largely supported the sexual function findings with inconsistent support for urinary function results. CONCLUSIONS: This population based study reveals that men undergoing robotic assisted radical prostatectomy likely experience less decline in early urinary continence and sexual function than those undergoing open radical prostatectomy. The clinical meaning of these differences is uncertain and longer followup will be required to establish whether these benefits are durable.

Prostate-specific antigen patterns in US and European populations: comparison of six diverse cohorts.

OBJECTIVE: To determine whether there are differences in prostate-specific antigen (PSA) levels at diagnosis or changes in PSA levels between US and European populations of men with and without prostate cancer (PCa). SUBJECTS AND METHODS: We analysed repeated measures of PSA from six clinically and geographically diverse cohorts of men: two cohorts with PSA-detected PCa, two cohorts with clinically detected PCa and two cohorts without PCa. Using multilevel models, average PSA at diagnosis and PSA change over time were compared among study populations. RESULTS: The annual percentage PSA change of 4-5% was similar between men without cancer and men with PSA-detected cancer. PSA at diagnosis was 1.7 ng/mL lower in a US cohort of men with PSA-detected PCa (95% confidence interval 1.3-2.0 ng/mL), compared with a UK cohort of men with PSA-detected PCa, but there was no evidence of a different rate of PSA change between these populations. CONCLUSION: We found that PSA changes over time are similar in UK and US men diagnosed through PSA testing and even in men without PCa. Further development of PSA models to monitor men on active surveillance should be undertaken in order to take advantage of these similarities. We found no evidence that guidelines for using PSA to monitor men cannot be passed between US and European studies.

Who and when should we screen for prostate cancer? Interviews with key opinion leaders.

Prostate cancer screening using prostate-specific antigen (PSA) is highly controversial. In this Q & A, Guest Editors for BMC Medicine's 'Spotlight on Prostate Cancer' article collection, Sigrid Carlsson and Andrew Vickers, invite some of the world's key opinion leaders to discuss who, and when, to screen for prostate cancer. In response to the points of view from the invited experts, the Guest Editors summarize the experts' views and give their own personal opinions on PSA screening.

Influence of age on incident diabetes and cardiovascular disease in prostate cancer survivors receiving androgen deprivation therapy.

PURPOSE: Observational data suggest that androgen deprivation therapy increases the risk of diabetes and cardiovascular disease. Using data from the population based PCOS we evaluated whether age at diagnosis and comorbidity impact the association of androgen deprivation therapy with incident diabetes and cardiovascular disease. MATERIALS AND METHODS: We identified men with nonmetastatic prostate cancer diagnosed from 1994 to 1995 who were followed through 2009 to 2010. We used multivariable logistic regression models to assess the relationship of androgen deprivation therapy exposure (2 or fewer years, greater than 2 years or none) with incident diabetes and cardiovascular disease, adjusting for age at diagnosis, race, stage and comorbidity. RESULTS: Of 3,526 eligible study participants 2,985 without diabetes and 3,112 without cardiovascular disease comprised the cohorts at risk. Androgen deprivation therapy was not associated with an increased risk of diabetes or cardiovascular disease in men diagnosed with prostate cancer before age 70 years. Prolonged androgen deprivation therapy and increasing age at diagnosis in older men was associated with an increased risk of diabetes (at age 76 years OR 2.1, 95% CI 1.0-4.4) and cardiovascular disease (at age 74 years OR 1.9, 95% CI 1.0-3.5). Men with comorbidities were at greater risk for diabetes (OR 4.3, 95% CI 2.3-7.9) and cardiovascular disease (OR 8.1, 95% CI 4.3-15.5) than men without comorbidities. CONCLUSIONS: Prolonged androgen deprivation therapy exposure increases the risk of cardiovascular disease and diabetes in men diagnosed with prostate cancer who are older than approximately 75 years, especially those with other comorbidities. Older men who receive prolonged androgen deprivation therapy should be closely monitored for diabetes and cardiovascular disease.

Self-Reported Health Status Predicts Other-Cause Mortality in Men with Localized Prostate Cancer: Results from the Prostate Cancer Outcomes Study.

BACKGROUND: Guidelines recommend against treating localized prostate cancer (PCa) in men with a greater than 10-year life expectancy. However, physicians have difficulty accurately estimating life expectancy. OBJECTIVE: We used data from a population-based observational study to develop a nomogram to estimate long-term other-cause mortality based on self-reported health status (SRHS), race/ethnicity, and age at diagnosis. DESIGN: This was an observational study. SUBJECTS: Men diagnosed with localized PCa from October 1994 through October 1995 participated in the study. MAIN MEASURES: Initial measures obtained 6 months after diagnosis included sociodemographic and tumor characteristics, treatment, and a single item on the SRHS, with response options ranging from excellent to poor. We used Surveillance, Epidemiology, and End-Results program data to determine date and cause of death through December 2010. We estimated other-cause mortality with proportional hazards survival analyses, accounting for competing risks. KEY RESULTS: We evaluated 2,695 men, of whom 74% underwent aggressive therapy (surgery or radiotherapy). At the initial survey, 18% reported excellent (E), 36% very good (VG), 31% good (G), and 15% fair/poor (F/P) health. Healthier men were younger, and more likely to be white, better educated, and to undergo surgery. At follow-up, 44% of the cohort had died; 78% of deaths were from causes other than PCa. SRHS predicted other-cause mortality; for men reporting E, VG, G, F/P health, the cumulative incidences of other-cause mortality were 20%, 29%, 40%, and 53%, respectively, p < 0.001. Compared to a reference of excellent SRHS, multivariable hazard ratios (95% CI) for other-cause mortality for men reporting VG, G, and F/P health were 1.22 (0.97-1.54), 1.73 (1.38-2.17), and 2.71 (2.11-3.48), respectively. CONCLUSIONS: Responses to a one-item SRHS measure were strongly associated with other-cause mortality 15 years after PCa diagnosis. Men reporting fair/poor health had substantial risks for other-cause mortality, suggesting limited benefit for undergoing aggressive treatment. SRHS can be considered in supporting informed decision-making about PCa treatment.

Observational studies and the natural history of screen-detected prostate cancer.

PURPOSE OF REVIEW: To review the recent observational studies and clinical trials that guide our understanding of the natural history of screen-detected prostate cancer. RECENT FINDINGS: Data from observational studies and clinical trials have been updated during the past year. The most important include the Scandinavian Prostate Cancer Group 4 study and the European Randomized Study of Prostate Cancer Screening. SUMMARY: Both retrospective population-based analyses and prospective randomized trials show that men who harbor low-volume low-grade prostate cancers have less than 6% risk of disease progression within a decade of diagnosis. For the men who pursue active surveillance prostate cancer mortality remains under 1% after a median follow-up of 6.8 years. Up to one-third of men abandon active surveillance protocols because of either prostate-specific antigen or biopsy progression. Around 10% abandon active surveillance because of anxiety. Researchers are actively exploring new imaging modalities and genetic markers to identify men whose prostate cancers are likely to progress. For now, patients with newly diagnosed prostate cancer must carefully weigh the threat posed by their disease against the possible benefits and harms associated with intervention. For some, active surveillance will be an appropriate choice.