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Background and Objective: Addition of darolutamide to androgen deprivation therapy (ADT) and docetaxel significantly improved overall survival (OS) in ARASENS (NCT02799602). Here we report on prostate-specific antigen (PSA) responses and their association with outcomes., Methods: ARASENS is an international, double-blind, phase 3 study in patients with metastatic hormone-sensitive prostate cancer (mHSPC) randomized to darolutamide 600 mg orally twice daily (n = 651) or placebo (n = 654), both with ADT + docetaxel. The proportion of patients with undetectable PSA (<0.2 ng/ml) and time to PSA progression (≥25% relative and ≥2 ng/ml absolute increase from nadir) were compared between groups in prespecified exploratory analyses. PSA outcomes by disease volume and the association of undetectable PSA with OS and times to castration-resistant prostate cancer (CRPC) and PSA progression were assessed in post hoc analyses., Key Findings and Limitations: The proportion of patients with undetectable PSA at any time was more than doubled with darolutamide versus placebo, at 67% versus 29% in the overall population, 62% versus 26% in the high-volume subgroup, and 84% versus 38% in the low-volume subgroup. Darolutamide delayed time to PSA progression versus placebo, with hazard ratios of 0.26 (95% confidence interval [CI] 0.21-0.31) in the overall population, 0.30 (95% CI 0.24-0.37) in the high-volume subgroup, and 0.093 (95% CI 0.047-0.18) in the low-volume subgroup. Undetectable PSA at 24 wk was associated with longer OS, with a hazard ratio of 0.49 (95% CI 0.37-0.65) in the darolutamide group, as well as longer times to CRPC and PSA progression, with similar findings in the disease volume subgroups., Conclusions and Clinical Implications: Darolutamide + ADT + docetaxel led to deep and durable PSA responses in patients with high- or low-volume mHSPC. Achievement of undetectable PSA (<0.2 ng/ml) was correlated with better clinical outcomes., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: We sought to evaluate the prognostic impact of prostate-specific antigen (PSA) at 6 months after completion of radiotherapy (RT) in patients treated with RT alone, RT plus short-term (st; 3-6 months), and RT plus long-term (lt; 24-36 months) androgen-deprivation therapy (ADT)., Patients and Methods: Individual patient data were obtained from 16 randomized trials evaluating RT ± ADT for localized prostate cancer (PCa) between 1987 and 2011. The lowest PSA recorded within 6 months after RT completion was identified and categorized as < or ≥0.1 ng/mL. The primary outcomes were metastasis-free survival (MFS), PCa-specific mortality (PCSM), and overall survival (OS), from 12 months after random assignment., Results: Ninety-eight percent (n = 2,339/2,376) of patients allocated to RT alone, 84% (n = 4,756/5,658) allocated to RT + stADT, and 77% (n = 1,258/1,626) allocated to RT + ltADT had PSA ≥0.1 ng/mL within 6 months after completing RT. PSA ≥0.1 ng/mL was associated with lower MFS and OS and higher PCSM among patients allocated to RT ± ADT (RT - MFS: hazard ratio [HR], 2.24 [95% CI, 1.21 to 4.16]; PCSM: subdistribution hazard ratio [sHR], 1.82 [0.51 to 6.49]; OS: HR, 1.72 [0.97 to 3.05]; RT + stADT - MFS: HR, 1.27 [1.12 to 1.44]; PCSM: sHR, 2.10 [1.52 to 2.92]; OS: HR, 1.26 [1.11 to 1.44]; RT + ltADT - MFS: HR, 1.58 [1.27 to 1.96]; PCSM: sHR, 1.97 [1.11 to 3.49]; OS: HR, 1.59 [1.27 to 1.99]). Five-year MFS rates among patients allocated to RT, RT + stADT, and RT + ltADT were 91% versus 79%, 83% versus 76%, and 87% versus 74%, respectively, based on PSA < or ≥0.1 ng/mL., Conclusion: PSA ≥0.1 ng/mL within 6 months after RT completion was prognostic for lt outcomes in patients treated with RT ± ADT for localized PCa. This can be used to counsel patients treated with RT ± ADT and in guiding clinical trial design evaluating novel systemic therapies with RT + ADT as well as (de)intensification strategies.

Purpose: Recently, we have shown that metastasis-free survival is a strong surrogate for overall survival (OS) in men with intermediate- and high-risk localized prostate cancer and can accelerate the evaluation of new (neo)adjuvant therapies. Event-free survival (EFS), an earlier prostate-specific antigen (PSA)-based composite end point, may further expedite trial completion., Methods: EFS was defined as the time from random assignment to the date of first evidence of disease recurrence, including biochemical failure, local or regional recurrence, distant metastasis, or death from any cause, or was censored at the date of last PSA assessment. Individual patient data from trials within the Intermediate Clinical Endpoints in Cancer of the Prostate-ICECaP-database with evaluable PSA and disease follow-up data were analyzed. We evaluated the surrogacy of EFS for OS using a 2-stage meta-analytic validation model by determining the correlation of EFS with OS (patient level) and the correlation of treatment effects (hazard ratios [HRs]) on both EFS and OS (trial level). A clinically relevant surrogacy was defined a priori as an R 2 ≥ 0.7., Results: Data for 10,350 patients were analyzed from 15 radiation therapy-based trials enrolled from 1987 to 2011 with a median follow-up of 10 years. At the patient level, the correlation of EFS with OS was 0.43 (95% CI, 0.42 to 0.44) as measured by Kendall's tau from a copula model. At the trial level, the R 2 was 0.35 (95% CI, 0.01 to 0.60) from the weighted linear regression of log(HR)-OS on log(HR)-EFS., Conclusion: EFS is a weak surrogate for OS and is not suitable for use as an intermediate clinical end point to substitute for OS to accelerate phase III (neo)adjuvant trials of prostate cancer therapies for primary radiation therapy-based trials.

Background: In the PREVAIL study, enzalutamide provided significant improvements versus placebo in clinical outcomes in chemotherapy-naïve men with metastatic castration-resistant prostate cancer (mCRPC). The association of post-treatment prostate-specific antigen (PSA) decline with clinical outcomes may provide important prognostic information., Objective: To evaluate associations between the magnitude of PSA decline from baseline to month 3 and clinical outcomes among enzalutamide recipients., Design, Setting, and Participants: This was a post hoc retrospective analysis of PREVAIL, an international, randomized, double-blind, placebo-controlled phase 3 study. Men with mCRPC and no prior chemotherapy from the enzalutamide arm were included (n=872). Patients were grouped by confirmed maximal PSA decline from baseline to month 3 of treatment (n=795 evaluable)., Outcome Measurements and Statistical Analysis: Primary outcomes were overall survival and radiographic progression-free survival. Secondary outcomes included PSA progression-free survival, radiographic response, and degradation of Functional Assessment of Cancer Therapy-Prostate score, which were estimated using the Kaplan-Meier method., Results and Limitations: Following 3mo of enzalutamide treatment, 88% (701/795), 80% (639/795), and 39% (307/795) of patients had postbaseline confirmed maximal PSA declines of ≥30%, ≥50%, and ≥90%, respectively, whereas 12% (94/795) had no confirmed maximal PSA decline or a decline of <30%. Greater degrees of PSA decline within the first 3mo of enzalutamide treatment were increasingly associated with longer overall survival, time to PSA and radiographic progression, higher objective soft-tissue responses, and longer time to quality-of-life deterioration than no PSA decline or declines of <30% from baseline. PSA flares (rise followed by fall) after enzalutamide treatment were rare (<1%)., Conclusions: The magnitude of PSA decline after 3mo of enzalutamide therapy was strongly associated with better clinical and patient-reported outcomes. This updated prognostic information is of clinical value to this patient population and their health care providers., Patient Summary: We report that decreases in PSA levels are closely linked to better health and survival after 3mo of enzalutamide treatment in men with metastatic prostate cancer. The PREVAIL trial is registered at clinicaltrials.gov as NCT01212991., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: Metastatic castration resistant prostate cancer with low baseline prostate specific antigen represents an early stage in the natural history of castration resistant prostate cancer progression (low volume disease), low prostate specific antigen producing disease or disease that is less dependent on androgen receptor biology (high volume disease). We analyzed outcomes in men with low prostate specific antigen and a high disease burden who received the oral androgen receptor inhibitor enzalutamide in the PREVAIL (Safety and Efficacy Study of Oral MDV3100 in Chemotherapy-Naive Patients with Progressive Metastatic Prostate Cancer) study., Materials and Methods: In this exploratory analysis low baseline prostate specific antigen was defined as less than 10 ng/ml. Post hoc analyses included radiographic progression-free and overall survival in the once daily enzalutamide and placebo arms. Patients were stratified post hoc by high volume disease, defined as more than 4 bone metastases and/or visceral disease, and low volume disease, defined as 4 or fewer bone metastases with no visceral disease., Results: Of 1,717 patients enrolled in PREVAIL 242 (14.1%) had low baseline prostate specific antigen, including 110 with high volume disease. Enzalutamide decreased the risk of radiographic progression relative to placebo in patients with low baseline prostate specific antigen (HR 0.20, 95% CI 0.10-0.42). This decrease was irrespective of tumor burden (high volume disease HR 0.17, 95% CI 0.06-0.51 and low volume disease HR 0.25, 95% CI 0.09-0.70). Median overall survival was not reached in patients with low baseline prostate specific antigen in either treatment arm., Conclusions: Chemotherapy naïve men with metastatic castration resistant prostate cancer and low baseline prostate specific antigen irrespective of disease burden may benefit from enzalutamide. This indicates that targeting the androgen receptor signaling pathway is a therapeutic option in similar patients., (Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Advanced prostate cancer is a phenotypically diverse disease that evolves through multiple clinical courses. PSA level is the most widely used parameter for disease monitoring, but it has well-recognized limitations. Unlike in clinical trials, in practice, clinicians may rely on PSA monitoring alone to determine disease status on therapy. This approach has not been adequately tested., Methods: Chemotherapy-naive asymptomatic or mildly symptomatic men (n=872) with metastatic castration-resistant prostate cancer (mCRPC) who were treated with the androgen receptor inhibitor enzalutamide in the PREVAIL study were analyzed post hoc for rising versus nonrising PSA (empirically defined as >1.05 vs ⩽1.05 times the PSA level from 3 months earlier) at the time of radiographic progression. Clinical characteristics and disease outcomes were compared between the rising and nonrising PSA groups., Results: Of 265 PREVAIL patients with radiographic progression and evaluable PSA levels on the enzalutamide arm, nearly one-quarter had a nonrising PSA. Median progression-free survival in this cohort was 8.3 months versus 11.1 months in the rising PSA cohort (hazard ratio 1.68; 95% confidence interval 1.26-2.23); overall survival was similar between the two groups, although less than half of patients in either group were still at risk at 24 months. Baseline clinical characteristics of the two groups were similar., Conclusions: Non-rising PSA at radiographic progression is a common phenomenon in mCRPC patients treated with enzalutamide. As restaging in advanced prostate cancer patients is often guided by increases in PSA levels, our results demonstrate that disease progression on enzalutamide can occur without rising PSA levels. Therefore, a disease monitoring strategy that includes imaging not entirely reliant on serial serum PSA measurement may more accurately identify disease progression.

Objective: The aim of this study was to determine factors associated with the development of biochemical recurrence (BCR) following radical prostatectomy in patients with pathological T2 prostate cancer and negative surgical margins., Materials and Methods: This retrospective multicentre cohort study included 1252 consecutive patients with pT2 pN0/Nx and negative surgical margins on radical prostatectomy and without any adjuvant treatment, performed in three Belgian centres. BCR-free survival curves were estimated using the Kaplan-Meier method. Univariate and multivariate analyses using the Cox proportional hazards model were performed to determine clinical and pathological predictive factors of BCR in this group of patients., Results: In total, 910 patients were included. BCR occurred in 107 patients (11.8%) at a median follow-up of 108 months. Overall 5 and 10 year BCR-free survival rates were 90% and 87%, respectively. On the multivariate analyses, serum prostate-specific antigen (PSA) level (p = .001) and surgical Gleason score of 7 or above (p = .001) were significantly associated with BCR in men with pathological T2 prostate cancer with negative surgical margins. Perineural invasion and capsular infiltration were not risk factors for recurrence., Conclusions: This study identified unfavourable risk factors in patients with pathological T2 and negative surgical margins following radical prostatectomy. The results suggest that patients with a surgical Gleason score of 7 or higher, unknown lymph-node status and high PSA values are at increased risk of recurrence.

Background: Early salvage radiation therapy (eSRT) represents a treatment option for patients who experience a prostate-specific antigen (PSA) rise after radical prostatectomy (RP); however, the optimal PSA level for eSRT administration is still unclear., Objective: To test the impact of PSA level on cancer control after eSRT according to pathologic tumour characteristics., Design, Setting, and Participants: The study included 716 node-negative patients with undetectable postoperative PSA who experienced a PSA rise after RP. All patients received eSRT, defined as local radiation to the prostate and seminal vesicle bed, delivered at PSA ≤ 0.5 ng/ml. Biochemical recurrence (BCR) after eSRT was defined as two consecutive PSA values ≥ 0.2 ng/ml., Outcome Measurements and Statistical Analysis: Multivariable Cox regression analysis tested the association between pre-eSRT PSA level and BCR after eSRT. Covariates consisted of pathologic stage (pT2 vs pT3a vs pT3b or higher), pathologic Gleason score (≤ 6, 7, or ≥ 8), and surgical margin status (negative vs positive). We tested an interaction with PSA level and baseline pathologic risk for the hypothesis that BCR-free survival differed by pre-eSRT PSA level. Three pathologic risk factors were identified: pathologic stage pT3b or higher, pathologic Gleason score ≥ 8, and negative surgical margins., Results and Limitations: Median follow-up among patients who did not experience BCR after eSRT was 57 mo (interquartile range: 27-105). At 5 yr after eSRT, BCR-free survival rate was 82% (95% confidence interval [CI], 78-85). At multivariable Cox regression analysis, pre-eSRT PSA level was significantly associated with BCR after eSRT (hazard ratio: 4.89; 95% CI, 1.40-22.9; p < 0.0001). When patients were stratified according to the number of risk factors at final pathology, patients with at least two pathologic risk factors showed an increased risk of 5-yr BCR as high as 10% per 0.1 ng/ml of PSA level compared with only 1.5% in patients with one or no pathologic risk factors., Conclusions: In this retrospective study, cancer control after eSRT greatly depended on pretreatment PSA. The absolute PSA level had a different prognostic value depending on the pathologic characteristics of the tumour. In patients with more adverse pathologic features, eSRT conferred better cancer control when administered at the very first sign of PSA rise. Conversely, the benefit of eSRT was less evident in men with favourable disease at RP., Patient Summary: In this retrospective study, cancer control after early salvage radiation therapy (eSRT) was influenced by pretreatment prostate-specific antigen (PSA) level. This effect was highest in men with at least two of the following pathologic features: pT3b/pT4 disease, pathologic Gleason score ≥ 8, and negative surgical margins. In these patients, eSRT conferred better cancer control when administered at the very first sign of PSA rise., (Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Prostate cancer is a common malignancy in men and the worldwide burden of this disease is rising. Lifestyle modifications such as smoking cessation, exercise, and weight control offer opportunities to reduce the risk of developing prostate cancer. Early detection of prostate cancer by prostate-specific antigen (PSA) screening is controversial, but changes in the PSA threshold, frequency of screening, and the use of other biomarkers have the potential to minimise the overdiagnosis associated with PSA screening. Several new biomarkers for individuals with raised PSA concentrations or those diagnosed with prostate cancer are likely to identify individuals who can be spared aggressive treatment. Several pharmacological agents such as 5α-reductase inhibitors and aspirin could prevent development of prostate cancer. In this Review, we discuss the present evidence and research questions regarding prevention, early detection of prostate cancer, and management of men either at high risk of prostate cancer or diagnosed with low-grade prostate cancer., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

To identify criteria beyond Tumour-Node-Metastasis (TMN)-, prostate-specific antigen (PSA)- and Gleason score-based standard classifications to enhance the stratification of non-metastatic high-risk prostate cancer. A detailed search of the literature was performed using PubMed. The authors reviewed the literature and used a modified Delphi approach to identify relevant approaches to enhance standard classifications. Specific criteria for high-risk prostate cancer vary across guidelines and clinical trials, reflecting the differing perspectives concerning the definition of 'risk' between different specialities within the urology/radiation oncology community. In addition to the present classifications, evidence exists that the measure of cancer volume can provide additional prognostic value. More accurate imaging, especially multiparametric magnetic resonance imaging can also provide information concerning staging and cancer volume, and thus may assist in the identification of patients with high-risk prostate cancer. A refined definition of non-metastatic high-risk prostate cancer is proposed. Within this high-risk cohort, patients with multiple high-risk criteria are especially at risk of prostate cancer-specific mortality., (© 2013 The Authors. BJU International © 2013 BJU International.)

Purpose: The aim of our study was to evaluate patterns and predictors of early biochemical recurrence (eBCR) after radical prostatectomy (RP) and adjuvant radiation therapy (aRT) in order to identify which individuals might benefit from additional treatments., Methods and Materials: We evaluated 390 patients with pT3N0 prostate cancer (PCa) receiving RP and aRT at 6 European centers between 1993 and 2006. Patients who were free from BCR at <2 years' follow-up were excluded. This resulted in 374 assessable patients. Early BCR was defined as 2 consecutive prostate-specific antigen (PSA) test values >0.2 ng/mL within 2 or 3 years after aRT. Uni- and multivariable Cox regression analyses predicting overall and eBCR after aRT were fitted. Covariates consisted of preoperative PSA results, surgical margins, pathological stage, Gleason score, and aRT dose., Results: Overall, 5- and 8-year BCR-free survival rates were 77.1% and 70.8%, respectively. At a median follow-up of 86 months after aRT, 33 (8.8%) and 55 (14.6%) men experienced BCR within 2 or 3 years after aRT, respectively. In multivariable analyses, Gleason scores of 8 to 10 represented the only independent predictor of eBCR after aRT (all, P≤.01). The risk of BCR was significantly higher in patients with a Gleason score of 8 to 10 disease than in those with Gleason 2 to 6 within 24 months after treatment, after adjusting for all covariates (all, P≤.04). However, given a 24-month BCR free period, the risk of subsequent BCR for men with poorly differentiated disease was equal to that of men with less aggressive disease (all, P≥.3)., Conclusions: High Gleason score represents the only predictor of eBCR after RP and aRT in patients affected by pT3N0 PCa. Given the association between early PSA recurrence, clinical progression, and mortality, these patients might be considered candidates for adjuvant medical therapy and/or prophylactic whole-pelvis radiation therapy in addition to aRT, delivered to the prostatic bed., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Purpose: Denosumab, an anti-RANK ligand monoclonal antibody, significantly increases bone metastasis-free survival (BMFS; hazard ratio [HR], 0.85; P = .028) and delays time to first bone metastasis in men with nonmetastatic castration-resistant prostate cancer (CRPC) and baseline prostate-specific antigen (PSA) ≥ 8.0 ng/mL and/or PSA doubling time (PSADT) ≤ 10.0 months. To identify men at greatest risk for bone metastasis or death, we evaluated relationships between PSA and PSADT with BMFS in the placebo group and the efficacy and safety of denosumab in men with PSADT ≤ 10, ≤ 6, and ≤ 4 months., Patients and Methods: A total of 1,432 men with nonmetastatic CRPC were randomly assigned 1:1 to monthly subcutaneous denosumab 120 mg or placebo. Enrollment began February 2006; primary analysis cutoff was July 2010, when approximately 660 men were anticipated to have developed bone metastases or died., Results: In the placebo group, shorter BMFS was observed as PSADT decreased below 8 months. In analyses by shorter baseline PSADT, denosumab consistently increased BMFS by a median of 6.0, 7.2, and 7.5 months among men with PSADT ≤ 10 (HR, 0.84; P = .042), ≤ 6 (HR, 0.77; P = .006), and ≤ 4 months (HR, 0.71; P = .004), respectively. Denosumab also consistently increased time to bone metastasis by PSADT subset. No difference in survival was observed between treatment groups for the overall study population or PSADT subsets., Conclusion: Patients with shorter PSADT are at greater risk for bone metastasis or death. Denosumab consistently improves BMFS in men with shorter PSADT and seems to have the greatest treatment effects in men at high risk for progression.

Objective: To compare the ability of clinicians vs a nomogram at predicting future bone scan positivity in patients with prostate cancer., Materials and Methods: This investigation was conducted during an advisory board meeting in June 2011. Details of 25 androgen deprivation therapy-naive prostate cancer patients were given to 24 prostate cancer experts, including urologists and oncologists. The clinicians were asked to predict the probability that the patients would have a positive bone scan if left untreated for 1 year. These predictions and those of the Slovin nomogram were compared with the actual occurrence of metastatic disease, and the discrimination ability was quantified using the concordance index (C index)., Results: A higher C index value was obtained with the Slovin nomogram (0.812) than with the clinicians (0.628). The nomogram outperformed all of the clinicians; individual clinician C index values varied between 0.47 and 0.75. The urologists provided superior predictions compared with the oncologists., Conclusion: Future bone scan positivity can be predicted more accurately using a nomogram than by expert clinicians. Nomograms should, therefore, become an integral part of the clinical decision-making process in the prostate cancer setting for patients with a rising prostate-specific antigen level after radical prostatectomy., (Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.)

Objective: • To assess the feasibility of radical prostatectomy (RP) in a series of patients with prostate cancer with very high prostate-specific antigen (PSA) levels by comparing the clinical outcomes of different PSA thresholds (20.1-50 ng/mL, 50.1-100 ng/mL and >100 ng/mL, respectively)., Patients and Methods: • Within a multicentre European retrospective database of 712 RP in patients with a baseline PSA level >20 ng/mL, we identified 48 patients with prostate cancer with a preoperative PSA level >100 ng/mL, 137 with a PSA level between 50.1 and 100 ng/mL and 527 with PSA values between 20.1 and 50 ng/mL. • Comparisons between groups were performed using chi-square test, analysis of variance and Kaplan-Meier analysis with log-rank test., Results: • Ten-year projected cancer-specific survival (79.8% in the PSA >100 ng/mL group vs 85.4% in the PSA 50.1-99 ng/mL group vs 90.9% in the PSA 20.1-50 ng/mL interval; P = 0.037) but not overall survival (59.6% in the PSA >100 ng/mL group vs 71.8% in the PSA 50.1-99 ng/mL group vs 75.3% in the PSA 20.1-50 ng/mL interval; P = 0.087) appeared significantly affected by the different PSA thresholds. • At a median follow-up of 78.7 months, 25.8%, 6.6% and 8.3% of patients in the PSA level groups for 20.1-50 ng/mL, 50.1-100 ng/mL and >100 ng/mL respectively, were cured by surgery alone., Conclusions: • Ten-year cancer-specific survival, while showing significant reduction with increasing PSA values intervals, remain relatively high even for PSA levels >100 ng/mL. • As part of a multimodal treatment strategy, RP may therefore be an option, even in selected patients with prostate cancer whose PSA level is >100 ng/mL., (© 2011 THE AUTHORS. BJU INTERNATIONAL © 2011 BJU INTERNATIONAL.)

Background and Purpose: In men with adverse pathology at the time of radical prostatectomy (RP), the most appropriate timing to administer radiotherapy (RT) remains a subject for debate. To determine whether salvage radiotherapy (SRT) upon early prostate-specific antigen (PSA) relapse is equivalent to immediate adjuvant radiotherapy (ART) post RP., Material and Methods: 130 patients receiving ART and 89 receiving SRT were identified. All had an undetectable PSA after RP. Homogeneous subgroups were built based on the status (±) of lymphatic invasion (LVI) and surgical margins (SM), to allow a comparison of ART and SRT. Biochemical disease-free survival (bDFS) was calculated from the date of surgery and from the end of RT. The multivariate analysis was performed using the Cox Proportional hazard model., Results: In the SM-/LVI- and SM+/LVI- groups, SRT was a significant predictor of a decreased bDFS from the date of surgery, while in the SM+/LVI+ group, there was a trend towards significance. From the end of RT, SRT was also a significant predictor of a decreased bDFS in three patient groups: SM-/LVI-, SM+/LVI- and SM+/LVI+. Gleason score >7 showed to be another factor on multivariate analysis associated with decreased bDFS in the SM-/LVI- group, from the date of surgery and end of RT. Preoperative PSA was a significant predictor in the SM-/LVI- group from the date of RP only., Conclusions: Immediate ART post RP for patients with high risk features in the prostatectomy specimen significantly reduces bDFS after RP compared with early SRT upon PSA relapse., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Prostate cancer (PCa) patients with pretreatment prostate-specific antigen (PSA) >20 ng/ml have a high risk of biochemical and clinical failure and even cancer-related death after local therapy. Pretreatment predictors of outcome after radical prostatectomy (RP) in this patient group are necessary., Objective: Our aim was to assess how the use of additional high-risk factors (biopsy Gleason score [bGS] > or = 8 or clinical stage 3-4) can improve prediction of treatment failure and cancer-related death after RP in patients with PSA >20., Design, Setting, and Participants: In a retrospective multicentre cohort study from six European centres between 1987 and 2005, 712 patients with PSA >20 ng/ml underwent RP and bilateral pelvic lymphadenectomy., Measurements: Subgroups were analysed to determine the relationship between the number of high-risk factors and histopathology, biochemical progression-free survival, clinical evidence of progressive disease, prostate cancer-specific mortality (PCSM), and overall mortality. Kaplan-Meier analysis with log-rank test and Cox multivariable analysis were applied., Results and Limitations: Median follow-up was 77 mo. The number of high-risk factors was significantly associated with unfavourable histopathology. Among patients with only PSA >20 ng/ml, 33% had pT2 PCa, 57.9% had bGS <7, 54% had negative surgical margins, and 85% were lymph node negative (pN0), whereas among patients with all three high-risk factors, 4.5% had pT2 PCa, 2.3% had bGS <7, 20.5% had negative margins, and 49% were pN0 (p<0.001). The strongest predictor of progression and mortality was bGS. PSA >20 ng/ml associated with bGS < or =7 resulted in 10-yr PCSM of 5%; when associated with bGS > or =8, PCSM was 35%. The main limitations of the study were retrospective design and varying treatment modalities., Conclusions: PCa patients with PSA >20 ng/ml have varying risk levels of disease progression and PCSM. Considering additional risk factors further stratifies this group into four subgroups that can guide the clinician in preoperative patient counselling., (Copyright 2010 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: The goal of this study was to evaluate the clinical impact of using the same total prostate-specific antigen (tPSA) and free PSA (fPSA) assays calibrated with World Health Organization (WHO) materials or with Hybritech Tandem-R calibrator., Methods: From the initial correlation study that included 150 patients, the clinical impact of the WHO calibration was simulated using a large cohort (n=4548) of referred patients. Interim reports of the European Study of Screening for Prostate Cancer (ERSPC) were used to evaluate the clinical outcomes of patients and the risk of prostate cancer (PCa)., Results: WHO calibration of tPSA assays leads to a reduction of about 20% in measured results (tPSA WHO=0.81 tPSA Hybritech+0.04; fPSA WHO=0.78 fPSA Hybritech+0.00; %fPSA WHO=0.92 %fPSA Hybritech+0.00). The simulation showed that the WHO calibration is associated with a risk of missing 15% of PCa., Conclusions: The discrepancies between the two calibrations lead to significant clinical misinterpretation with decreased detection of PCa if tPSA cut-off thresholds are not adjusted.

Background: To predict poor outcome in patients with a biochemical recurrence (rising PSA) after radical prostatectomy (RP), urologists rely primarily on Gleason score, PSA doubling time, and time from surgery to biochemical (i.e., PSA) recurrence. In the present study, we assess the value of RT-PCR detection circulating prostate cells in blood of patients with a rising PSA., Methods: RNA from blood samples was obtained from 55 patients with a rising PSA and from 45 patients without evidence of biochemical failure (PSA < 0.1 ng/ml). Both groups were matched for age, Gleason score, pT stage, and interval between radical prostatectomy and PCR testing., Results: PSA positive cells were detected in 1/45 (2%) patients without a PSA recurrence and 19/55 (34%) patients with a PSA recurrence. In the rising PSA group, mean PSA doubling time was significantly shorter in patients with positive RT-PCR (5 months) than in patients with negative RT-PCR (16 months; P = 0.001). An earlier onset of recurrence was also detected in patients with a positive RT-PCR (31 months for positive RT-PCR vs. 50 months for negative RT-PCR) but this result did not achieve statistical significance (P = 0.102). Salvage radiation therapy was administered in 15 patients. Three of the five patients with a positive RT-PCR progressed during radiotherapy whereas 7 of the 10 patients with a negative RT-PCR obtained a complete response and none have progressed., Conclusions: These preliminary results suggest that RT-PCR detection of prostate cells in blood of patients after RP correlates with rapidly progressing biochemical failure after RP., (Copyright 2003 Wiley-Liss, Inc.)

Objectives: Despite several publications, the ability of the free/total (F/T) prostate-specific antigen (PSA) ratio to predict the pathologic extension of prostate cancer is still a matter of controversy. In addition, its ability to predict biochemical recurrence after radical prostatectomy has not yet been reported., Methods: Since January 6, 1996, the F/T PSA ratio was prospectively measured preoperatively in 343 patients undergoing radical prostatectomy as the first treatment for localized prostate cancer., Results: The ability to predict organ-confined disease was measured by receiver operating characteristic analysis. The areas under the curve were 0.66 for PSA density, 0.61 for total PSA, 0.60 for Gleason score, and 0.587 for the F/T PSA ratio. In multiple logistic regression analyses, the F/T PSA ratio was not a relevant predictor of organ-confined disease (Wald statistic 0.345 for P = 0.55). Similar results were obtained in the subgroup of patients with a PSA level between 2.5 and 10 ng/mL. The biochemical survival for the 270 patients who did not receive adjuvant therapy was 86% at 61 months. Statistically significant univariate predictors (P <0.05) of PSA recurrence were pT stage (log-rank 18.2) and Gleason grade (log-rank 8.8). The F/T PSA ratio was not a significant predictor of recurrence in the univariate analysis (log-rank 3.6 for P = 0.314) and in multivariate analysis (Wald statistic 0.2 for P = 0.97)., Conclusions: These results suggest that the F/T PSA ratio is not helpful for the prediction of organ-confined disease and PSA recurrence after radical prostatectomy.

Circulating prostate cells can be detected in cancer patients by using reverse transcriptase-PCR (RT-PCR) assay for prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSM) mRNA. A quality-control study involving a conventional RT-PCR assay was performed and, surprisingly, detected both transcripts in many negative control cell lines and in normal blood samples. The existence of an illegitimate transcription of the PSA and PSM genes was evidenced by sequence analysis of several PSM and PSA-PCR products. Sequencing indeed demonstrated the presence of a PSA or PSM polymorphism in some but not all the cell lines and patient samples, as well as a heterozygous mutation (G to A; Asp to Asn) in the Jurkat cell line. Moreover, the amount of PSA transcript in MCF-7, a PSA-negative breast line, increased after incubation with cycloheximide. Interestingly, the frequency of positivity was as high as 12% in male samples if only tested once, but dropped to 3% upon multiple testing of the same cDNA. This highlights the stochastic effects in RT-PCR results at high sensitivity, hence the importance of repetitive testing in clinical samples. Decreasing the number of cycles avoided the amplification of illegitimate transcripts but also affected the limit of detection, as evidenced with PSA and PSM cDNA containing plasmids, mixing of LNCap with normal blood samples, and the PSA-PSM-negative K562 cell line. The current data raise the need for a multicentric standardization of the RT-PCR methodology used to amplify PSA and PSM transcripts.

Objectives: Improved discrimination between prostate cancer (PC) and benign prostatic hyperplasia (BPH) is clearly needed. Our aim in this study was to evaluate whether the free to total prostate-specific antigen (PSA) ratio would be useful in the gray zone of 1.8-10 ng/mL total PSA range., Methods: In a consecutive series of 435 clinic patients referred for prostate evaluation, 308 had a total PSA < 10 ng/mL (92 had PC and 216 BPH). Free and total PSA were measured, and the free to total PSA ratio calculated., Results: Total PSA values were significantly different between the two groups. For the 200 patients with a total PSA < 6 ng/mL, no significant difference in total PSA values were seen (P = 0.411), whereas free to total PSA ratios remained statistically different (P < 0.001). Receiver operating characteristic (ROC) curve analysis comparing the performances of total PSA over the ratio of free to total PSA showed a clear advantage for the ratio at all sensitivity levels., Conclusions: These data demonstrate that in a significant number (n = 308) of prostatic patients in the diagnostic gray zone of 1.8-10 ng/mL total PSA, the routine use of free to total PSA might be advantageous in discriminating between cancer and benign hyperplasia. This advantage remained for total PSA < 4 ng/mL. Further study is warranted to confirm these findings in an unselected population.

Background: Serum prostate-specific antigen (PSA) exists in different molecular forms, and their respective concentration has been proposed as a useful tool to improve discrimination between benign prostatic hypertrophy (BPH) and prostate cancer (PC)., Methods: The relevance of the free to total PSA ratio was prospectively studied in a selected urology clinic population of 420 patients. Total serum PSA ranged from 2.1 to 30 ng/ml; 154 had PC and 266 had BPH., Results: Receiver operating characteristic (ROC) curves were constructed for the total population (total-PSA range from 2.1 to 30 ng/ml) and for the diagnostic gray zone of 2.1-10 ng/ml. For the two groups, the free to total PSA ratio had a higher specificity than total-PSA for all sensitivity levels. Cut-off values were found to, vary with prostate weight., Conclusions: Although free to total PSA ratio demonstrated better performances than total-PSA, its use in screening appears problematic, due to the low prevalence of prostate cancer.

Background: Gonadotropin releasing hormone (GnRH) antagonists suppress follicle-stimulating hormone (FSH) to lower levels than GnRH agonists. This may partially explain the differences between these agents on prostate cancer outcomes. In this post-hoc analysis, FSH and prostate specific antigen (PSA) responses and the impact of cross-over from leuprolide to degarelix were evaluated from a 1-year comparative study (CS21) and its extension study (CS21A). Materials and methods: Overall, 610 patients were enrolled in CS21, wherein PSA and FSH levels were evaluated monthly. CS21A evaluated 386 patients, including those previously treated with degarelix (n = 251) who continued to receive degarelix, and those previously treated with leuprolide (n = 135) who crossed-over to receive degarelix. PSA and FSH levels were evaluated in CS21A for 3 months after cross-over. The associations between measurements were assessed using Spearman's correlation coefficient. The impact of class variables on FSH suppression were evaluated using Analysis of Variance. Results: Rapid PSA and FSH suppression was observed and maintained in the degarelix arm (CS21 and CS21A), while patients on leuprolide experienced rising PSA during CS21. Patients crossed-over from leuprolide to degarelix achieved a suppression of FSH and a significant PSA decrease. PSA and FSH levels were significantly (p < .05) correlated at months 1, 3, 6, 12 and 13 in the degarelix arm. Conclusions: Significant FSH suppression with GnRH antagonists may explain its advantage over GnRH agonists in terms of better prostate cancer control. The effect of profound FSH suppression is analogous to the need for profound testosterone suppression for tumor control. [ABSTRACT FROM AUTHOR]

Introduction: The aim of the study was to identify the appropriate level of Charlson comorbidity index (CCI) in older patients (>70 years) with high-risk prostate cancer (PCa) to achieve survival benefit following radical prostatectomy (RP). Methods: We retrospectively analyzed 1008 older patients (>70 years) who underwent RP with pelvic lymph node dissection for high-risk prostate cancer (preoperative prostate-specific antigen >20 ng/mL or clinical stage ≥T2c or Gleason ≥8) from 14 tertiary institutions between 1988 and 2014. The study population was further grouped into CCI < 2 and ≥2 for analysis. Survival rate for each group was estimated with Kaplan-Meier method and competitive risk Fine-Gray regression to estimate the best explanatory multivariable model. Area under the curve (AUC) and Akaike information criterion were used to identify ideal 'Cut off' for CCI. Results: The clinical and cancer characteristics were similar between the two groups. Comparison of the survival analysis using the Kaplan-Meier curve between two groups for non-cancer death and survival estimations for 5 and 10 years shows significant worst outcomes for patients with CCI ≥ 2. In multivariate model to decide the appropriate CCI cut-off point, we found CCI 2 has better AUC and p value in log rank test. Conclusion: Older patients with fewer comorbidities harboring high-risk PCa appears to benefit from RP. Sicker patients are more likely to die due to non-prostate cancer-related causes and are less likely to benefit from RP. [ABSTRACT FROM AUTHOR]