Standardized prostate cancer incidence and mortality rates following initial non-malignant biopsy result.

OBJECTIVES: To compare the incidence of subsequent prostate cancer diagnosis and death following an initial non-malignant systematic transrectal ultrasonography (TRUS) biopsy with that in an age- and calendar-year matched population over a 20-year period. SUBJECTS AND METHODS: This population-based analysis compared a cohort of all men with initial non-malignant TRUS biopsy in Denmark between 1995 and 2016 (N = 37 231) with the Danish population matched by age and calendar year, obtained from the NORDCAN 9.1 database. Age- and calendar year-corrected standardized prostate cancer incidence (SIR) and prostate cancer-specific mortality ratios (SMRs) were calculated and heterogeneity among age groups was assessed with the Cochran's Q test. RESULTS: The median time to censoring was 11 years, and 4434 men were followed for more than 15 years. The corrected SIR was 5.2 (95% confidence interval [CI] 5.1-5.4) and the corrected SMR was 0.74 (95% CI 0.67-0.81). Estimates differed among age groups (P < 0.001 for both), with a higher SIR and SMR among younger men. CONCLUSION: Men with non-malignant TRUS biopsy have a much higher incidence of prostate cancer but a risk of prostate cancer death below the population average. This underlines that the oncological risk of cancers missed in the initial TRUS biopsy is low. Accordingly, attempts to increase the sensitivity of initial biopsy are unjustified. Moreover, current follow-up after non-malignant biopsy is likely to be overaggressive, particularly in men over the age of 60 years.

Diagnostic Age, Age at Death and Stage Migration in Men Dying with or from Prostate Cancer in Denmark.

The impact of changes in diagnostic activity and treatment options on prostate cancer epidemiology remains a subject of debate. Newly published long-term survival outcomes may not represent contemporary patients and new perspectives are in demand. All men dying in Denmark with prostate cancer diagnosis during a 10-year period were analyzed to address the stage migration of and time lived with prostate cancer diagnosis. All male deaths in Denmark between 2007 and 2016 (n = 261,657) were obtained and crosslinked with The Danish Prostate Cancer Registry (DaPCaR) and the Danish Cancer Registry. Correlation in diagnostic age and stage (localized, locally advanced, metastatic), age at death and cause of death were investigated by Kruskal-Wallis test and linear regression in 15,692 men diagnosed with prostate cancer. Prostate cancer mortality remained stable during the study period. Among the men who died of prostate cancer, 65% had locally advanced or metastatic disease at diagnosis. Age at diagnosis declined in men diagnosed with localized disease and remained constant in men with locally advanced or metastatic disease. Age at death increased in all men. Despite increased efforts to detect prostate cancer early, two-thirds of men who die from prostate cancer still have advanced prostate cancer at the time of diagnosis. Our data show increased life-expectancy in men diagnosed with prostate cancer, however, this benefit must be weighed against increased time of living with the disease and overdiagnosis. The intensified treatment of elderly men and men with advanced disease may be the key to lower prostate cancer mortality.

A Nationwide Analysis of Risk of Prostate Cancer Diagnosis and Mortality following an Initial Negative Transrectal Ultrasound Biopsy with Long-Term Followup.

PURPOSE: Magnetic resonance imaging (MRI) targeted prostate biopsy has been shown to find many high-grade prostate cancers in men with concurrent negative transrectal ultrasound (TRUS) systematic biopsy. The oncologic risk of such tumors can be explored by looking at long-term outcomes of men with negative TRUS biopsy followed without MRI. The aim was to analyze the mortality after initial and second negative TRUS biopsy. MATERIALS AND METHODS: All men who underwent initial TRUS biopsies between January 1, 1995 and December 31, 2016 in Denmark were included. A total of 37,214 men had a negative initial TRUS biopsy and 6,389 underwent a re-biopsy. Risk of cause-specific mortality was analyzed with competing risks. Diagnosis of Gleason score ≥7 prostate cancer following negative biopsies was analyzed with multivariable logistic regression including time to re-biopsy, prostate specific antigen (PSA), age and digital rectal examination. RESULTS: The 15-year prostate cancer-specific mortality was 1.9% (95% CI: 1.7-2.1). Prostate cancer-specific mortality was 1.3% (95% CI: 0.9-1.6) and 4.6% (95% CI: 3.4-5.8) for men with PSA <10 and >20 ng/ml, respectively. Of the TRUS re-biopsies 12% were Gleason score ≥7 and risk of Gleason score ≥7 increased with longer time to re-biopsy (p <0.001). Mortality after re-biopsy was similar to after initial biopsy. CONCLUSIONS: Men with negative TRUS biopsies have a very low prostate cancer-specific mortality, especially with PSA <10 ng/ml. This raises serious questions about the routine use of MRI targeting for initial prostate biopsy and suggests that MRI targeting should only be recommended for men with PSA >10 ng/ml after negative biopsy.

Risk of depression after diagnostic prostate cancer workup - A nationwide, registry-based study.

OBJECTIVE: To compare the risk of depression after diagnostic workup for prostate cancer (PCa), regardless of the histopathologic outcome, with that of a cancer-free population. METHODS: A nationwide cohort of Danish men who had a prostatic biopsy sample in 1998-2011 was identified from the Danish Prostate Cancer Registry and compared to an age-matched cohort from the background population. Men with other cancers, major psychiatric disorder, or prior use of antidepressants were excluded. The risk of depression defined as hospital contact for depression or prescription for antidepressants was determined from cumulative incidence functions and multivariate Cox regression models. RESULTS: Of 54,766 men who underwent diagnostic workup for PCa, benign results were found for 21,418 and PCa was diagnosed in 33,347. During up to 18 years of follow-up, the adjusted hazard of depression was higher in men with PCa than in the background population, with the highest risk in the two years after diagnosis (hazard ratio (HR) 2.77, 95% CI 2.66-2.87). Comorbidity and lowest or highest income were significant risk factors for depression and the cumulative incidence was substantially higher in men with metastatic or high-risk disease. In men with benign histopathology the HR for depression was 1.22 (95% CI 1.14-1.31) in the first two years but no different from the background population after that. CONCLUSIONS: Diagnostic workup for PCa is associated with an increased risk of depression, mainly among men with a diagnosis of PCa. Clinicians should be aware of depressive symptoms in prostate cancer patients.

Detection of Clinically Significant Prostate Cancer by Systematic TRUS-Biopsies in a Population-Based Setting Over a 20 Year Period.

OBJECTIVE: To assess the performance of systematic TRUS-biopsies in a population-based setting to detect clinically significant PCa (csPCa) in combination with age, clinical tumor category (cT), and prostate-specific antigen (PSA) in men referred for the first biopsy. METHODS: We identified all men referred for PCa work-up because of elevated PSA who underwent initial TRUS-biopsies in the nationwide Danish Prostate Cancer Registry (DaPCaR) between January 1st, 1995 and December 31st, 2016, in Denmark. Risk of histologic findings in initial TRUS-biopsies categorized as non-malignant, insignificant PCa, or significant PCa (csPCa). We defined csPCa as any biopsy containing Gleason score 3 + 4 or above as in the PRECISION trial. We assessed risk of csPCa with absolute risk, logistic regression model, and predicted risks. RESULTS AND LIMITATIONS: After exclusions, our cohort included 39,886 men. The diagnostic hit rate for csPCa was 40.8 %. Men with PSA > 20 ng/mL and ≥cT2 harbor a risk >75% for finding csPCa in the first TRUS biopsy-set. Men with cT1 tumors and PSA < 20 ng/mL have a risk of non-malignant histology of at least 58%. Limitations include the high number of exclusions based on missing information. CONCLUSION: The diagnostic accuracy of systematic TRUS-biopsies is high for men with palpable tumors and high PSA. Our data point to the fact that not all men need pre-biopsy MRI to find csPCa.

The impact of positive surgical margins on salvage radiation or androgen deprivation therapy following radical prostatectomy - a nationwide study.

BACKGROUND: The extent to which positive surgical margins (PSM) affect the risk of subsequent salvage radiation therapy (sRT) or androgen depletion therapy (ADT) following radical prostatectomy (RP) is not well described. Initiation of additional therapies after RP depend on patient preference, individual factors, local guidelines, and life expectancy. The aim of this study was to analyze differences between margin status in risk of subsequent treatment for PCa following RP in a retrospective population-based cohort from Denmark. METHODS: Patients who underwent RP were identified in The Danish Prostate Cancer Registry (DaPCaR). Subsequent sRT and ADT were assessed in uni- and multivariate settings and validated with receiver operating characteristic (ROC). RESULTS: PSM was associated with an increased risk of sRT (HR = 1.85, p < .001) and receiving ADT (HR:1.39, p = .007). Margin status only had a minor impact on the predictive ability for sRT (area under the curve (AUC): p < .001) and no significant impact for subsequent ADT (AUC: p = 1). Significant inter-institutional difference in the association between PSM with sRT or ADT was observed. CONCLUSION: PSM is associated with the risk of sRT and initiation of ADT, however this association is weak. Our results underline that factors beyond tumor characteristics play a major role for initiation of sRT and ADT.

Risk of Depression After Radical Prostatectomy-A Nationwide Registry-based Study.

BACKGROUND: Development of depression in prostate cancer patients depends on multiple disease- and patient-related factors. OBJECTIVE: To investigate the risk of depression following radical prostatectomy focussing on the impact of surgery and subsequent treatment with salvage radiation or androgen deprivation therapy. DESIGN, SETTING, AND PARTICIPANTS: A population-based cohort study of 5570 men who underwent radical prostatectomy in Denmark from 1998 to 2011 was identified in the Danish Prostate Cancer Registry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Data on covariates and primary outcome defined as a hospital contact for depression or a redeemed antidepressant prescription were obtained from nationwide Danish registries. The risk of depression was evaluated using cumulative incidence functions and Cox models with time since surgery as an underlying time scale. Exposure to salvage procedures was included as time-varying covariates, and analyses were adjusted for confounders. RESULTS AND LIMITATIONS: The cumulative incidence of depression was increased in men who had undergone surgery compared with cancer-free men throughout follow-up of up to 18yr, particularly among men on androgen deprivation therapy. Compared with no subsequent treatment, the risk of depression was increased with subsequent androgen deprivation therapy (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.4-2.3), salvage radiation (HR 1.3, 95% CI 1.0-1.6), and the treatments combined (HR 2.2, 95% CI 1.8-2.8) after adjustments for age, year of surgery, income, and cohabitation status. Further adjustment for comorbidity hardly changed the estimates. CONCLUSIONS: Radical prostatectomy and subsequent salvage procedures increase the risk of depression, and men with subsequent androgen deprivation therapy are mainly at risk. Clinicians should thus be aware of depressive symptoms in patients receiving treatment for postsurgical relapse. PATIENT SUMMARY: In a population-based study, we found that radical prostatectomy and subsequent treatments with either radiation or endocrine manipulation significantly increased the risk of developing clinical depression.

Vitamin D levels and the risk of prostate cancer and prostate cancer mortality.

BACKGROUND: Vitamin D has a role in bone turnover and potentially bone-metastatic spread of prostate cancer (PCa). The aim of this observational study was to address the association between levels of serum vitamin D, diagnosis of PCa and subsequent mortality in men who underwent a biopsy of the prostate. METHODS: All men who underwent prostatic biopsy in the Danish PCa Registry (DaPCaR) and who had a serum vitamin D measurement during the period 2004 to 2010 (n = 4,065) were identified. Men were categorized by clinical cut-offs based on seasonally adjusted serum vitamin D levels in <25 (deficient), 25-50 (insufficient), 50-75 (sufficient) and >75 nmol/L (high) serum vitamin D. Logistic regression model for association between vitamin D and risk of PCa diagnosis and multivariate survival analyses were applied. RESULTS: No association between serum vitamin D and risk of PCa was found. Overall survival was lowest for serum vitamin D deficiency and a significantly higher PCa specific mortality (HR: 2.37, 95%CI: 1.45-3.90, p < .001) and other cause mortality (HR: 2.08, 95%CI: 1.33-3.24, p = .001) was found for PCa patients with serum vitamin D deficiency compared to serum vitamin D sufficiency. CONCLUSION: No association was found between serum vitamin D categories and risk of PCa in men who underwent biopsy of the prostate. Men with PCa and serum vitamin D deficiency had a higher overall and PCa specific mortality compared to men with a sufficient level of serum vitamin D.

What is the risk of prostate cancer mortality following negative systematic TRUS-guided biopsies? A systematic review.

OBJECTIVE: To investigate the risk of prostate cancer-specific mortality (PCSM) following initial negative systematic transrectal ultrasound-guided (TRUS) prostate biopsies. DESIGN: Systematic review. DATA SOURCES: PubMed and Embase were searched using a string combination with keywords/Medical Subject Headings terms and free text in the search builder. Date of search was 13 April 2020. STUDY SELECTION: Studies addressing PCSM following initial negative TRUS biopsies. Randomised controlled trials and population-based studies including men with initial negative TRUS biopsies reported in English from 1990 until present were included. DATA EXTRACTION: Data extraction was done using a predefined form by two authors independently and compared with confirm data; risk of bias was assessed using the Newcastle-Ottawa Scale for cohort studies when applicable. RESULTS: Four eligible studies were identified. Outcomes were reported differently in the studies as both cumulative incidence and Kaplan-Meier estimates have been used. Regardless of the study differences, all studies reported low estimated incidence of PCSM of 1.8%-5.2% in men with negative TRUS biopsies during the following 10-20 years. Main limitation in all studies was limited follow-up. CONCLUSION: Only a few studies have investigated the risk of PCSM following initial negative biopsies and all studies included patients before the era of MRI of the prostate. However, the studies point to the fact that the risk of PCSM is low following initial negative TRUS biopsies, and that the level of prostate-specific antigen before biopsies holds prognostic information. This may be considered when advising patients about the need for further diagnostic evaluation. PROSPERO REGISTRATION NUMBER: CRD42019134548.

The use of transrectal ultrasound-guided biopsy following the introduction of prostate-specific antigen testing in Denmark: a population-based analysis.

OBJECTIVE: Incidence rates of prostate cancer in Denmark resemble those of countries that endorse prostate-specific antigen (PSA) screening. So far, no studies have described the consequences of PSA testing on diagnostic activity on a population level. The aim of this study was to describe the frequency of systematic transrectal ultrasound-guided biopsy (TRUS-gb) activity, including rebiopsy rates, in Denmark between 1995 and 2011. MATERIALS AND METHODS: All men who underwent TRUS-gb during the period were identified in the Danish Prostate Cancer Registry. In total, 83,041 biopsy sets from 64,430 individuals were identified. The diagnostic rate and the frequency of rebiopsy were analyzed. Age, histology and PSA were compared at the time of biopsy. RESULTS: The number of TRUS-gb per 100,000 men per year increased 4.6-fold. The mean number of TRUS-gb procedures per individual increased from 1.08 in 1995 to 1.46 in 2011 (p = .0001), and the proportion of men with negative initial biopsy sets who underwent rebiopsy increased from 22% in 1995 to 41% in 2004, later decreasing to 31% in 2009. CONCLUSIONS: The diagnostic activity in Denmark and the rebiopsy rates in men with initial negative TRUS-gb have increased substantially, and guidelines for the management of men with a negative initial biopsy are highly warranted.

The prognostic impact of incidental prostate cancer following radical cystoprostatectomy: a nationwide analysis.

BACKGROUND: To determine the prevalence and prognostic impact of incidental prostate cancer in patients undergoing radical cystoprostatectomy. METHODS: A nationwide population-based study of incidental prostate cancer diagnosed following radical cystoprostatectomy. Information on vital status, Gleason score, positive and negative tumor margins, pT-category and subsequent prostate cancer therapies were obtained from the Danish Prostate Cancer Registry and by manual chart review. RESULTS: A total of 1,450 men who underwent radical cystoprostatectomy in Denmark from 1995-2011 were identified. Forty-six men were excluded from analysis, thus 1,404 patients were eligible. The median follow-up was 7.8 years. A total of 466 (33.2%) had incidental prostate cancer diagnosed. No statistical differences in 10- and 15-year cumulative overall mortality were observed when comparing men with, or without, incidental prostate cancer. In men diagnosed with incidental prostate cancer, neither Gleason score, positive surgical margins or locally advanced prostate cancer (pT3-4) was associated with mortality. Only 0.9% received post-operative prostate cancer-related treatment. CONCLUSION: In this population-based cohort of patients with incidental prostate cancer diagnosed at radical cystoprostatectomy, we found no impact of incidental prostate cancer on overall mortality, regardless of Gleason score, surgical margin status and pathological T-category. Patients diagnosed with incidental prostate cancer following radical cystoprostatectomy are unlikely to benefit from additional follow-up.

Diagnostic characteristics of lethal prostate cancer.

BACKGROUND: The diagnostic characteristics of men who eventually die from prostate cancer (PCa) and the extent to which early diagnostic strategies have affected these characteristics are unclear. We aimed to investigate trends in survival and clinical presentation at diagnosis in men who eventually died from PCa. PATIENTS AND METHODS: Based on the national database, the Danish Prostate Cancer Registry, a nationwide population-based study of all 19,487 men who died from PCa in Denmark between 1995 and 2013 was conducted. Trends in median survival and trends in age, prostate-specific antigen (PSA), clinical stage, and Gleason score (GS) at diagnosis were analysed. RESULTS: A total of 46.9%, 16.8%, and 36.3% had metastatic (M+), locally advanced/lymph node positive (LaN+), and localised disease, respectively, at diagnosis. Only 0.15% had localised disease, GS ≤ 6 and PSA<10. Over time, the proportion of men with M+ disease at diagnosis decreased from 54.0-38.3% (p < 0.0001), whereas the proportion LaN + disease increased from 8.6-27.3% (p < 0.0001). The proportion of localised disease remained stable at 33.2-41.9%. Median survival increased 2.11 years from 1.88 (95% CI: 1.68-2.08) in 1995 to 3.99 (95% CI: 3.71-4.28) years in 2013, p < 0.0001. CONCLUSIONS: In a large population-based study, the results confirmed concurrent literature that the majority of men who eventually died from PCa had LaN+ or M+ disease at diagnosis. The proportion of men with M+ disease at diagnosis decreased significantly over time, parallelled by an increase in median survival. Taken together, this indicates a lead-time effect on survival, which presently, however, is not substantial enough to result in a reduced PCa-specific mortality.

Antibiotic prophylaxis and complications following prostate biopsies - a systematic review.

INTRODUCTION: Transrectal ultrasound-guided biopsies (TRUS-gb) are associated with both mild and serious complications. Prophylactic antibiotics reduce the risk of septicaemia and mortality; however, no international consensus exists on the timing and duration of antibiotics, including the optimal drug strategy. We reviewed the current evidence supporting use of prophylactic antibiotics and the risk of complications following prostate biopsies. METHODS: This review was drafted in accordance with the Prisma Guidelines. The PubMed, Embase and Cochrane databases were searched. RESULTS: A total of 19 eligible trials were identified. One trial demonstrated a significant reduction in the risk of infection after biopsy and reported that oral ciprofloxacin as either a single-dose or a three-day regimen was superior to oral chloramphenicol and norfloxacin. Of three studies investigating the timing of the first dose of antibiotic, one study found that administration 24 h before biopsy versus administration immediately before reduced the relative risk of post-biopsy infection by 55%. Seven studies compared different durations of antibiotic prophylaxis. None showed any benefit from continuing prophylaxis beyond a single dose or a one-day regimen. CONCLUSION: Evidence supporting a specific antibiotic regimen for TRUS-gb prophylaxis is scarce. Widespread use of fluoroquinolone prophylaxis may be associated with an increase in resistant Escherichia coli strains, posing a potentially major health issue in the future. .

Systematic review: does endocrine therapy prolong survival in patients with prostate cancer?

Objective Primary androgen deprivation therapy (ADT) remains the gold standard in the management of patients with advanced prostate cancer (PCa). ADT relieves symptoms and reduces tumor burden, but it has never been demonstrated to increase either PCa-specific or overall survival per se. Several trials have challenged this dogma. The aim of this study was to evaluate how endocrine therapy (ET) affects survival in different clinical settings of PCa. Materials and methods A review of published phase II, III and IV studies evaluating the effect of ET on survival was performed. Results In localized and locally advanced non-metastatic PCa, neoadjuvant ET before radical prostatectomy has no effect on survival. Neoadjuvant and adjuvant ET in combination with curatively intended radiotherapy results in PCa-specific and overall survival benefit, although the duration of ET remains under debate. In N + disease, the timing of ET is under debate, although data suggest that early ET is associated with decreased PCa-specific and overall mortality. In M + disease, no proper randomized trials have been performed in patients with newly diagnosed M1 disease. In metastatic castration-resistant PCa, two novel endocrine agents have been proven to increase overall survival significantly compared to placebo. Conclusions ET has never been proven to increase survival in newly diagnosed metastatic PCa in a randomized clinical trial. Nonetheless, a number of trials supports that ET with proper timing, sequencing and in combination with other therapeutic modalities increases survival in several stages of PCa.