Anti-androgen monotherapy versus gonadotropin-releasing hormone agonists in men with advanced, non-metastatic prostate cancer: a register-based, observational study.

BACKGROUND: In randomised controlled trials, men with advanced, non-metastatic prostate cancer (PCa) treated with anti-androgen monotherapy (AA) had similar all-cause mortality as men treated with gonadotropin-releasing hormone (GnRH) agonists. Using real-world evidence (i.e., observational data), we aimed to further assess the difference in mortality between these two drug categories. MATERIAL AND METHODS: We emulated a trial using data from Prostate Cancer data Base Sweden 3.0. We specifically focused on men diagnosed in 2006-2012 with high-risk PCa who had no distant metastasis. They either received primary hormonal therapy with AA (n = 2078) or GnRH agonists (n = 4878) who were followed for a median time of 5 years. Risk of death from PCa and other causes was assessed using competing risk analyses and Cox proportional hazards regression analyses, including propensity score matching. RESULTS: The cumulative 5-year PCa mortality was lower for men treated with AA (16% [95% confidence interval, CI, 15-18%]) than men treated with GnRH agonists (22% [95% CI 21-24%]). The 5-year other cause mortality was also lower for men on AA (17% [95% CI 15-19%] compared to men on GnRH agonists (27% [95% CI 25-28%]). In regression analyses, the risk of PCa death was similar, GnRH agonists versus AA (reference), hazard ratio (HR) 1.08 (95% CI 0.95-1.23), but the risk of death from all causes was higher for men on GnRH agonists, HR 1.23 (95% CI 1.13-1.34). Consistent results were seen in the propensity score-matched cohort. CONCLUSION: Our results indicate that the use of AA as primary hormonal therapy in men with high-risk non-metastatic PCa does not increase PCa-specific mortality compared to GnRH. Using AA instead of GnRH agonists may result in shorter time on/exposure to GnRH-treatment, which may reduce the risk of adverse events associated with this treatment.

Prostate-specific antigen doubling time as a progression criterion in an active surveillance programme for patients with localized prostate cancer.

OBJECTIVES: To elucidate the role of prostate-specific antigen (PSA) doubling time (PSAdt) as a progression criterion in patients with low-risk prostate cancer managed by active surveillance (AS). To assess the correlation between PSAdt during AS and final histopathology after radical prostatectomy (RP) in patients meeting predefined progression criteria. PATIENTS AND METHODS: A total of 258 consecutive patients on an AS programme were included in the study. The PSAdt was calculated in patients with two or more PSA values, and 95% confidence intervals (CIs) were calculated in patients with four or more PSA values. Progression risk groups were defined as follows: high-risk: PSAdt <3 years, rebiopsy Gleason score (GS) ≥4 + 3, more than three positive biopsy cores, and/or bilateral tumour or cT ≥2c disease; intermediate-risk: PSAdt 3-5 years, GS = 3 + 4 or cT2b disease; and low-risk: PSAdt >5 years, without histopathological or clinical progression. Definitive treatment was recommended for patients in the high-risk group and treatment options were discussed with those in the intermediate-risk group. RESULTS: A total of 2291 PSA values obtained during AS were available, of which 2071 were considered valid in the 258 patients. PSAdt values with 95% CIs were calculated in 221 patients based on a median of 8 PSA values. The 95% CIs for PSAdt overlapped considerably and in up to 91% of the patients, the 95% CIs overlapped among the risk group definitions. A total of 26% (68/258 patients) underwent RP after meeting the progression criteria. There was no association between preoperative PSAdt and final histopathology (P = 0.87). CONCLUSION: The uncertainty of calculated PSAdt during AS leads to a significant risk of patients being misclassified in terms of risk of progression, which limits the use of PSAdt in the management of patients on AS.

Risk of biochemical recurrence and positive surgical margins in patients with pT2 prostate cancer undergoing radical prostatectomy.

BACKGROUND AND OBJECTIVE: To investigate risk factors associated with positive surgical margins (PSM) and biochemical recurrence (BR) in organ confined tumors (pT2) after radical prostatectomy (RP) for localized prostate cancer (PCa). METHODS: Between 1995 and 2011, 1,649 patients underwent RP at our institution. The study includes the 1,133 consecutive patients with pT2 tumors at final histopathology. Logistic regression analysis was used for risk of PSM. Risk of BR, defined as the first PSA ≥ 0.2 ng/ml, was analyzed with Kaplan-Meier and Cox regression analysis. RESULTS: Median follow-up was 3.6 years (range: 0.5-15.5 years). In logistic regression, NS surgery was independently associated with an increased risk of pT2 PSM (OR = 1.68, 95% CI: 1.3-2.0, P = 0.01) relative to non-NS surgery. NS surgery was not independently associated with BR but the interaction of PSM and NS surgery trended (P = 0.08) to increase the risk of BR compared to PSM and non-NS surgery. CONCLUSION: Several factors influence the risk of pT2 PSMs in radical prostatectomy. In our cohort pT2 PSM is associated with NS surgery and trend to increase risk of BR compared to non-NS surgery. The optimal selection of candidates for NS surgery is still not clear.

Prognostic implication of gait function following treatment for spinal cord compression in men diagnosed with prostate cancer.

Background: Malignant spinal cord compression (MSCC) is a severe complication of metastatic prostate cancer (PCa) and may compromise neurological functions, including gait function. This study aimed to evaluate the association between survival and gait function prior to, immediately after and 6 weeks following radiotherapy for MSCC in PCa patients.Patient sample: All PCa patients admitted with MSCC at Rigshospitalet, Denmark from January 1, 2010 to December 31, 2011 were included. Patients were followed until death to analyze gait function as a prognostic factor.Methods: Of the 76 included patients, four patients underwent surgical decompression followed by radiotherapy and 72 patients received only radiotherapy. Gait was evaluated prior to radiotherapy, immediately after radiotherapy and at 6 weeks follow-up.Results: Before radiotherapy, 88% had normal gait function and 12% had complete loss of gait function. Corresponding percentages after radiotherapy were 72% and 28%, respectively. Median overall survival following MSCC was 4.9 months (95% CI = 3.6-6.2) with a 3-, 6-, and 12-months survival probability of 64%, 42%, and 21%, respectively. Multivariate analyses demonstrated that patients without gait function after radiotherapy had a 2.6-2.8-fold increased risk of dying compared to men with gait function. Patients with more than two vertebrae involved had a 2.3-3.4-fold increased risk of dying when compared to patients with 1-2 vertebral metastases.Conclusions: PCa patients with MSCC have a poor prognosis. Most likely reflecting differences in tumor burden, preserved gait function following radiotherapy is associated with better prognosis. Further prospective studies are required to confirm this association.

The CPC Risk Calculator: A New App to Predict Prostate-specific Antigen Recurrence During Follow-up After Radical Prostatectomy.

BACKGROUND: It can be challenging to predict the risk of biochemical recurrence (BR) during follow-up after radical prostatectomy (RP) in men who have undetectable prostate-specific antigen (PSA), even years after surgery. OBJECTIVE: To establish and validate a contemporary nomogram that predicts the absolute risk of BR every year after RP in men with undetectable PSA while accounting for competing risks of death. DESIGN, SETTING, AND PARTICIPANTS: A total of 3746 patients from Rigshospitalet (Copenhagen, Denmark) and Stanford Urology (Stanford, CA, USA) who underwent RP between 1995 and 2013 were included. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Time to BR was defined as the first PSA result ≥0.2 ng/ml. BR risk was computed using multiple cause-specific Cox regression including preoperative PSA, pT category, RP Gleason score (GS), and surgical margin (R) status. Death without BR was considered a competing event. The nomogram presents the future risk of BR for a man who is alive and without BR at the time of follow-up. Validation assessed the discrimination and accuracy using time-dependent area under the curve and Brier scores. RESULTS AND LIMITATIONS: The nomogram predicts risk of BR up to 12 yr after RP at an individual level. As example, the risk of BR for a man with pT3a, R-, GS 3 + 4, and preoperative PSA ≤10 ng/ml followed for 5 yr with undetectable PSA is 18% for the next 5 yr. External validation demonstrated both high accuracy and discrimination. The CPC Risk Calculator is available as a free Android and iOS App. Declining discrimination and accuracy after 7 yr of follow-up is the main limitation. CONCLUSIONS: This nomogram can be used as a tool to inform men with undetectable PSA during follow-up after RP about their future risk of BR, and may aid in decisions on the necessity for further follow-up. The nomogram is the first to be available as a free app. PATIENT SUMMARY: We developed an easily interpretable nomogram to evaluate the risk of prostate-specific antigen elevation (cancer recurrence) following complete removal of the prostate (radical prostatectomy). The tool can aid both physicians and patients in evaluating the future risk of cancer recurrence during follow-up after surgery. The model is available as a free mobile app that can be downloaded from the App Store.

The risk of biochemical recurrence for intermediate-risk prostate cancer after radical prostatectomy.

OBJECTIVES: To report oncological outcomes including biochemical recurrence (BR) following radical prostatectomy (RP) from a large consecutive cohort operated in an 18-year period. Additionally, an in-depth analysis of outcomes among D'Amico intermediate-risk patients is presented. MATERIALS AND METHODS: A total of 2,091 patients with PCa who underwent RP at Department of Urology, Rigshospitalet, Copenhagen, Denmark between 1995 and 2013 were included. Univariate and multiple cause-specific Cox regression analyses for BR were applied using competing risk models. Death prior to BR was considered a competing event. BR was defined as the first PSA ≥0.2 ng/ml. No patient received adjuvant therapy prior to BR. RESULTS: Overall, the 5- and 10-years cumulative incidence of BR was 21.9% and 32.0%. The 10-year cumulative incidence of BR was 17.9%, 31.9% and 47.9% for D'Amico low-, intermediate- and high-risk patients, respectively. Among intermediate-risk patients, the 10-year cumulative incidence of BR was 24.0%, 39.9%, and 47.9% for patients harboring one, two or three risk factors, respectively (Gray test: p < 0.0001). In multivariate analysis, PSA, RP GS, pT category, and positive surgical margins were significantly associated with an increased risk of BR. CONCLUSIONS: The risk of BR among patients with intermediate-risk disease is not uniform and is highly dependent on the number of risk factors per patient. Intermediate-risk patients have a comparable risk of recurrence as high-risk patients, and this should be taken into consideration when counseling patients prior to RP.

Association of Radical Local Treatment with Mortality in Men with Very High-risk Prostate Cancer: A Semiecologic, Nationwide, Population-based Study.

BACKGROUND: Current guidelines recommend androgen deprivation therapy only for men with very high-risk prostate cancer (PCa), but there is little evidence to support this stance. OBJECTIVE: To investigate the association between radical local treatment and mortality in men with very high-risk PCa. DESIGN, SETTING, AND PARTICIPANTS: Semiecologic study of men aged <80 yr within the Prostate Cancer data Base Sweden, diagnosed in 1998-2012 with very high-risk PCa (local clinical stage T4 and/or prostate-specific antigen [PSA] level 50-200ng/ml, any N, and M0). Men with locally advanced PCa (local clinical stage T3 and PSA level <50ng/ml, any N, and M0) were used as positive controls. INTERVENTION: Proportion of men who received prostatectomy or full-dose radiotherapy in 640 experimental units defined by county, diagnostic period, and age at diagnosis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PCa and all-cause mortality rate ratios (MRRs). RESULTS AND LIMITATIONS: Both PCa and all-cause mortality were half as high in units in the highest tertile of exposure to radical local treatment compared with units in the lowest tertile (PCa MRR: 0.51; 95% confidence interval [CI], 0.28-0.95; and all-cause MRR: 0.56; 95% CI, 0.33-0.92). The results observed for locally advanced PCa for highest versus lowest tertile of exposure were in agreement with results from randomized trials (PCa MRR: 0.75; 95% CI, 0.60-0.94; and all-cause MRR: 0.85; 95% CI, 0.72-1.00). Although the semiecologic design minimized selection bias on an individual level, the effect of high therapeutic activity could not be separated from that of high diagnostic activity. CONCLUSIONS: The substantially lower mortality in units with the highest exposure to radical local treatment suggests that radical treatment decreases mortality even in men with very high-risk PCa for whom such treatment has been considered ineffective. PATIENT SUMMARY: Men with very high-risk prostate cancer diagnosed and treated in units with the highest exposure to surgery or radiotherapy had a substantially lower mortality.

Associations between statin use and progression in men with prostate cancer treated with primary androgen deprivation therapy.

INTRODUCTION: In several observational studies, statin use has been associated with reduced risk of progression and mortality in men with prostate cancer (PCa). The study aim was to investigate the association between statin use at time of PCa diagnosis and time to PCa progression in men with advanced or metastatic PCa receiving androgen deprivation therapy (ADT) as primary treatment. PATIENTS AND METHODS: The study population consisted of all men receiving ADT as primary therapy at two Danish Urological Departments in 2007-2013. The primary outcome was time to progression defined as castration-resistant PCa (CRPC) or PCa death. Survival analyses were conducted with Kaplan-Meier analyses, cause specific Cox proportional hazards models, and competing risk analyses. RESULTS: A total of 537 men were included, of whom 141 were statin users at time of diagnosis. The median follow-up time was 5.7 years (95% CI: 5.1-6.2). No significant difference in progression-free survival between statin users and non-statin users was observed at 5 years; 29% for statin users (95% CI: 19-40%) and 28% (95% CI: 23-34%) for non-statin users, p = 0.31. In multivariable Cox analyses, there was no significant association between statin use and risk of progression, HR 0.98 (95% CI: 0.72-1.32). In competing risk analyses the 5-year cumulative incidence of progression was 55% (95% CI: 46-64%) for statin users and 62% (95% CI: 57-67%) for non-statin users, p = 0.11. CONCLUSION: In the current study, statin use at time of PCa diagnosis was unrelated to time to progression in men primarily treated with ADT.

Gonadotropin-releasing Hormone Agonists, Orchiectomy, and Risk of Cardiovascular Disease: Semi-ecologic, Nationwide, Population-based Study.

BACKGROUND: In observational studies, men with prostate cancer treated with gonadotropin-releasing hormone (GnRH) agonists had a higher risk of cardiovascular disease (CVD) compared to men who had undergone orchiectomy. However, selection bias may have influenced the difference in risk. OBJECTIVE: To investigate the association of type of androgen deprivation therapy (ADT) with risk of CVD while minimising selection bias. DESIGN, SETTING, AND PARTICIPANTS: Semi-ecologic study of 6556 men who received GnRH agonists and 3330 men who underwent orchiectomy as primary treatment during 1992-1999 in the Prostate Cancer Database Sweden 3.0. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We measured the proportion of men who received GnRH agonists as primary treatment in 580 experimental units defined by healthcare provider, diagnostic time period, and age at diagnosis. Incident or fatal CVD events in units with high and units with low use of GnRH agonists were compared. Net and crude probabilities were also analysed. RESULTS AND LIMITATIONS: The risk of CVD was similar between units with the highest and units with the lowest proportion of GnRH agonist use (relative risk 1.01, 95% confidence interval [CI] 0.93-1.11). Accordingly, there was no difference in the net probability of CVD after GnRH agonist compared to orchiectomy (hazard ratio 1.02, 95% CI 0.96-1.09). The 10-yr crude probability of CVD was 0.56 (95% CI 0.55-0.57) for men on GnRH agonists and 0.52 (95% CI 0.50-0.54) for men treated with orchiectomy. The main limitation was the nonrandom allocation to treatment, with younger men with lower comorbidity and less advanced cancer more likely to receive GnRH agonists. CONCLUSION: Our data do not support previous observations that GnRH agonists increase the risk of CVD in comparison to orchiectomy. PATIENT SUMMARY: We found a similar risk of cardiovascular disease between medical and surgical treatment as androgen deprivation therapy for prostate cancer.

Improved survival for patients with de novo metastatic prostate cancer in the last 20 years.

INTRODUCTION: During recent years, several new life-prolonging therapeutic options have been introduced for patients with metastatic prostate cancer (mPCa). The aim of the present study was to evaluate the changes in the survival of patients diagnosed with mPCa prior to and in the early period of the implementation of these new agents. PATIENTS AND METHODS: The study population consisted of 207 men diagnosed in 1997 and 316 men diagnosed in the period 2007-2013 with de novo mPCa and managed with initial endocrine therapy. Men were followed for overall survival and PCa-specific survival. RESULTS: At the time of diagnosis, men diagnosed in the period 2007-2013 had less co-morbidity, lower prostrate-specific antigen levels and lower clinical tumour categories than men diagnosed in 1997. A significantly higher proportion of men diagnosed in 1997 were managed with surgical castration (57% versus 9%). Only one patient diagnosed in 1997 received second-line therapy compared with 81 men (26%) diagnosed in the period 2007-2013. The median overall survival was significantly longer for men diagnosed between 2007 and 2013 compared with men diagnosed in 1997 (39.4 months versus 24.2 months, p < 0.0001). Likewise, the cumulative incidence of PCa-specific death was higher among men diagnosed in 1997 compared with men diagnosed between 2007 and 2013, with 5-year cumulative incidences of 72% and 47%, respectively (p < 0.0001). CONCLUSION: Survival in men diagnosed with metastatic PCa has improved significantly over time. The improved survival can in part be explained by lead-time bias, but also by the introduction of new life-prolonging treatments.

Pulmonary Function in Patients With Germ Cell Cancer Treated With Bleomycin, Etoposide, and Cisplatin.

PURPOSE: For patients with germ cell cancer, various pulmonary toxicity risk factors have been hypothesized for treatment with bleomycin, etoposide, and cisplatin (BEP). Because existing studies have shortcomings, we present a large, unselected cohort of patients who have undergone close monitoring of lung function before, during, and after treatment with BEP to disclose valid pulmonary toxicity risk factors. PATIENTS AND METHODS: All patients who were treated with BEP at Rigshospitalet, Copenhagen, Denmark, from 1984 to 2007, were included. Pulmonary function tests (PFTs) that measured the diffusing capacity of the lungs for carbon monoxide (DLCO), forced expiratory volume in 1 second, and forced vital capacity were performed systematically before, during, and after treatment with BEP for 5 years of follow-up. According to local protocol, bleomycin was discontinued if hemoglobin-corrected DLCO (DLCOc) decreased ≥ 25% compared with pretreatment value. Covariates of possible importance were evaluated with a multiple regression analysis for pretreatment PFTs and with a mixed model for follow-up PFTs. Bleomycin was adjusted on the basis of PFT results and was thus omitted as covariate. RESULTS: Overall, 565 patients were evaluated with a PFT before or after treatment with BEP. During BEP, 15 patients died of progressive disease or toxicity, including one patient from bleomycin-induced pneumonitis. Post-treatment DLCOc decreased significantly, with a rebound during follow-up. Forced expiratory volume in 1 second and forced vital capacity remained unchanged after BEP but increased significantly to levels above pretreatment during follow-up. International Germ Cell Cancer Collaborative Group (IGCCCG) prognostic group, mediastinal primary, pulmonary metastases, and smoking all significantly influenced baseline PFT results. Pulmonary surgery, pulmonary embolism, IGCCCG poor prognosis, and smoking influenced PFT during follow-up. Mediastinal primary, pulmonary metastases, age, or doses of cisplatin and etoposide had no influence on follow-up PFT, and renal function did not influence PFT. CONCLUSION: After 5 years of follow-up, pulmonary impairment in patients with germ cell cancer who were treated with BEP was limited. Exceptions were patients treated with pulmonary surgery, those who suffered pulmonary embolism, and those in the IGCCCG poor prognostic group.

Active surveillance strategy for patients with localised prostate cancer: criteria for progression.

BACKGROUND: Active surveillance - an initial observational strategy - offers a tailored management of patients with localised prostate cancer. The aim of the strategy is to appoint patients with potentially lethal prostate cancer to curatively intended treatment, while patients with slowly evolving tumours are spared from an unnecessary curative intervention. MATERIAL AND METHODS: All data included were derived from a single-institution active surveillance cohort of 317 patients which was followed prospectively at Rigshospitalet from 2002 until 2013. The patients were managed with serial PSA measurements, repeated biopsies, and regular digital rectal examinations. The programme recommended change of management from active surveillance to curatively intended treatment based on PSA doubling time, deteriorating histopathology in repeated prostatic biopsies, and increased clinical tumour category. RESULTS: The programme entailed close monitoring during the first 5 years with 3-4 out-patient contacts annually. Altogether, 2-3 biopsy sessions were performed in most patients. Complications necessitating hospital admissions arose in almost 10% of the repeated biopsy sessions. The 5-year cumulative incidence of curatively intended treatment was estimated to be 39.5%. Active surveillance resulted in a 34.8% cost-reduction following 3.7 years compared to the estimated cost of immediate radical prostatectomy. The calculated PSA doubling times were associated with wide 95% confidence intervals, which resulted in a significant risk of being misclassified according to the definition of progression. The interobserver agreement of biopsy histopathology between expert uropathologist was substantial. Still, the pathologists' disagreement would have resulted in different treatment recommendations in up to 10% of the re-evaluated biopsies. Neither PSA doubling time nor increased clinical tumour category was associated with final histopathological findings following subsequent radical prostatectomy. Although the level of significance was only met in univariate analysis, biopsy progression was associated with defined final histopathological findings at radical prostatectomy that was perceived as unacceptable for a continued observational strategy. CONCLUSION: The thesis has demonstrated that active surveillance is feasible and reduces the number of patients undergoing curative intended treatment. However, active surveillance necessitates close monitoring during the first 5 years. PSA doubling time is unreliable as a progression criterion, while progression on repeated biopsy in part seems to fulfil the requirements of a dependable progression criterion. The need for more accurate progression criteria in the management of prostate cancer patients on active surveillance is emphasised.

[Active surveillance is a useful strategy in the management of patients with low-risk prostate cancer]. / Regelmæssig kontrol kan anvendes til overvågning af patienter med lavrisikoprostatacancer.

Radical prostatectomy has in randomised settings failed to demonstrate a survival difference in patients with low-risk prostate cancer when tested against an observational strategy. Active surveillance has been introduced in order to reduce overtreatment by distinguishing between cancers with a biological potential, and truly indolent cancers best left untreated. Preliminary results from large prospective active surveillance cohorts are promising; however, uncertainties persist concerning optimal patient selection and follow-up, as well as the long-term safety.

Poor association between the progression criteria in active surveillance and subsequent histopathological findings following radical prostatectomy.

OBJECTIVE: The objective of this study was to investigate the association between active surveillance (AS) progression criteria and histopathology features in subsequent radical prostatectomy (RP) specimens. MATERIALS AND METHODS: Of 229 patients managed on AS, 80 patients underwent RP, of whom 68 met at least one of the following three progression criteria: progression on rebiopsy, short prostate-specific antigen (PSA) doubling time (PSAdt) and increase clinical tumour category (cT). Patients revealing histopathological features in the RP specimens involving GS ≥ 7 (3 + 4) were considered to have achieved a potential survival gain from the procedure (timely RP). The association between the progression criteria and timely RP was analysed using univariate logistic regression analyses. RESULTS: Of the 68 patients who met at least one of the progression criteria, 66% had timely RP features. Progression on rebiopsy was significantly associated with timely RP [odds ratio (OR) = 5.00, 95% confidence interval (CI) 1.51-16.51]. Although not statistically significant, progression defined by PSAdt was negatively associated with timely RP (OR = 0.36, 95% CI 0.13-1.00). Increase in cT showed no association with timely RP (OR = 1.17, 95% CI 0.35-3.87). CONCLUSIONS: A poor association was found between the progression criteria employed in the AS programme and histopathology features after subsequent RP. Only progression on rebiopsy was significantly associated with final histopathology.

ERG protein expression over time: from diagnostic biopsies to radical prostatectomy specimens in clinically localised prostate cancer.

AIMS: We evaluated the consistency in ERG protein expression from diagnostic specimens through rebiopsies to radical prostatectomies in patients with clinically localised prostate cancer to investigate the validity of ERG status in biopsies. METHODS: ERG expression was assessed by immunohistochemistry (IHC) in 625 biopsy sets and 86 radical prostatectomy specimens from 265 patients with prostate cancer managed on active surveillance. For IHC, a rabbit monoclonal primary antibody was used (clone: EPR3864). TMPRSS2-ERG fluorescence in situ hybridisation (FISH) analyses were performed in 74 biopsies using the FISH ZytoLight TriCheck Probe (SPEC ERG/TMPRSS2). FISH results were correlated with IHC findings. RESULTS: The concordance between FISH and IHC was 97.3% and IHC demonstrated a sensitivity and specificity for ERG rearrangement of 100% and 95.5%, respectively. Applying IHC, 38.1% of patients were ERG-positive, 53.6% were ERG-negative and 8.3% showed both ERG-positive and negative tumour foci (ERG heterogeneous) at diagnosis. When ERG status was dichotomised (ERG-positive or heterogeneous vs ERG-negative), 95.6%-97.1% of patients did not experience ERG reclassification during the first two rounds of rebiopsies. The concordance in ERG status between biopsies and surgical specimen was 89.5%-94.2% depending on the number of rebiopsies included. Sampling bias was assumed to explain most (81.3%) of the mismatches in ERG status. CONCLUSIONS: Consistency in ERG status ranged from 90% to 95% for patients undergoing serial biopsies and radical prostatectomy. This indicates that biopsies can be used reliably to investigate ERG's prognostic and predictive value.

[Active surveillance is a useful strategy in the management of patients with low-risk prostate cancer].

Radical prostatectomy has in randomised settings failed to demonstrate a survival difference in patients with low-risk prostate cancer when tested against an observational strategy. Active surveillance has been introduced in order to reduce overtreatment by distinguishing between cancers with a biological potential, and truly indolent cancers best left untreated. Preliminary results from large prospective active surveillance cohorts are promising; however, uncertainties persist concerning optimal patient selection and follow-up, as well as the long-term safety.

Enzalutamide treatment in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy and abiraterone acetate.

OBJECTIVE: The aim of this study was to record prostate-specific antigen (PSA) response and overall survival (OS) for a group of metastatic castration-resistant prostate cancer (mCRPC) patients treated with enzalutamide following progression after abiraterone treatment in the post-chemotherapy setting. MATERIAL AND METHODS: Twenty-four mCRPC patients with progression after abiraterone treatment following primary docetaxel therapy received enzalutamide 160 mg/day. The percentage PSA response was recorded following first line docetaxel, abiraterone and enzalutamide treatment. Fischer's exact test, Mann-Whitney U test and linear regression model were used to test for differences in PSA response. RESULTS: All patients had a follow-up of at least 3 months. The median PSA response following 1 month of enzalutamide was -12% (range -56% to 76%), while the median best PSA response was -22% (-76% to 76%). Forty-six percent had a greater than 30% decrease in PSA. The PSA response to enzalutamide did not correlate with the number of prior cancer treatments (p = 0.57), time from diagnosis to mCRPC (p = 0.11) or prior response to docetaxel (p = 0.67). However, patients treated with second line cabazitaxel had an inferior PSA response to enzalutamide (p = 0.03), and there was a trend for the PSA response to abiraterone to correlate with the PSA response to the succeeding enzalutamide (B = 0.22, p = 0.05). The median OS was 4.8 months. CONCLUSIONS: Previous abiraterone therapy is associated with a less marked fall in PSA following enzalutamide therapy in post-chemotherapy mCRPC patients compared with reported results in randomized trials. Larger prospective studies of sequencing are warranted.

Early biochemical recurrence, urinary continence and potency outcomes following robot-assisted radical prostatectomy.

OBJECTIVE: The aim of this study was to describe recovery of urinary continence and potency and report oncological and functional outcomes using the survival, continence and potency (SCP) system for patients undergoing robot-assisted radical prostatectomy (RARP). MATERIAL AND METHODS: From 2009 to 2012, 232 patients underwent RARP. Self-reported continence, erection sufficient for intercourse (ESI) and scores on the five-item version of the International Index of Erectile Function-5 (IIEF-5) were registered by questionnaire and physician's interview preoperatively and at 3, 6 and 12 month follow-up, and subsequently on a yearly basis. Continence was defined as 0 pads, and potency as ESI or IIEF-5 greater than 17 with or without the aid of phosphodiesterase type 5 inhibitors. Oncological success was defined as absence of biochemical failure (BF) [prostate-specific antigen (PSA) ≥ 0.2 ng/ml]. The SCP system was used to evaluate combined oncological and functional outcomes. RESULTS: In total, 184 patients were followed for more than 1 year. The 12 month BF-free survival rate was 97.7%. Median time to regain continence was 6.2 months; 12 months postoperatively 79.9% used 0 pads/day. Of patients with preoperative ESI, 77.6% (67.9-86.1) and 34.4% (24.1-47.5) maintained ESI 12 months postoperatively after bilateral and unilateral nerve-sparing surgery (NS), respectively. NS (p < 0.0001), increasing prostate volume (p = 0.014) and lower age (p < 0.0001) were positively associated with recovery of potency. Using the SCP system and defining potency as ESI, functional and oncological success 12 months after surgery was achieved in 69 out of 135 (51.1%) preoperative continent and potent patients who underwent unilateral or bilateral NS, and did not require adjuvant treatment; when defining potency as IIEF greater than 17, this figure was 45 out of 108 (41.7%). As expected, the proportions were significantly higher for bilateral than for unilateral NS (p ≤ 0.0014). CONCLUSION: RARP provides good early BF-free survival, continence and potency recovery rates for patients eligible for NS.

ERG protein expression in diagnostic specimens is associated with increased risk of progression during active surveillance for prostate cancer.

BACKGROUND: Compelling biomarkers identifying prostate cancer patients with a high risk of progression during active surveillance (AS) are needed. OBJECTIVE: To examine the association between ERG expression at diagnosis and the risk of progression during AS. DESIGN, SETTING, AND PARTICIPANTS: This study included 265 patients followed on AS with prostate-specific antigen (PSA) measurements, clinical examinations, and 10-12 core rebiopsies from 2002 to 2012 in a prospectively maintained database. ERG immunohistochemical staining was performed on diagnostic paraffin-embedded formalin-fixed sections with a ready-to-use kit (anti-ERG, EPR3864). Men were characterised as ERG positive if a minimum of one tumour focus demonstrated ERG expression. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall AS progression was defined as clinical progression: increased clinical tumour category ≥cT2b by digital rectal examination and ultrasound, and/or histopathologic progression: upgrade of Gleason score, more than three positive cores or bilateral positive cores, and/or PSA progression: PSA doubling time <3 yr. Risk of progression was analysed using multiple cause-specific Cox regression and stratified cumulative incidences (Aalen-Johansen method). Curatively intended treatment, watchful waiting, and death without progression were treated as competing events. RESULTS AND LIMITATIONS: A total of 121 of 142 ERG-negative and 96 of 123 ERG-positive patients had complete diagnostic information. In competing risk models, the ERG-positive group showed significantly higher incidences of overall AS progression (p<0.0001) and of the subgroups PSA progression (p<0.0001) and histopathologic progression (p<0.0001). The 2-yr cumulative incidence of overall AS progression was 21.7% (95% confidence interval [CI], 14.3-29.1) in the ERG-negative group compared with 58.6% (95% CI, 48.7-68.5) in the ERG-positive group. ERG positivity was a significant predictor of overall AS progression in multiple Cox regression (hazard ratio: 2.45; 95% CI, 1.62-3.72; p<0.0001). The main limitation of this study is its observational nature. CONCLUSIONS: In our study, ERG positivity at diagnosis can be used to estimate the risk of progression during AS. If confirmed, ERG status can be used to individualise AS programmes. PATIENT SUMMARY: The tissue biomarker ERG identifies active surveillance patients with an increased risk of disease progression.

Risk factors associated with positive surgical margins following radical prostatectomy for clinically localized prostate cancer: can nerve-sparing surgery increase the risk?

OBJECTIVE: The aim of this study was to evaluate the impact of preoperative and surgical parameters, including nerve-sparing technique, on the risk of positive surgical margins (PSM) following radical prostatectomy for clinically localized prostate cancer. MATERIAL AND METHODS: A prospective consecutive single-institution Danish cohort of 1148 patients undergoing RP between 1995 and 2011 was investigated. To analyse the impact of covariates on risk of PSM, a multivariate logistic regression model was used, including cT category, biopsy Gleason score, prostate-specific antigen (PSA), percentage positive biopsies for cancer (PPB), surgeon and surgical technique. RESULTS: The overall rate of PSM was 31.4%. The risk of PSM depended (p value for Wald χ(2)) on PSA (p < 0.0001), PPB (p = 0.003), nerve-sparing surgery (p = 0.03) and the surgeon (p < 0.0001). For every doubling of PSA, the risk of PSM increased by 56%, beginning at 0.5 ng/ml [odds ratio (OR) = 1.56, 95% confidence interval (CI) 1.3-1.9, p < 0.01], and every 10% increase in PPB resulted in an 11% increased risk of PSM (OR = 1.11, 95% CI 1.0-1.2, p = 0.002). Two out of the six surgeons had a 50% reduction of risk of PSM compared to the referent surgeon. Nerve-sparing surgery increased the risk of PSM by 50% compared to wide resection (OR = 1.5, 95% CI 1.0-2.1, p = 0.03). CONCLUSION: Both preoperative and surgical parameters affect the risk of PSM after radical prostatectomy. Surgeon and high preoperative PSA, PPB and cT category were confirmed as predictors of PSM. Surprisingly, nerve-sparing surgery was independently associated with increased risk of PSM. The correct selection of candidates for nerve-sparing surgery remains unresolved.