Downgrading from Biopsy Grade Group 4 Prostate Cancer in Patients Undergoing Radical Prostatectomy for High or Very High Risk Prostate Cancer.

PURPOSE: We examined rates of Grade Group 4 downgrading at radical prostatectomy among men diagnosed with high and very high risk prostate cancer at biopsy. MATERIALS AND METHODS: A pooled cohort of 1,776 patients from 3 tertiary referral centers who underwent radical prostatectomy for National Comprehensive Cancer Network® high risk (prostate specific antigen greater than 20 ng/ml, or Grade Group 4-5, or clinical stage T3 or greater) or very high risk (primary Gleason pattern 5, or more than 4 biopsy cores with Grade Group 4-5, or 2 or more high risk features) disease from 2005 to 2015 were reviewed. Overall 893 patients with Grade Group 4 disease at biopsy were identified and 726 patients were available for analysis. Multivariable logistic regression models were fit to determine factors associated with downgrading to Grade Group 3 or less at radical prostatectomy. RESULTS: Overall 333 (45%) cases were downgraded to Grade Group 3 or less at radical prostatectomy. Of these cases 198 (27%) had concordant Grade Group 4 biopsy and radical prostatectomy pathology and 195 (27%) were upgraded at radical prostatectomy to Grade Group 5. Of high risk cases with biopsy Grade Group 4 disease 49% had any downgrading vs 29% of very high risk cases (p <0.0001). Downgrading to Grade Group 2 or less occurred in 16% (98 of 604) of high risk and 7% (8 of 122) of very high risk cases (p <0.01). Downgraded cases had a lower prostate specific antigen, fewer positive biopsy cores and lower clinical stage (p <0.01). On multivariable analysis fewer positive biopsy cores were significantly associated with downgrading at radical prostatectomy (p <0.01). CONCLUSIONS: In this cohort of patients with high risk/very high risk prostate cancer, downgrading from biopsy Grade Group 4 at radical prostatectomy occurred less frequently than in other published reports. Any downgrading was significantly less common in very high risk compared to high risk patients, and downgrading to Grade Group 2 or less occurred in a minority of cases in high risk and very high risk patients.

Outcomes of very high-risk prostate cancer after radical prostatectomy: Validation study from 3 centers.

BACKGROUND: Among men with localized high-risk prostate cancer (PCa), patients who meet very high-risk (VHR) criteria have been shown to experience worse outcomes after radical prostatectomy (RP) in a previous study. Variations of VHR criteria have been suggested to be prognostic in other single-center cohorts, but multicenter outcomes validating VHR criteria have not been described. This study was designed to validate VHR criteria for identifying which PCa patients are at greatest risk for cancer progression. METHODS: Patients with high-risk PCa undergoing RP (2005-2015) at 3 tertiary centers were pooled. The outcomes of men with VHR PCa were compared with the outcomes of those who did not meet VHR criteria. The high-risk criteria were a clinical stage of T3 to T4, a prostate-specific antigen level > 20 ng/mL, or a biopsy Gleason grade sum of 8 to 10. The VHR criteria were multiple high-risk features, >4 biopsy cores with a Gleason grade sum of 8 to 10, or primary Gleason grade pattern 5. Biochemical recurrence, metastasis (METS), and cancer-specific mortality (CSM) were assessed with competing risks regressions. Overall mortality was assessed with Cox survival models. RESULTS: Among 1981 patients with high-risk PCa, men with VHR PCa (n = 602) had adverse pathologic outcomes: 37% versus 25% for positive margins and 37% versus 15% for positive lymph nodes (P < .001 for both comparisons). Patients with VHR PCa also had higher adjusted hazard ratios for METS (2.78; 95% confidence interval [CI], 2.08-3.72), CSM (6.77; 95% CI, 2.91-15.7), and overall mortality (2.44; 95% CI, 1.56-3.80; P < .001 for all comparisons). CONCLUSIONS: In a validation study of patients who underwent treatment for high-risk PCa, VHR criteria were strongly associated with adverse pathologic and oncologic outcomes.

Radical prostatectomy or radiotherapy for high- and very high-risk prostate cancer: a multidisciplinary prostate cancer clinic experience of patients eligible for either treatment.

OBJECTIVE: To compare radical prostatectomy (RP) vs radiotherapy (RT) with androgen-deprivation therapy (ADT) in the setting of patients with high-risk and very high-risk (VHR) prostate cancer who were deemed eligible for either therapy and made a treatment choice after consultation in a multidisciplinary prostate cancer clinic (MDPCC), and to compare the MDPCC patients' outcomes to a matched Surveillance, Epidemiology and End Results (SEER) cohort. PATIENTS AND METHODS: Prospectively collected, retrospective study comparing patients who underwent RP (231 patients) vs RT+ADT (73) from 2004 to 2013. Biochemical recurrence (BCR), local recurrence, distant metastasis failure, and overall survival (OS) were calculated for each treatment group overall and according to National Comprehensive Cancer Network risk strata. A propensity score matched comparison with a SEER cohort was performed for OS. RESULTS: There was no difference in local recurrence (hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.0-7.9; P = 0.06), distant metastasis failure (HR 2.5, 95% CI 0.8-7.8; P = 0.1) and OS (HR 1.35, 95% CI 0.4-4.8; P = 0.6) between patients undergoing RP vs RT+ADT. Patients treated via the MDPCC survived on average 16.9 months (95% CI 13.1-20.8) longer than those in the matched SEER cohort. CONCLUSIONS: Long-term outcomes appear similar amongst patients with high-risk and VHR prostate cancer deemed eligible for either RP or RT, and treated after consultation in a MDPCC. Outcomes of the MDPCC patients were superior to those of the matched SEER cohort.

Does time from diagnosis to treatment of high- or very-high-risk prostate cancer affect outcome?

OBJECTIVE: To determine whether time from diagnosis to treatment impacted outcomes in a multicentre cohort of high- and very-high-risk (VHR) patients with prostate cancer undergoing radical prostatectomy (RP). PATIENTS AND METHODS: In all, 1392 patients from three tertiary centres who underwent RP for either high-risk or VHR disease, from 2005 to 2015, were identified. The cohort was divided into tertiles based on time from diagnostic biopsy to RP. Cumulative incidence of biochemical recurrence (BCR), metastasis, and prostate cancer-specific mortality (PCSM) were calculated for each tertile. The Kaplan-Meier method was used to evaluate for differences in all-cause mortality (ACM) amongst tertiles. Competing risks regression models, as well as Cox proportional hazards regression models, were fitted to assess the association between time-to-event outcomes and patient characteristics. RESULTS: The median (interquartile range [IQR]) time from biopsy to RP was 68 (50-94) days. The median (IQR) follow-up was 31 (12.1-55.7) months. The cumulative incidence of BCR (P = 0.14), metastasis (P = 0.15), and PCSM (P = 0.69) did not differ amongst time-to-treatment tertiles of VHR patients. Also, Kaplan-Meier estimates of ACM (P = 0.53) did not differ amongst time-to-treatment tertiles. Similarly, BCR, metastasis, PCSM, and ACM did not significantly differ amongst time-to-treatment tertiles in multivariable modelling. CONCLUSION: In this pooled meta-dataset of patients with high-risk or VHR prostate cancer, time from diagnosis to RP did not appear to significantly contribute to differences in clinical outcomes. This finding supports the safety of enrollment of such patients into neoadjuvant clinical trials.

Surgeon-led prostate cancer lymph node staging: pathological outcomes stratified by robot-assisted dissection templates and patient selection.

OBJECTIVES: To evaluate the perioperative, pathological, and oncological outcomes from surgeon-led pathological staging of pelvic lymph node (LN) metastases at the time of robot-assisted radical prostatectomy (RARP). PATIENTS AND METHODS: Over the 6-year period of 2006-2012, three distinct pelvic LN dissection (PLND) strategies were used in chronological order at a single cancer referral hospital. Strategies were characterised by both an omission of PLND (pNx) vs inclusion decision threshold, and standard vs extended templates for patients selected for PLND. The three cohorts included: (i) omission vs standard template (04/2006-10/2007), for dominant Gleason score 4-5 or a prostate-specific antigen (PSA) level of >10 ng/mL; (ii) omission/standard vs extended template (11/2007-12/2010), for dominant Gleason score 4-5, PSA level of >10 ng/mL, any single core >7 mm, or >3 ipsilateral positive cores; and (iii) extended template with minimal exceptions (01/2011-08/2012). Standard outcomes data compared included: Clavien-Dindo complication rates, LN metrics (yield, percentage positive), and biochemical recurrence (BCR). A novel metric comprised 'pNx regret': the rate of pNx patients upgraded/upstaged. Exploratory analyses included selection criteria for reduced PLND templates, i.e. low-yield subsets. RESULTS: Standard PLND yielded 8-10 LNs and a positive-LN yield of 2.2-6.2%. The addition of an extended PLND (E-PLND) significantly increased the yield to 14-20 LNs and the positive-LN yield to 17.4-18.4% (both P < 0.001). E-PLND had the highest impact on the percentage of positive LNs (%pN1) for high-risk disease (9.3 vs 32.8%, P = 0.002), modest for intermediate risk (4.2 vs 10.9%, P = 0.003), and minimal impact on low risk disease (4.1 vs 0%, P = 0.401). The combined strategies of setting a very low threshold for E-PLND and sending separate LN packets increased the LN yields (18 vs 24, P < 0.001), but did not significantly change the observed %pN1 rates by clinical risk group (P = 0.975). Efforts to reduce the need for E-PLND included omission by clinical criteria, but resulting in 'pNx regret' in 16-19%. A third of patients with unilateral disease and positive LNs were found to have contralateral disease. A subset of men with minimal biopsy volume Gleason score 4 + 3 had pN1 rates after E-PLND of three of 14 (21%) compared to minimal biopsy volume Gleason score 3 + 4 pN1 rates after E-PLND of 0 of 31. E-PLND takes about twice as long to perform but with no statistically significant difference in complications (5.0 vs 6.0%, P = 0.511). The 5-year BCR rates were higher for E-PLND, given the selection criteria, but not different for overall survival. CONCLUSIONS: The net benefit of E-PLND remains uncertain, and therapeutic impact will probably require a randomised trial, given the strong selection criteria. E-PLND contributes to oncological staging in a significant number of high- and intermediate-risk patients, and should be bilateral. Immediate concerns include longer operative times, but no higher complication rates.

Baseline and longitudinal plasma caveolin-1 level as a biomarker in active surveillance for early-stage prostate cancer.

OBJECTIVES: To evaluate the role of caveolin-1 (Cav-1) as a predictor of disease reclassification (DR) in men with early prostate cancer undergoing active surveillance (AS). PATIENTS AND METHODS: We analysed archived plasma samples prospectively collected from patients with early prostate cancer in a single-institution AS study. Of 825 patients enrolled, 542 had ≥1 year of follow-up. Baseline and longitudinal plasma Cav-1 levels were measured using an enzyme-linked immunosorbent assay. Tumour volume or Gleason grade increases were criteria for DR. Logistic regression analyses were used to assess associations between clinicopathological characteristics and reclassification risk. RESULTS: In 542 patients, 480 (88.6%) had stage cT1c disease, 542 (100.0%) had a median prostate-specific antigen level of 4.1 ng/mL, and 531 (98.0%) had a median Cancer of the Prostate Risk Assessment score of 1. In all, 473 (87.3%) had a Gleason score of 3+3. After a median of 3.1 years of follow-up, disease was reclassified in 163 patients (30.1%). The mean baseline Cav-1 level was 2.2 ± 8.5 ng/mL and the median 0.2 ng/mL (range, 0-85.5 ng/mL). In univariate analysis, baseline Cav-1 was a significant predictor for risk of DR (odds ratio [OR] 1.82, 95% confidence interval [CI] 1.24-2.65; P = 0.002). In multivariate analysis, with adjustments for age, tumour length, group risk stratification and number of positive cores, reclassification risk associated with Cav-1 remained significant (OR 1.91, 95% CI 1.28-2.84; P = 0.001). CONCLUSION: Baseline plasma Cav-1 level was an independent predictor of disease classification. New methods for refining AS and intervention may result.

Quality of life after brachytherapy or bilateral nerve-sparing robot-assisted radical prostatectomy for prostate cancer: a prospective cohort.

OBJECTIVE: To provide comparative data on quality of life (QoL) after prostate cancer treatment to help patients make an informed decision regarding their choice of treatment. METHODS: Patients with pathologically proven, non-metastatic, T1-T3bN0 prostate cancer were included in this prospective non-randomized study if they were to receive treatment with curative intent. Sample size was at least 181 patients per cohort/treatment type. QoL was recorded at baseline and at each follow-up using the Expanded Prostate Cancer Index Composite (EPIC) instrument. The minimal clinically important difference was defined as half of the standard deviation of the baseline score for each domain. A mixed effects model was used to compare the different treatments. Data are presented on the brachytherapy and the bilateral nerve-sparing robot-assisted radical prostatectomy (RARP) cohorts. Hormonotherapy was not allowed. RESULTS: Between November 2007 and January 2013, 181 patients who received brachytherapy and 210 patients who underwent RARP were included. Of the patients who underwent RARP, 178 had bilateral nerve-sparing and were included in the present analysis. Response rate to EPIC questionnaires were higher in the brachytherapy than in the RARP arm: 82% vs 57% at 2 years after treatment and 55% vs 45% at 4 years after treatment. In the mixed effects model, patients in the RARP arm had better QoL with regard to urinary irritation/obstruction or bother and bowel function, and lower QoL regarding sexual function and urinary incontinence. Results were confirmed in a propensity score-matched model. Patient satisfaction was significantly higher in the brachytherapy group at 1, 2 and 3 years after treatment. CONCLUSION: This prospective non-randomized study shows long-term differences in QoL domains after bilateral nerve-sparing RARP and brachytherapy. Differences in patient satisfaction should be further explored. These results could be used to counsel patients in the decision-making process.

Sequencing robot-assisted extended pelvic lymph node dissection prior to radical prostatectomy: a step-by-step guide to exposure and efficiency.

OBJECTIVE: To describe a novel, step-by-step approach to robot-assisted extended pelvic lymph node dissection (ePLND) at the time of robot-assisted radical prostatectomy (RARP) for intermediate-high risk prostate cancer. PATIENT AND METHODS: The sequence of ePLND is at the beginning of the operation to take advantage of greater visibility of the deeper hypogastric planes. The urachus is left intact for an exposure/retraction point. The anatomy is described in terms of lymph nodes (LNs) that are easily retrieved vs those that require additional manipulation of the anatomy, and a determined surgeon. A representative cohort of 167 RARPs was queried for representative metrics that distinguish the ePLND: 146 primary cases and 21 with neoadjuvant systemic therapy. RESULTS: The median (interquartile range, IQR) LN yield was 22 (16-28) for primary surgeries and 21 (16-23) for neoadjuvant cases. The percentage of cases with positive LNs (pN1) was 16.4% for primary and 29% for neoadjuvant. The hypogastric LNs were involved in 75% of pN1 primary cases and uniquely positive in 33%. Each side of ePLND took the attending surgeon a median (IQR) of 16 (13-20) min and trainees 25 (24-38) min. CONCLUSIONS: Robot-assisted ePLND before RARP provides an anatomical approach to surgical extirpation mimicking the open approach. We think this sequence offers efficiency and efficacy advantages in high-risk and select intermediate-risk patients with prostate cancer undergoing RARP.

Disease reclassification risk with stringent criteria and frequent monitoring in men with favourable-risk prostate cancer undergoing active surveillance.

OBJECTIVES: To determine the frequency of disease reclassification and to identify clinicopathological variables associated with it in patients with favourable-risk prostate cancer undergoing active surveillance (AS). PATIENTS AND METHODS: We assessed 191 men, selected by what may be the most stringent criteria used in AS studies yet conducted, who were enrolled in a prospective cohort AS trial. Clinicopathological characteristics were analysed in a multivariate Cox proportional hazards regression model. Key features were an extended biopsy with a single core positive for Gleason score (GS) 3 + 3 (<3 mm) or 3 + 4 (<2 mm) and a prostate-specific antigen (PSA) level <4 ng/mL (adjusted for prostate volume). Biopsies were repeated every 1-2 years and clinical evaluations every 6 months. Disease was reclassified when PSA level increased by 30% from baseline, or when biopsy tumour length increased beyond the enrolment criteria, more than one positive core was detected or any grade increased to a dominant 4 pattern or any 5 pattern. RESULTS: Disease was reclassified in 32 patients (16.8%) including upgrading to GS 4 + 3 in five patients (2.6%). The median (interquartile range) follow-up time among survivors was 3 (1.9-4.6) years. Overall, 13 of the 32 (40.6%) had incremental increases in GS. Tumour length (hazard ratio 2.95, 95% confidence interval [CI] 1.34-6.46; P = 0.007) and older age (hazard ratio 1.05, 95% CI 1.00-1.09; P = 0.05) were identified as significant and marginally significant predictors of disease reclassification, respectively. Disease remained stable in 83.2% of patients. CONCLUSION: The need persists for improvements in risk stratification and predictive indicators of cancer progression.

Robot-assisted extended pelvic lymph node dissection (PLND) at the time of radical prostatectomy (RP): a video-based illustration of technique, results, and unmet patient selection needs.

OBJECTIVE: • To describe the differences in technique and results between standard vs extended template pelvic lymph node dissection (PLND) at the time of radical prostatectomy (RP) using a robot-assisted (RA) technique. PATIENTS AND METHODS: • Using extended templates illustrated for the open surgical technique, a RA technique was developed to solve obstacles related to surgical exposure, identification of key landmarks, proper sequencing of operative steps, and prevention of complicationsshown in the accompanying video. • From May 2006 to October 2007, 261 patients underwent a standard PLND, and from November 2007 to November 2010, 670 underwent an extended PLND (E-PLND) by one surgeon. RESULTS: • The lymph node (LN) yield increased from a median(interquartile range) of 8 (5-11) to 16 (11-21) with the extended technique (P < 0.001). • The ratio of positive LNs increased from 7% to 18%. Among E-PLND cases by risk group, positive LNs were found in 39%, 9%, and 3% of high-, intermediate-, and low-risk cases, and the later two groups strongly associated with upgrading and/or upstaging. • Extensive clipping appears necessary to avoid postoperative lymphoceles, and peritoneal fenestration for the extraperitoneal technique. • The median operative duration for E-PLND was 42 min, roughly double that of a standard PLND. CONCLUSIONS: • E-PLND is feasible with a RA technique, and increases the LN yield and positive LN ratio;the latter especially in high-risk disease. • The procedure takes twice as long and requires several updates in technique shown in the video.

Therapeutic Consequences of Omitting a Pelvic Lymph Node Dissection at Radical Prostatectomy when Grade and/or Stage Increase.

OBJECTIVE: To analyze the effect on biochemical recurrence (BCR) of omitting PLND in subsequently upgraded/upstaged patients (pNx regret). Using nomograms, patients with low to intermediate-risk prostate cancer can be selected to omit a pelvic lymph node dissection (PLND) at the time of a radical prostatectomy (RP). However, some patients will experience upgraded pathology and/or stage. MATERIALS AND METHODS: We searched a prospectively maintained single institution/multi-surgeon cohort of patients treated by RP and >5-year follow-up. From 2006-2012, 1026 (521 pNx and 505 pN0/1) eligible patients with biopsy Gleason Score ≤3+4 and cT1c-cT2 undergoing RARP were included in the study. RESULTS: Gleason upgrading from ≤3+4 to >3+4 and/or pT3-4 occurred in 17% of pNx and 32% of pN0/N1 (p<0.001). BCR occurred in 5% of the pNx, and 7% of the PLND group. Five-year BCR free survival was higher in the pNx group (94.7% vs. 91%, P = .048). BCR occurred in 3% in the non-pNx regret and 18% in the pNx regret patients. However, with propensity score matching with pNx regret and pN0/N1 patients, 5-year BCR free survival rates were similar (81% vs 77%, P = .466). CONCLUSIONS: Low to favorable intermediate-risk patients who PLND was omitted and experienced upgrading or upstaging (pNx regret), have a higher predicted BCR. However, when matched to a similar cohort with pN0/N1, the BCR did not differ. Omission of a PLND does not appear to alter the rates of BCR compared to PLND inclusion.

Prediction of Organ-confined Disease in High- and Very-high-risk Prostate Cancer Patients Staged with Magnetic Resonance Imaging: Implications for Clinical Trial Design.

BACKGROUND: High-risk (HR) prostate cancer (PCa) is a heterogeneous disease leading to difficulties in designing appropriate inclusion criteria for clinical trials. OBJECTIVE: To describe clinical predictors of organ-confined disease in HR or very-high-risk (VHR) PCa patients staged with multiparametric magnetic resonance imaging with endorectal coil (mp-MRI-ER). DESIGN, SETTING, AND PARTICIPANTS: We reviewed 366 HR/VHR PCa patients who had preoperative mp-MRI-ER, and underwent radical prostatectomy and extended pelvic lymph node dissection between 2006 and 2015. INTERVENTION: Radical prostatectomy with preoperative mp-MRI-ER. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We used multivariable logistic regression modeling to assess for associations with ≤ pT2N0 stage and multivariable cox modeling to assess for associations with biochemical failure. RESULTS AND LIMITATIONS: Of 366 patients, 132 had ≤ pT2N0 disease. For the entire cohort, negative staging mp-MRI-ER (odds ratio [OR] 1.73, 95% confidence interval [CI] 1.06-2.83, p = 0.03), lower prostate-specific antigen (PSA; OR 0.98, 95% CI 0.97-1.00, p = 0.02), and fewer cores of Gleason ≥8 cancer (OR 0.86, 95% CI 0.79-0.93, p = 0.0002) were associated with ≤pT2N0 disease. In HR patients only, negative mp-MRI-ER (OR 3.41, 95% CI 1.73-6.72, p = 0.0004) and fewer than four cores of Gleason ≥8 disease (OR 3.38, 95% CI 1.20-9.56, p = 0.02) were still associated with ≤pT2N0 disease. Lack of non-organ-confined disease on MRI was associated with superior biochemical recurrence-free survival (p = 0.02). Limitations of this study include lack of a central review or quality control of the MRI reporting. CONCLUSIONS: In HR PCa, negative staging mp-MRI-ER, fewer positive cores of Gleason >8, and lower PSA were significant predictors of pathologic organ-confined disease. Improved prediction of organ-confined disease in HR patients may allow for their inclusion into studies evaluating treatments from which they would otherwise be excluded based solely on their HR status. PATIENT SUMMARY: In patients with high-risk prostate cancer, prostate magnetic resonance imaging along with other clinical parameters may help determine which patients are likely to have disease confined to the prostate and thus be eligible for clinical trials that they otherwise might be excluded from based on their high-risk status alone.

Ductal Prostate Cancers Demonstrate Poor Outcomes with Conventional Therapies.

BACKGROUND: Ductal prostate adenocarcinoma (DAC) is a rare, aggressive, histologic variant of prostate cancer that is treated with conventional therapies, similar to high-risk prostate adenocarcinoma (PAC). OBJECTIVE: To assess the outcomes of men undergoing definitive therapy for DAC or high-risk PAC and to explore the effects of androgen deprivation therapy (ADT) in improving the outcomes of DAC. DESIGN, SETTING, AND PARTICIPANTS: A single-center retrospective review of all patients with cT1-4/N0-1 DAC from 2005 to 2018 was performed. Those undergoing radical prostatectomy (RP) or radiotherapy (RTx) for DAC were compared with cohorts of high-risk PAC patients. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Metastasis-free survival (MFS) and overall survival (OS) rates were analyzed using Kaplan-Meier and Cox regression models. RESULTS AND LIMITATIONS: A total of 228 men with DAC were identified; 163 underwent RP, 34 underwent RTx, and 31 had neoadjuvant therapy prior to RP. In this study, 163 DAC patients and 155 PAC patients undergoing RP were compared. Similarly, 34 DAC patients and 74 PAC patients undergoing RTx were compared. DAC patients undergoing RP or RTx had worse 5-yr MFS (75% vs 95% and 62% vs 93%, respectively, p < 0.001) and 5-yr OS (88% vs 97% and 82% vs 100%, respectively, p < 0.05) compared with PAC patients. In the 76 men who received adjuvant/salvage ADT after RP, DAC also had worse MFS and OS than PAC (p < 0.01). A genomic analysis revealed that 10/11 (91%) DACs treated with ADT had intrinsic upregulation of androgen-resistant pathways. Further, none of the DAC patients (0/15) who received only neoadjuvant ADT prior to RP had any pathologic downgrading. The retrospective nature was a limitation. CONCLUSIONS: Men undergoing RP or RTx for DAC had worse outcomes than PAC patients, regardless of the treatment modality. Upregulation of several intrinsic resistance pathways in DAC rendered ADT less effective. Further evaluation of the underlying biology of DAC with clinical trials is needed. PATIENT SUMMARY: This study demonstrated worse outcomes among patients with ductal adenocarcinoma of the prostate than among high-grade prostate adenocarcinoma patients, regardless of the treatment modality.

Determining Clinically Based Factors Associated With Reclassification in the Pre-MRI Era using a Large Prospective Active Surveillance Cohort.

OBJECTIVE: To report biopsy-related and oncologic outcomes in a large prospective active surveillance cohort that was initiated in the premagnetic resonance imaging era and to additionally identify clinical factors associated with disease reclassification in order to inform future studies designed to improve enrollment and follow-up on active surveillance. METHODS: Patients were prospectively enrolled at a single institution from 2006 to 2014 and followed until 2016. Men with Gleason 6 or 7 disease were eligible, and those with >6 months follow-up were included in the analysis. Patients were risk stratified based on clinical/pathologic criteria, including based on a combination of baseline and confirmatory biopsy tumor characteristics. Reclassification-free survival, based on tumor volume increase or Gleason score increase, was analyzed using multivariable Cox proportional hazards models. RESULTS: Of 825 enrolled patients, 682 met inclusion criteria. Median follow-up was 40 months (range 6.6-126.8). Disease was reclassified in 249 (36.5%), and 157 (23.0%) underwent treatment. A single positive core with a negative confirmatory biopsy was significantly associated with time to reclassification (median not met vs 43 months, log rank test P <.001). Composite tumor length, defined as the combined tumor length between baseline and confirmatory biopsies, was associated with shorter Gleason upgrade-free survival (hazard ratio 1.24, 95% confidence interval 1.11-1.40, P <.001) in multivariable analysis. CONCLUSION: Baseline stratification using clinical factors including tumor length may refine risk stratification and offer the foundation on which new systems that incorporate modalities such as magnetic resonance imaging may be based.

Prostate cancer upgrading or downgrading of biopsy Gleason scores at radical prostatectomy: prediction of "regression to the mean" using routine clinical features with correlating biochemical relapse rates.

Recommendations for managing clinically localized prostate cancer are structured around clinical risk criteria, with prostate biopsy (PB) Gleason score (GS) being the most important factor. Biopsy to radical prostatectomy (RP) specimen upgrading/downgrading is well described, and is often the rationale for costly imaging or genomic studies. We present simple, no-cost analyses of clinical parameters to predict which GS 6 and GS 8 patients will change to GS 7 at prostatectomy. From May 2006 to December 2012, 1590 patients underwent robot-assisted radical prostatectomy (RARP). After exclusions, we identified a GS 6 cohort of 374 patients and a GS 8 cohort of 91 patients. During this era, >1000 additional patients were enrolled in an active surveillance (AS) program. For GS 6, 265 (70.9%) of 374 patients were upgraded, and the cohort included 183 (48.9%) patients eligible for AS by the Prostate Cancer Research International Active Surveillance Study (PRIAS) standards, of which 57.9% were upgraded. PB features that predicted a >90% chance of upgrading included ≥ 7 cores positive, maximum foci length ≥ 8 mm in any core, and total tumor involvement ≥ 30%. For GS 8, downgrading occurred in 46 (50.5%), which was significantly higher for single core versus multiple cores (80.4% vs 19.6%, P = 0.011). Biochemical recurrence (BCR) occurred in 3.4% of GS 6 upgraded versus 0% nonupgraded, and in GS 8, 19.6% downgraded versus 42.2% nondowngraded. In counseling men with clinically localized prostate cancer, the odds of GS change should be presented, and certain men with high-volume GS 6 or low-volume GS 8 can be counseled with GS 7-based recommendations.

A decade of robot-assisted radical prostatectomy training: Time-based metrics and qualitative grading for fellows and residents.

OBJECTIVES: As modern urology residency and fellowship training in robot-assisted surgery evolves toward standardized curricula (didactics, dry/wet-laboratory exercises, and surgical assistance), additional tools are needed to evaluate on-console performance. At the start of our robotics program in 2006, we set-up a time- and quality-based evaluation program and aim to consolidate this data into a simple set of metrics for self-evaluation. MATERIALS AND METHODS: Using our index procedure of robot-assisted radical prostatectomy (RARP), we prospectively collected data on 2,215 cases over 10 years from 6 faculty surgeons and 94 trainees (43 urologic oncology fellows and 51 urology residents). The steps of the operation were divided into 11 consistent steps, and the metrics included time to completion and quality using a 6-level grading system. Time metrics were consolidated into quartiles for benchmarking. RESULTS: The median times for trainees to complete each step were 15% to 120% higher than those of the staff (P<0.001). Each step can be presented with quartile-based time metrics by pooled trainee and staff results. Steps performed by trainees were carefully chosen for a high success rate, and on our Likert-like scale were graded 4 to 5 in more than 95% of cases. There were no grade 0 (very poor) cases, and grades 1 (multiple technical errors) and 2 (could not be completed but without safety issues) were rare (<1%). CONCLUSIONS: RARP training can be evaluated with a time-based metric that allows a quartile-based comparison to a large experience of trainees and staff. As a trainee progress through a rotation, these benchmarks can assist in prioritizing the need for more attention to a basic step vs. progression to more advanced steps.

Positive margin length and highest Gleason grade of tumor at the margin predict for biochemical recurrence after radical prostatectomy in patients with organ-confined prostate cancer.

BACKGROUND: To evaluate the pathologic features after radical prostatectomy to determine if the length of positive surgical margin (PSM) and the highest Gleason grade within the tumor at the PSM could risk stratify patients for biochemical recurrence (BCR). METHODS: We performed a retrospective, matched, cohort study to identify patients with pathologically organ-confined (pT2) tumors and negative nodes (pN0/Nx), receiving no adjuvant therapy. Specimens underwent single pathologist review. BCR-free survival was estimated using the Kaplan-Meier method and compared between subgroups using two-sided log-rank test. Using Classification and Regression Tree analysis (CART), we identified an optimal cutoff for the PSM length which differentiated risk for BCR. Cox proportional hazards regression models were fit to assess the association between variables and BCR-free survival. RESULTS: Two-hundred PSM patients were matched to 200 patients with negative surgical margins (NSM). Median follow-up was 64 months. 5 year BCR-free survival was 90% (95% CI 84-97%) in the NSM group and 70% (95% CI 63-79%) in the PSM group. There was an increased risk of BCR with any PSM. Multivariable analysis demonstrated an association with length of PSM ( > 1 mm vs. ≤ 1 mm, HR 2.29; 95% CI 1.2-4.5) and having a highest Gleason grade of the cancer focus at the margin ≥ 4 (HR 6.8; 95% CI 1.6-29). CONCLUSIONS: We demonstrated that patients with pathologic T2 tumors with PSM > 1 mm or a Gleason grade of tumor focus at the margin ≥ 4 are at elevated risk for BCR. However, this study suggests that patients with pT2 tumors with positive surgical margins have a relatively low risk of biochemical recurrence and adjuvant radiation may be over treating this sub population. The subsets at greatest risk for BCR may benefit from more frequent PSA monitoring to direct salvage therapies.

Radical Prostatectomy in Metastatic Castration-resistant Prostate Cancer: Feasibility, Safety, and Quality of Life Outcomes.

Ongoing prospective studies are evaluating treatment of the primary tumor in men with de novo metastatic prostate cancer (PCa). One potential benefit is prevention of morbidity from local progression. Thus, local therapy may be best applied selectively to men with local progression once resistance to first-line therapies has occurred. Here, we gather support for the hypothesis that radical prostatectomy (RP) is safe and preserves quality of life (QOL) when applied in men with metastatic castration-resistant PCa (mCRPC). We analyzed 14 patients who underwent RP in the setting of mCRPC from 2008 to 2016. Median time from mCRPC to RP was 5.1 mo (interquartile range [IQR] 1.4-12.0). Median preoperative and <3 mo postoperative Expanded Prostate Cancer Index Composite urinary function QOL scores were 84 (IQR 70-95) and 78 (IQR 62-81), respectively. There were one Clavien Grade III, three Grade II, and one Grade I complications postoperatively. In these patients with mCRPC, RP was feasible with limited minor complications. PATIENT SUMMARY: We report on a select group of men with metastatic castration-resistant prostate cancer who had prostatectomy. Prostatectomy is highly investigational in this setting and should not be used outside of a clinical trial other than for symptom relief.

Performance of a Prostate Cancer Genomic Classifier in Predicting Metastasis in Men with Prostate-specific Antigen Persistence Postprostatectomy.

BACKGROUND: Prostate cancer patients who have a detectable prostate-specific antigen (PSA) postprostatectomy may harbor pre-existing metastatic disease. To our knowledge, none of the commercially available genomic biomarkers have been investigated in such men. OBJECTIVE: To evaluate if a 22-gene genomic classifier can independently predict development of metastasis in men with PSA persistence postoperatively. DESIGN, SETTING, AND PARTICIPANTS: A multi-institutional study of 477 men who underwent radical prostatectomy (RP) between 1990 and 2015 from three academic centers. Patients were categorized as detectable PSA (n=150) or undetectable (n=327) based on post-RP PSA nadir ≥0.1 ng/ml. OUTCOME MEASUREMENTS AND STATISITICAL ANALYSIS: Cumulative incidence curves for metastasis were constructed using Fine-Gray competing risks analysis. Penalized Cox univariable and multivariable (MVA) proportional hazards models were performed to evaluate the association of the genomic classifier with metastasis. RESULTS AND LIMITATIONS: The median follow-up for censored patients was 57 mo. The median time from RP to first postoperative PSA was 1.4 mo. Detectable PSA patients were more likely to have higher adverse pathologic features compared with undetectable PSA patients. On MVA, only genomic high-risk (hazard ratio [HR]: 5.95, 95% confidence interval [CI]: 2.02-19.41, p=0.001), detectable PSA (HR: 4.26, 95% CI: 1.16-21.8, p=0.03), and lymph node invasion (HR: 12.2, 95% CI: 2.46-70.7, p=0.003) remained prognostic factors for metastasis. Among detectable PSA patients, the 5-yr metastasis rate was 0.90% for genomic low/intermediate and 18% for genomic high risk (p<0.001). Genomic high risk remained independently prognostic on MVA (HR: 5.61, 95% CI: 1.48-22.7, p=0.01) among detectable PSA patients. C-index for Cancer of the Prostate Risk Assessment Postsurgical score, Gandaglia nomogram, and the genomic classifier plus either Cancer of the Prostate Risk Assessment Postsurgical score or Gandaglia were 0.69, 0.68, and 0.82 or 0.81, respectively. Sample size was a limitation. CONCLUSIONS: Despite patients with a detectable PSA harboring significantly higher rates of aggressive clinicopathologic features, Decipher independently predicts for metastasis. Prospective validation of these findings is warranted and will be collected as part of the ongoing randomized trial NRG GU-002. PATIENT SUMMARY: Decipher independently predicted metastasis for patients with detectable prostate-specific antigen after prostatectomy.

The implications of ageing and life expectancy in prostate cancer treatment.

In patients diagnosed with prostate cancer, the selection of treatment, including the type of therapy and its aggressiveness, is often based on a patient's age and life expectancy. Life expectancy estimates are too often calculated solely on the patient's chronological age, overlooking comorbid conditions and their severity, which can greatly affect life expectancy. If, in addition to chronological age, comorbid conditions are used to assess a patient's life expectancy, the most appropriate treatment options are more likely to be selected. Older, healthy patients might be able to tolerate more aggressive treatment than would be administered on the basis of their age alone, and younger patients with numerous comorbid conditions could avoid harsh therapy that might not be appropriate given their current state of health. The key idea to consider in treatment selection is what a patient's quality of life would be like with or without a particular treatment option. In an era of precision medicine, decisions regarding the provision of health care should be made rationally and on the basis of objective estimates of the threat of disease and the benefits and costs of intervention and within the context of the patient's characteristics and desires.