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Objective: To determine the impact of empiric antibiotics on men with an elevated prostate-specific antigen (PSA) level., Subjects/patients and Methods: Men of any age with a PSA level of >2.5 ng/mL and normal digital rectal examination undergoing their first prostate biopsy were recruited from five medical centres. Patients with previous biopsy, prostate cancer, urinary tract infection (UTI) or prostatitis within the prior year, antibiotic use within 1 month, 5α-reductase inhibitor use, allergy to fluoroquinolones or clinical suspicion of UTI were excluded. Men were randomised to 2 weeks of ciprofloxacin or no antibiotic. A PSA measurement was obtained 21-45 days after randomisation immediately before prostate biopsy. The primary endpoint was the change in PSA level between baseline and immediately before biopsy., Results: Complete data were available for 77 men with a mean (interquartile range) age of 60.6 (53-66) years. In the control group of men not receiving antibiotic (39 men), the mean baseline and pre-biopsy PSA levels were 6.5 and 6.9 ng/mL, respectively (P = 0.8). In men receiving ciprofloxacin (38 men), the mean baseline PSA level was 7.6 ng/mL and after 2 weeks of ciprofloxacin was 8.5 ng/mL (P = 0.7). Compared with controls not receiving antibiotic, use of ciprofloxacin was not associated with a statistically significant change in PSA level (P = 0.33). Prostate cancer was detected in 36 (47%) men, 23 (59%) in the control group and 13 (34%) in the antibiotic group (P = 0.04). Detection rates were not significantly associated with the change in PSA level between baseline and biopsy. The primary limitation of the study is early stoppage due to an interim futility analysis and poor accrual., Conclusion: Despite not meeting the target accrual goal, empiric use of antibiotics for asymptomatic men with an elevated PSA level does not appear to be of clinical benefit., (© 2013 The Authors. BJU International © 2013 BJU International.)

Purpose: The long-term risk of prostate cancer-specific mortality (PCSM) after radical prostatectomy is poorly defined for patients treated in the era of widespread prostate-specific antigen (PSA) screening. Models that predict the risk of PCSM are needed for patient counseling and clinical trial design., Methods: A multi-institutional cohort of 12,677 patients treated with radical prostatectomy between 1987 and 2005 was analyzed for the risk of PCSM. Patient clinical information and treatment outcome was modeled using Fine and Gray competing risk regression analysis to predict PCSM., Results: Fifteen-year PCSM and all-cause mortality were 12% and 38%, respectively. The estimated PCSM ranged from 5% to 38% for patients in the lowest and highest quartiles of predicted risk of PSA-defined recurrence, based on a popular nomogram. Biopsy Gleason grade, PSA, and year of surgery were associated with PCSM. A nomogram predicting the 15-year risk of PCSM was developed, and the externally validated concordance index was 0.82. Neither preoperative PSA velocity nor body mass index improved the model's accuracy. Only 4% of contemporary patients had a predicted 15-year PCSM of greater than 5%., Conclusion: Few patients will die from prostate cancer within 15 years of radical prostatectomy, despite the presence of adverse clinical features. This favorable prognosis may be related to the effectiveness of radical prostatectomy (with or without secondary therapy) or the low lethality of screen-detected cancers. Given the limited ability to identify contemporary patients at substantially elevated risk of PCSM on the basis of clinical features alone, the need for novel markers specifically associated with the biology of lethal prostate cancer is evident.

Objectives: For prostate cancer screening, the role of prostate-specific antigen (PSA) velocity (PSAV) in conjunction with total PSA is controversial. We evaluated the relationship of PSAV to histologic findings on biopsy and assessed whether PSAV provides independent predictive information., Methods: From a community-based cohort of 25,276 men screened from 1991 to 2001, 1851 underwent a first biopsy for an elevated PSA and nonsuspicious digital rectal examination with a PSAV available from the year before biopsy. We analyzed the association between PSAV and biopsy histology., Results: The histologic findings on biopsy were cancer in 468 (25%), prostatic inflammation in 135 (7%), and benign prostate tissue in 1248 (68%). The cancer detection rate was associated with PSAV and, depending on PSAV, ranged from 13% to 36% (P <0.001). Among men with a PSAV less than 0.5 ng/mL per year, the cancer rate ranged from 27% to 36%, at a PSAV of 0.5 to 3.0 ng/mL per year was 24% to 28%, and at a PSAV greater than 3.0 ng/mL per year was 13% to 18%. On multivariable analysis adjusting for age and PSA, PSAV was independently associated with risk of cancer on biopsy (P <0.0005). The rate of prostatic inflammation was directly associated with PSAV (PSAV of 3.0 ng/mL per year or less: 5% to 9%; PSAV greater than 3.0 ng/mL per year: 11% to 13%, P = 0.01)., Conclusions: In screened men with an elevated PSA undergoing biopsy, PSAV provides independent predictive information for estimating prostate cancer risk. Modest increases in PSA are associated with an increased risk of cancer, whereas more dramatic PSA rises are associated with a diminishing risk of cancer and higher rate of inflammation.

Purpose: Prostate specific antigen velocity 2.0 ng/ml per year or greater in the year before prostate cancer diagnosis is associated with cancer specific survival following radical prostatectomy and radiation therapy. We evaluated the relationship between prediagnosis prostate specific antigen velocity and cancer progression following primary radiation therapy., Materials and Methods: We analyzed the records of 24,893 men from a community based prostate cancer screening study and identified 237 with clinically localized prostate cancer who elected primary radiation therapy. Our final cohort consisted of 130 men, including 83 treated with external beam radiation and 47 treated with brachytherapy. Patient specific variables at diagnosis were analyzed for their value in predicting biochemical progression using American Society for Therapeutic and Radiation Oncology criteria., Results: Mean followup +/- SD was 64 +/- 35 months. Prostate specific antigen at diagnosis, family history of prostate cancer and prediagnosis prostate specific antigen velocity 2.0 ng/ml per year or greater were associated with cancer progression following brachytherapy or external beam radiation. Of men with prostate specific antigen velocity 2.0 ng/ml per year or greater 38% had cancer progression compared to 12% with prostate specific antigen velocity less than 2.0 ng/ml per year (OR 4.3, p = 0.003). The 6-year progression-free survival estimate was 57% in men with prostate specific antigen velocity 2.0 ng/ml per year or greater and 82% in men with prostate specific antigen velocity less than 2.0 ng/ml per year (p < 0.001). On multivariate analysis absolute prostate specific antigen at diagnosis and prostate specific antigen velocity 2.0 ng/ml per year or greater were independently associated with cancer progression in men treated with external beam radiation therapy or brachytherapy., Conclusions: Men with a prediagnosis prostate specific antigen velocity of 2.0 ng/ml per year or greater are at increased risk for cancer progression following brachytherapy or external beam radiation compared to men with a prostate specific antigen velocity of less than 2.0 ng/ml per year.

Background: Assessing the extent of disease in newly diagnosed prostate cancer (PC) patients is crucial for tailoring an appropriate treatment approach. Prostate-specific membrane antigen (PSMA)–targeted positron emission tomography/computed tomography (PET/CT) reportedly has greater accuracy than conventional imaging for staging PC. As with any imaging modality, pitfalls and nonspecific findings do occur. The PSMA reporting and data system (PSMA-RADS) version 1.0 offers structured interpretation of PSMA-targeted studies and classifies lesions by likelihood of clinical significance. The aim of this retrospective study was to evaluate the clinical significance of equivocal bone findings on staging PSMA-targeted imaging, as defined by PSMA-RADS version 1.0, in the preoperative setting. Fifteen of 406 consecutive patients staged by PET/CT prior to radical prostatectomy had equivocal bone lesions. The scans were retrospectively scored with the PSMA-RADS version 1.0 system, blinded to disease course and follow-up data. Postoperative persistence of prostate-specific antigen levels supported by imaging and histological findings was used as the reference standard for the true significance of equivocal imaging findings. Results: Thirteen of the 15 patients had an overall PSMA-RADS score of 3B, of whom only two had true metastatic disease. The remaining patients had scores of 4 (n = 1) or 5 (n = 1), all confirmed as true positive prostate-related malignant lesions. A per-lesion analysis identified 29 bone lesions, of which 27 were scored PSMA-RADS 3B, and only three of them were true metastases. Thus, debatable lesions proved to have no clinical significance in 84.6% of cases, and only 11% of equivocal PSMA-RADS 3B bone lesions were true positive. Conclusions: In intermediate and high-risk patients staged prior to radical prostatectomy, the majority of PSMA-RADS 3B lesions are of no clinical relevance. Bone lesions judged as being highly suspicious for metastases (PSMA-RADS 4/5) were all validated as true positives. [ABSTRACT FROM AUTHOR]

Purpose: Long-term prostate cancer specific mortality after radical prostatectomy is poorly defined in the era of widespread screening. An understanding of the treated natural history of screen detected cancers and the pathological risk factors for prostate cancer specific mortality are needed for treatment decision making. Materials and Methods: Using Fine and Gray competing risk regression analysis we modeled clinical and pathological data, and followup information on 11,521 patients treated with radical prostatectomy at a total of 4 academic centers from 1987 to 2005 to predict prostate cancer specific mortality. The model was validated on 12,389 patients treated at a separate institution during the same period. Median followup in the modeling and validation cohorts was 56 and 96 months, respectively. Results: The overall 15-year prostate cancer specific mortality rate was 7%. Primary and secondary Gleason grade 4–5 (each p <0.001), seminal vesicle invasion (p <0.001) and surgery year (p = 0.002) were significant predictors of prostate cancer specific mortality. A nomogram predicting 15-year prostate cancer specific mortality based on standard pathological parameters was accurate and discriminating with an externally validated concordance index of 0.92. When stratified by patient age at diagnosis, the 15-year prostate cancer specific mortality rate for pathological Gleason score 6 or less, 3 + 4, 4 + 3 and 8–10 was 0.2% to 1.2%, 4.2% to 6.5%, 6.6% to 11% and 26% to 37%, respectively. The 15-year prostate cancer specific mortality risk was 0.8% to 1.5%, 2.9% to 10%, 15% to 27% and 22% to 30% for organ confined cancer, extraprostatic extension, seminal vesicle invasion and lymph node metastasis, respectively. Only 3 of 9,557 patients with organ confined, pathological Gleason score 6 or less cancer died of prostate cancer. Conclusions: Poorly differentiated cancer and seminal vesicle invasion are the prime determinants of prostate cancer specific mortality after radical prostatectomy. The prostate cancer specific mortality risk can be predicted with remarkable accuracy after the pathological features of prostate cancer are known. [Copyright &y& Elsevier]

Abstract: Objectives: Commonly used definitions for high-risk prostate cancer identify men at increased risk of PSA relapse after radical prostatectomy (RP). We assessed how accurately these definitions identify patients likely to receive secondary cancer therapy, experience metastatic progression, or die of prostate cancer. Materials and methods: Among 5960 men with clinically localized or locally advanced prostate cancer who underwent RP, we identified eight different high-risk subsets, each comprising 4–40% of the study population. Estimates of freedom from radiation therapy, hormonal therapy, and metastatic progression after surgery were generated for each high-risk cohort with the Kaplan-Meier method, and hazard ratios (HR) were calculated with a Cox proportional hazards regression. The cumulative incidence and HR for prostate cancer–specific mortality (PCSM) were estimated with competing risk analysis. Results: Each of the studied high-risk criteria was associated with increased hazard of secondary cancer therapy (HR=1.3–5.2, p <0.05) and metastatic progression (HR=2.1–6.9, p <0.05). However, depending on the definition, the probability of freedom from additional therapy 10 yr after surgery ranged from 35% to 76%. The 10-yr cumulative incidence of PCSM in high-risk patients ranged from 3% to 11% (HR=3.2–10.4, p <0.0005). Conclusions: Commonly used definitions for high-risk prostate cancer identify men at increased risk of secondary cancer therapy, metastatic progression, and PCSM following RP. However, a substantial proportion of high-risk patients remain free from additional therapy or metastatic disease many years after surgery. The risk of PCSM within 10 yr of treatment is remarkably low, even for patients at the highest risk of recurrent disease. [Copyright &y& Elsevier]

Purpose: Standardized criteria are lacking to define high risk, clinically localized prostate cancer before definitive treatment. Reliance on simple risk stratification schemes to define high risk cancers has led many physicians and patients toward therapeutic nihilism, inappropriately selecting androgen deprivation instead of definitive local therapy. Of patients undergoing radical prostatectomy we identified those at high risk based on 8 previously described definitions. We examined pathological characteristics and prostate specific antigen outcomes. Materials and Methods: The study population included 4,708 men treated with radical prostatectomy alone between 1985 and 2004. Estimates of prostate specific antigen relapse for patients at high risk were generated with the Kaplan-Meier method. Cox proportional hazards regression was used to estimate the HR for recurrence in high risk vs nonhigh risk cohorts. Results: Depending on the definition used patients at high risk composed 3% to 38% of the study population. The proportion of patients with extracapsular extension, seminal vesicle invasion and lymph node metastasis among men with high risk cancer was 35% to 71%, 10% to 33% and 7% to 23%, respectively. Of the high risk tumors 22% to 63% proved to be confined to the prostate pathologically. While patients at high risk had a 1.8 to 4.8-fold increased hazard of prostate specific antigen relapse, their 5-year relapse-free probability after radical prostatectomy alone was 49% (95% CI 39 to 58) to 80% (95% CI 77 to 83). Of patients at high risk who had relapse 25% across all definitions experienced relapse more than 2 years after surgery and in 26% to 39% prostate specific antigen doubling time at recurrence was 10 months or greater. Conclusions: Patients diagnosed with high risk cancer by currently available definitions do not have a uniformly poor prognosis after radical prostatectomy. Many cancers classified clinically as high risk are actually confined to the prostate pathologically. The risk of extraprostatic disease and prostate specific antigen relapse varies greatly depending on the definition used. [Copyright &y& Elsevier]

Abstract: Objectives: To characterise the natural history of metastatic prostate cancer after radical prostatectomy (RP) in patients followed expectantly for rising prostate-specific antigen (PSA) (noncastrate metastases). Methods: Cox proportional hazards analyses were used to assess predictors of survival among 95 patients who developed clinically detectable noncastrate metastases after RP. The initial metastatic phenotype was characterised as minimal (nodal or axial skeletal involvement) or extensive (appendicular skeletal involvement or visceral metastases). Estimates of survival after diagnosis of metastases were generated with the Kaplan-Meier method. Results: Median disease-specific survival from diagnosis of noncastrate metastases was 6.6 yr (95% confidence interval [CI], 5.2, 7.9). The initial site of metastatic disease was bone, lymph node, and viscera in 63%, 36%, and 6% of patients, respectively. Thirteen patients (14%) had extensive disease at their first metastatic manifestation. Longer PSA doubling time in the rising PSA state (hazard ratio [HR] 0.8 for each month increase in doubling time; 95%CI, 0.67–0.94) and the initial metastatic phenotype (HR 0.3 for minimal vs. extensive disease; 95%CI, 0.1–0.6) were associated with improved survival. The prostatectomy Gleason score, lymph node status at RP, PSA level at diagnosis of metastases, and interval from surgery to diagnosis of metastases did not correlate with outcome. Conclusion: Men who develop noncastrate metastases after RP may have a durable survival. Favourable prognostic indicators include longer PSA doubling time preceding diagnosis of metastases and initial involvement of axial skeleton or lymph nodes. [Copyright &y& Elsevier]

Background: The aim of the current study was to assess whether and to what extent monitoring response to treatment using prostate-specific membrane antigen (PSMA)-based positron-emitting tomography/computerized tomography (PET/CT) studies contribute clinically relevant data to routine clinical follow-up during treatment of patients with metastatic prostate cancer (PCa). Results: Fifty-two patients with metastatic PCa who underwent [68Ga]Ga-PSMA-11 PET/CT imaging and serum prostate-specific antigen (PSA) level measurements before and during treatment were investigated. Response was categorized by serum PSA dynamics according to improvement, stable disease, and disease progression and compared to change in imaging findings on pre- and post-treatment PET/CTs. McNemar's test was used to assess agreement between PET/CT- and PSA-based responses to treatment. Thirty-four patients (65.4%) had compatible biochemical- and imaging-based response to treatment. However, the imaging and biochemical responses were discrepant in 18/52 patients (34.6%). PET/CT showed progressive disease in 5/52 patients (9.6%) and improvement/stable disease in 13/52 (25%) compared to biochemical assessment results. Discrepancy between imaging and biochemical response was most prominent in biochemically stable patients (90.9%), followed by patients with biochemical progression (33.3%), and in only few (8.7%) patients with biochemical improvement. The imaging-based response was suitable for choosing subsequent treatment in 22 of 30 patients (73.3%) with longer follow-up (median time of 10.3 months (IQR 6.3–18.2)). The relevance of the imaging methodology was reflected by its ability to assess individual lesions in cases of heterogeneous lesion responses, reveal the appearance of new lesions, and identify lesions that required specific consideration, such as targeted radiotherapy. Conclusions: Results of this retrospective analysis showed that biochemical responses to treatment and [68Ga]Ga-PSMA-11 PET/CT-based responses to treatment differ in one third of metastatic PCa patients. The latter additionally enabled lesion-based and not solely patient-based analysis. Monitoring response during treatment by [68Ga]Ga-PSMA-11 PET/CT is suitable for decision-making in patient management and choice of treatment in the majority of patients. [ABSTRACT FROM AUTHOR]

Objective To test the expandability of active surveillance (AS) to Gleason score 3+4 cancers by assessing the unfavorable disease risk in a large multi-institutional cohort. Materials and methods We performed a retrospective analysis including 2,323 patients with localized Gleason score 3+4 prostate cancer who underwent a radical prostatectomy between 2005 and 2013 from 6 academic centers. We analyzed the rates of biopsy downgrading/upgrading and advanced stage in the overall cohort by employing standardized AS criteria (using biopsy Gleason score 3+4). Results The final pathologic Gleason score was 3+3 = 6 in 8%, 3+4 = 7 in 67%, 4+3 = 7 in 20%, and 8 to 10 in 5% cases. The overall rate of unfavorable disease (upgrading or advanced stage or both) was 46%. In multivariable analysis, prostate-specific antigen (PSA) level>10 ng/ml, PSA density (PSAD) >0.15 ng/ml/g, clinical stage >T1, and>2 positive cores were predictors of unfavorable disease. According to the AS criteria used, the risk of unfavorable disease ranged from 30% to 42%. In patients without any risk factor (PSA level≤10 ng/ml, PSAD ≤0.15 ng/ml/g, T1c, and≤2 positive cores), the unfavorable disease rate was 19%. The main limitations of this study are the retrospective design and nonstandardization of pathologic assessment between centers. Conclusions Approximately half of patients with biopsy Gleason score 3+4 cancer have unfavorable disease at final pathology. Nevertheless, expanding AS eligibility to these patients may be acceptable provided adherence to strict selection criteria leading to a<20% risk of unfavorable disease. Future tools for selection such as magnetic resonance imaging, early rebiopsy, and serum markers may be especially beneficial in this group of patients. [ABSTRACT FROM AUTHOR]