Do Phosphodiesterase Type 5 Inhibitors Increase the Risk of Biochemical Recurrence After Radical Prostatectomy?

PURPOSE: There have been conflicting studies on the association between phosphodiesterase type 5 inhibitor (PDE5i) use and biochemical recurrence (BCR) following radical prostatectomy (RP). Our aim was to determine whether PDE5i drug exposure after RP increases the risk of BCR in patients undergoing RP. MATERIALS AND METHODS: An institutional database of prostate cancer patients treated between January 2009 and December 2020 was reviewed. BCR was defined as 2 PSA measurements greater than 0.1 ng/mL. PDE5i exposure was defined using a 0 to 3 scale, with 0 representing never use, 1 sometimes use, 2 regularly use, and 3 routinely use. The risk of BCR with any PDE5i exposure, the quantity of exposure, and the duration of PDE5i exposure were assessed by multivariable Cox proportional hazards models. RESULTS: The sample size included 4630 patients to be analyzed, with 776 patients having BCR. The median follow-up for patients without BCR was 27 (IQR 12, 49) months. Eighty-nine percent reported taking a PDE5i at any time during the first 12 months after RP, and 60% reported doing so for 6 or more months during the year after RP. There was no evidence of an increase in the risk of BCR associated with any PDE5i use (HR 1.05, 95% CI 0.84, 1.31, P = .7) or duration of PDE5i use in the first year (HR 0.98 per 1 month duration, 95% CI 0.96, 1.00, P = .055). Baseline oncologic risk was lower in patients using PDE5i, but differences between groups were small, suggesting that residual confounding is unlikely to obscure any causal association with BCR. CONCLUSIONS: Prescription of PDE5i to men after RP can be based exclusively on quality of life considerations. Patients receiving PDE5is can be reassured that their use does not increase the risk of BCR.

The oncologic risk of magnetic resonance imaging-targeted and systematic cores in patients treated with radical prostatectomy.

BACKGROUND: Magnetic resonance imaging (MRI)-targeted prostate biopsy (MRI-biopsy) detects high-Grade Group (GG) prostate cancers not identified by systematic biopsy (S-biopsy). However, questions have been raised whether cancers detected by MRI-biopsy and S-biopsy, grade-for-grade, are of equivalent oncologic risk. The authors evaluated the relative oncologic risk of GG diagnosed by S-biopsy and MRI-biopsy. METHODS: This was a retrospective analysis of all patients who had both MRI-biopsy and S-biopsy and underwent with prostatectomy (2014-2022) at Memorial Sloan Kettering Cancer Center. Three logistic regression models were used with adverse pathology as the primary outcome (primary pattern 4, any pattern 5, seminal vesicle invasion, or lymph node involvement). The first model included the presurgery prostate-specific antigen level, the number of positive and negative S-biopsy cores, S-biopsy GG, and MRI-biopsy GG. The second model excluded MRI-biopsy GG to obtain the average risk based on S-biopsy GG. The third model excluded S-biopsy GG to obtain the risk based on MRI-biopsy GG. A secondary analysis using Cox regression evaluated the 12-month risk of biochemical recurrence. RESULTS: In total, 991 patients were identified, including 359 (36%) who had adverse pathology. MRI-biopsy GG influenced oncologic risk compared with S-biopsy GG alone (p < .001). However, if grade was discordant between biopsies, then the risk was intermediate between grades. For example, the average risk of advanced pathology for patients who had GG2 and GG3 on S-biopsy was 19% and 66%, respectively, but the average risk was 47% for patients who had GG2 on S-biopsy and patients who had GG3 on MRI-biopsy. The equivalent estimates for 12-month biochemical recurrence were 5.8%, 15%, and 10%, respectively. CONCLUSIONS: The current findings cast doubt on the practice of defining risk group based on the highest GG. Because treatment algorithms depend fundamentally on GG, further research is urgently required to assess the oncologic risk of prostate tumors depending on detection technique. PLAIN LANGUAGE SUMMARY: Using magnetic resonance imaging (MRI) to help diagnose prostate cancer can help identify more high-grade cancers than using a systematic template biopsy alone. However, we do not know if high-grade cancers diagnosed with the help of an MRI are as dangerous to the patient as high-grade cancers diagnosed with a systematic biopsy. We examined all of our patients who had an MRI biopsy and a systematic biopsy and then had their prostates removed to find out if these patients had risk factors and signs of aggressive cancer (cancer that spread outside the prostate or was very high grade). We found that, if there was a difference in grade between the systematic biopsy and the MRI-targeted biopsy, the risk of aggressive cancer was between the two grades.

Predictive value of kallikrein forms and ß-microseminoprotein in blood from patients with evidence of detectable levels of PSA after radical prostatectomy.

PURPOSE: To determine whether ß-microseminoprotein or any of the kallikrein forms in blood-free, total or intact PSA or total hK2-predict metastasis in patients with evidence of detectable levels of PSA in blood after radical prostatectomy. METHOD: We determined marker concentrations in blood from 173 men treated with radical prostatectomy and evidence of detectable levels of PSA in the blood (PSA ≥ 0.05) after surgery between 2014 and 2015 and at least 1 year after any adjuvant therapy. We used Cox regression to determine whether any marker was associated with metastasis using both univariate and multivariable models that included standard clinical predictors. RESULTS: Overall, 42 patients had metastasis, with a median follow-up of 67 months among patients without an event. The levels of intact and free PSA and free-to-total PSA ratio were significantly associated with metastasis. Discrimination was highest for free PSA (c-index: 0.645) and free-to-total PSA ratio (0.625). Only free-to-total PSA ratio remained associated with overall metastasis (either regional or distant) after including standard clinical predictors (p = 0.025) and increased discrimination from 0.686 to 0.697. Similar results were found using distant metastasis as an outcome (p = 0.011; c-index increased from 0.658 to 0.723). CONCLUSION: Our results provide evidence that free-to-total PSA ratio can risk stratifying patients with evidence of detectable levels of PSA in blood after RP. Further research is warranted on the biology of prostate cancer markers in patients with evidence of detectable levels of PSA in blood after radical prostatectomy. Our findings on the free-to-total ratio for predicting adverse oncologic outcomes need to be validated in other cohorts.

Oncologic outcomes of patients with lymph node invasion at prostatectomy and post-prostatectomy biochemical persistence.

BACKGROUND: Pathologic nodal invasion at prostatectomy is frequently associated with persistently elevated prostate-specific antigen (PSA) and with increased risk of disease recurrence. Management strategies for these patients are poorly defined. We aimed to explore the long-term oncologic outcomes and patterns of disease progression. METHODS: We included men treated between 2000 and 2017 who had lymph node invasion at radical prostatectomy and persistently detectable prostate-specific antigen post-prostatectomy. Postoperative imaging and management strategies were collated. Patterns of recurrence and probability of metastasis-free survival, prostate cancer-specific survival, and overall survival (OS) were assessed. RESULTS: Among our cohort of 253 patients, 126 developed metastasis. Twenty-five had a positive scan within 6 months of surgery; of these, 15 (60%) had a nodal metastasis, 10 (40%) had a bone metastasis, and 4 (16%) had local recurrence. For metastasis-free survival, 5- and 10-year probabilities were 52% (95% CI 45%, 58%) and 37% (95% CI 28%, 46%), respectively. For prostate cancer-specific survival, 5- and 10-year probabilities were 89% (95% CI 84%, 93%) and 67% (95% CI 57%, 76%), respectively. A total of 221 patients proceeded to hormonal deprivation treatment alone. Ten patients received postoperative radiotherapy. CONCLUSIONS: Biochemical persistence in patients with lymph node invasion is associated with high risk of disease progression and reduced prostate cancer-specific survival. Management was hindered by the limitation of imaging modalities utilized during the study period in accurately detecting residual disease. Novel molecular imaging may improve staging and help design a therapeutic strategy adapted to patients' specific needs.

Outcomes of Grade Group 2 and 3 Prostate Cancer on Initial Versus Confirmatory Biopsy: Implications for Active Surveillance.

BACKGROUND: Active surveillance (AS) is recommended as the preferred treatment for men with low-risk disease. In order to optimize risk stratification and exclude undiagnosed higher-grade disease, most AS protocols recommend a confirmatory biopsy. OBJECTIVE: We aimed to compare outcomes among men with grade group (GG) 2/3 prostate cancer on initial biopsy with those among men whose disease was initially GG1 but was upgraded to GG2/3 on confirmatory biopsy. DESIGN, SETTING, AND PARTICIPANTS: We reviewed patients undergoing radical prostatectomy (RP) in two cohorts: "immediate RP group," with GG2/3 cancer on diagnostic biopsy, and "AS group," with GG1 cancer on initial biopsy that was upgraded to GG2/3 on confirmatory biopsy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Probabilities of biochemical recurrence (BCR) and salvage therapy were determined using multivariable Cox regression models with risk adjustment. Risks of adverse pathology at RP were also compared using logistic regression. RESULTS AND LIMITATIONS: The immediate RP group comprised 4009 patients and the AS group comprised 321 patients. The AS group had lower adjusted rates of adverse pathology (27% vs 35%, p = 0.003). BCR rates were lower in the AS group, although this did not reach conventional significance (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.50-1.06, p = 0.10) compared with the immediate RP group. Risk-adjusted 1- and 5-yr BCR rates were 4.6% (95% CI 3.0-6.5%) and 10.4% (95% CI 6.9-14%), respectively, for the AS group compared with 6.3% (95% CI 5.6-7.0%) and 20% (95% CI 19-22%), respectively, in the immediate RP group. A nonsignificant association was observed for salvage treatment-free survival favoring the AS group (HR 0.67, 95% CI 0.42, 1.06, p = 0.087). CONCLUSIONS: We found that men with GG1 cancer who were upgraded on confirmatory biopsy tend to have less aggressive disease than men with the same grade found at initial biopsy. These results must be confirmed in larger series before recommendations can be made regarding a more conservative approach in men with upgraded pathology on surveillance biopsy. PATIENT SUMMARY: We studied men with low-risk prostate cancer who were initially eligible for active surveillance but presented with more aggressive cancer on confirmatory biopsy. We found that outcomes for these men were better than the outcomes for those diagnosed initially with more serious cancer.

A Novel Expert Coaching Model in Urology, Aimed at Accelerating the Learning Curve in Robotic Prostatectomy.

INTRODUCTION/BACKGROUND: The surgical residency model assumes that upon completion, a surgeon is ready to practice and grow independently. However, many surgeons fail to improve after reaching proficiency, which in certain instances has correlated with worse clinical outcomes. Coaching addresses this problem and furthers surgeons' education post-residency. Currently, surgical coaching programs focus on medical students and residents, and have been shown to improve residents' and medical students' technical and non-technical abilities. Coaching programs also increase the accuracy of residents, fellows, and attendings in self-assessing their surgical ability. Despite the potential benefits, coaching remains underutilized and poorly studied. We developed an expert-led, face-to-face, video-based surgical coaching program at a tertiary medical center among specialized attending surgeons. Our goal was to evaluate the feasibility of such a program, measure surgeons' attitudes towards internal peer coaching, determine whether surgeons found the sessions valuable and educational, and to subjectively self-assess changes in operative technique. METHODS/MATERIALS: Surgeons who perform robot-assisted laparoscopic prostatectomies were chosen and grouped by number of cases completed: junior (<100 cases), intermediate (100-500 cases), and senior (>500 cases). Surgeons were scheduled for 3 1-hour coaching sessions 1-2 months apart (February-October 2019), meeting individually with the coach (PS), an expert Urologic Oncologist with thousands of cases of experience performing radical prostatectomy. He received training on coaching methodology prior to beginning the coaching program. Before each session, surgeons selected 1 of their recent intraoperative videos to review. During sessions, the coach led discussion on topics chosen by the surgeon (i.e. neurovascular bundle dissection, apical dissection, bladder neck); together, they developed goals to achieve before the next session. Subsequent sessions included presentation and discussion of a case occurring subsequent to the prior session. Sessions were coded by discussion topics and analyzed based on level of experience. Surgeons completed a survey evaluating the experience. RESULTS: All 6 surgeons completed 3 sessions. Five surgeons completed the survey; most respondents evaluated themselves as having improved in desired areas and feeling more confident performing the discussed steps of the operation. Discussed surgical principles varied by experience group; when subjectively quantifying the difficulty of surgical steps, the more difficult steps were discussed by the higher experience groups compared to the junior surgeons. The senior surgeons also focused more on oncologic potency, continence outcomes, and more theory-driven questions while the junior surgeons tended to focus more on anatomic and technique-based questions such as tissue handling and the use of cautery and clips. Overall, the surgeons thought this program provoked critical discussion and subsequently modified their technique, and "agreed" or "strongly agreed" that they would seek further sessions. CONCLUSIONS: Surgical coaching at a large medical center is not only feasible but was rated positively by surgeons across all levels of experience. Coaching led to subjective self-improvement and increased self-confidence among most surgeons. Surgeons also felt that this program offered a safe space to acquire new skills and think critically after finishing residency/fellowship. Themes discussed and takeaways from the sessions varied based on surgeon experience level. While further research is needed to more objectively quantify the impact coaching has on surgeon metrics and patient outcomes, the results of this study supports the initial "proof-of-concept" of peer-based surgical coaching and its potential benefits in accelerating the learning curve for surgeons' post-residency.

MRI-guided focused ultrasound focal therapy for patients with intermediate-risk prostate cancer: a phase 2b, multicentre study.

BACKGROUND: Men with grade group 2 or 3 prostate cancer are often considered ineligible for active surveillance; some patients with grade group 2 prostate cancer who are managed with active surveillance will have early disease progression requiring radical therapy. This study aimed to investigate whether MRI-guided focused ultrasound focal therapy can safely reduce treatment burden for patients with localised grade group 2 or 3 intermediate-risk prostate cancer. METHODS: In this single-arm, multicentre, phase 2b study conducted at eight health-care centres in the USA, we recruited men aged 50 years and older with unilateral, MRI-visible, primary, intermediate-risk, previously untreated prostate adenocarcinoma (prostate-specific antigen ≤20 ng/mL, grade group 2 or 3; tumour classification ≤T2) confirmed on combined biopsy (combining MRI-targeted and systematic biopsies). MRI-guided focused ultrasound energy, sequentially titrated to temperatures sufficient for tissue ablation (about 60-70°C), was delivered to the index lesion and a planned margin of 5 mm or more of normal tissue, using real-time magnetic resonance thermometry for intraoperative monitoring. Co-primary outcomes were oncological outcomes (absence of grade group 2 and higher cancer in the treated area at 6-month and 24-month combined biopsy; when 24-month biopsy data were not available and grade group 2 or higher cancer had occurred in the treated area at 6 months, the 6-month biopsy results were included in the final analysis) and safety (adverse events up to 24 months) in all patients enrolled in the study. This study is registered with ClinicalTrials.gov, NCT01657942, and is no longer recruiting. FINDINGS: Between May 4, 2017, and Dec 21, 2018, we assessed 194 patients for eligibility and treated 101 patients with MRI-guided focused ultrasound. Median age was 63 years (IQR 58-67) and median concentration of prostate-specific antigen was 5·7 ng/mL (IQR 4·2-7·5). Most cancers were grade group 2 (79 [78%] of 101). At 24 months, 78 (88% [95% CI 79-94]) of 89 men had no evidence of grade group 2 or higher prostate cancer in the treated area. No grade 4 or grade 5 treatment-related adverse events were reported, and only one grade 3 adverse event (urinary tract infection) was reported. There were no treatment-related deaths. INTERPRETATION: 24-month biopsy outcomes show that MRI-guided focused ultrasound focal therapy is safe and effectively treats grade group 2 or 3 prostate cancer. These results support focal therapy for select patients and its use in comparative trials to determine if a tissue-preserving approach is effective in delaying or eliminating the need for radical whole-gland treatment in the long term. FUNDING: Insightec and the National Cancer Institute.

Morbidity of salvage radical prostatectomy: limited impact of the minimally invasive approach.

PURPOSE: We aimed to report the morbidity profile of salvage radical prostatectomy (SRP) after radiotherapy failure and assess the impact of minimally invasive surgery (MIS) on postoperative complications and functional outcomes. MATERIALS AND METHODS: Between 1985 and 2019, a total of 293 patients underwent SRP; 232 underwent open SRP; and 61 underwent laparoscopic SRP with or without robotic assistance. Complications were recorded and classified into standardized categories per the Clavien-Dindo classification. RESULTS: Twenty-nine patients (10%) experienced grade 3 complications within 30 days, 22 (9.5%) after open and 7 (11%) after MIS (p = 0.6). Between 30 and 90 days after surgery, 7.3% of patients in the open group and 10% in the MIS group had grade 3 complications (p = 0.5). The most common complication was bladder neck contracture (BNC), representing 40% of the 30-90 day complications. Within one year of SRP, 81 patients (31%, 95% CI 25%, 37%) developed BNC; we saw non-significant lower rates in MIS (25 vs 32%; p = 0.4). Functional outcomes were poor after SRP and showed no difference between open and MIS groups for urinary continence (16 vs 18%, p = 0.7) and erectile function (7 vs 13%, p = 0.4). 5 year cancer-specific survival and overall survival was 95% and 88% for the entire cohort, respectively. CONCLUSIONS: Our outcomes suggest poor functional recovery after SRP, regardless of the operative approach. Currently there is no evidence favoring the use of open or MIS approach. Further studies are required to ensure comparable outcomes between these approaches.

Oncologic Outcomes of Total Length Gleason Pattern 4 on Biopsy in Men with Grade Group 2 Prostate Cancer.

PURPOSE: Gleason Score 7 prostate cancer comprises a wide spectrum of disease risk, and precise substratification is paramount. Our group previously demonstrated that the total length of Gleason pattern (GP) 4 is a better predictor than %GP4 for adverse pathological outcomes at radical prostatectomy. We aimed to determine the association of GP4 length on prostate biopsy with post-prostatectomy oncologic outcomes. MATERIALS AND METHODS: We compared 4 GP4 quantification methods-including maximum %GP4 in any single core, overall %GP4, total length GP4 (mm) across all cores and length GP4 (mm) in the highest volume core-for prediction of biochemical recurrence-free survival after radical prostatectomy using multivariable Cox proportional hazards regression. RESULTS: A total of 457 men with grade group 2 prostate cancer on biopsy subsequently underwent radical prostatectomy. The 3-year biochemical recurrence-free survival probability was 85% (95% CI 81-88). On multivariable analysis, all 4 GP4 quantification methods were associated with biochemical recurrence-maximum %GP4 (HR=1.30; 95% CI 1.07-1.59; p=0.009), overall %GP4 (HR=1.61; 95% CI 1.21-2.15; p=0.001), total length GP4 (HR=2.48; 95% CI 1.36-4.52; p=0.003) and length GP4 in highest core (HR=1.32; 95% CI 1.11-1.57; p=0.001). However, we were unable to identify differences between methods of quantification with a relatively low event rate. CONCLUSIONS: These findings support further studies on GP4 quantification in addition to the ratio of GP3 and GP4 to classify prostate cancer risk. Research should also be conducted on whether GP4 quantification could provide a surrogate endpoint for disease progression for trials in active surveillance.

Association of Family History of Cancer with Clinical and Pathological Outcomes for Prostate Cancer Patients on Active Surveillance.

PURPOSE: The impact of germline mutations associated with hereditary cancer syndromes in patients on active surveillance (AS) for prostate cancer is poorly defined. We examined the association between family history of prostate cancer (FHP) or family history of cancer (FHC) and risk of progression or adverse pathology at radical prostatectomy (RP) in patients on AS. MATERIALS AND METHODS: Patients on AS at a single tertiary-care center between 2000-2019 were categorized by family history. Disease progression was defined as an increase in Gleason grade on biopsy. Adverse pathology was defined as upgrading/upstaging at RP. Multivariable Cox and logistic regression models were used to assess association between family history and time to progression or adverse pathology, respectively. RESULTS: Among 3,211 evaluable patients, 669 (21%) had FHP, 34 (1%) had FHC and 95 (3%) had both; 753 progressed on AS and 481 underwent RP. FHP was associated with increased risk of progression (HR 1.31; 95% CI, 1.11-1.55; p=0.002) but FHC (HR 0.67; 95% CI, 0.30-1.50; p=0.3) or family history of both (HR 1.22; 95% CI, 0.81-1.85; p=0.3) were not. FHP, FHC or both were not associated with adverse pathology at RP (p >0.4). CONCLUSIONS: While FHP was associated with an increased risk of progression on AS, wide confidence intervals render this outcome of unclear clinical significance. FHC was not associated with risk of progression on AS. In the absence of known genetically defined hereditary cancer syndrome, we suggest FHP and/or FHC should not be used as a sole trigger to preclude patients from enrolling on AS.

Impact of Zone of Origin in Anterior Dominant Prostate Cancer: Long-Term Biochemical Recurrence-Free Survival in an Anatomically Well-Characterized Cohort.

INTRODUCTION: Our goal was to determine whether zonal origin of anterior dominant prostate cancers is associated with clinical outcome among patients treated with radical prostatectomy. METHODS: We investigated the clinical outcomes of 197 patients with previously well-characterized anterior dominant prostatic tumors on radical prostatectomy. Univariable Cox proportional hazards models were used to test for an association between anterior peripheral zone (PZ) or transition zone (TZ) tumor location and clinical outcomes. RESULTS: Zonal origin of anterior dominant tumors: 97/197 (49%) anterior PZ, 70 (36%) TZ, 14 (7%) both zones and 16 (8%) indeterminate zone. Comparing anterior PZ and TZ tumors, there were no significant differences in Grade group, incidence of extraprostatic extension or surgical margin positivity rate. Overall, 19 (9.6%) patients experienced biochemical recurrence (BCR), including 10 with anterior PZ origin and 5 with TZ origin. Median followup time among those without BCR was 9.5 years (IQR 7.2, 12.7). BCR-free survival at 5 and 10 years was 91% and 89% for anterior PZ tumors, and 94% and 92% for TZ tumors, respectively. On univariate analysis, there was no evidence of a difference in time to BCR between anterior PZ and TZ tumor zone of origin (p=0.5). CONCLUSIONS: In this anatomically well-characterized cohort of anterior dominant prostate cancers, long-term BCR-free survival was not significantly associated with zone of origin. Future studies utilizing zone of origin as a parameter should consider separating anterior and posterior PZ localization, as outcomes may differ.

Characterization of Symptoms after Radical Prostatectomy and Their Relation to Postoperative Complications.

PURPOSE: Many patients will experience symptoms in the initial days after radical prostatectomy (RP), but early patient-reported symptoms have not been well characterized. Our objective was to illustrate the pattern of symptoms experienced after RP and the relation of severe symptoms to postoperative complications. MATERIALS AND METHODS: In 2016, electronic patient-reported symptom monitoring began at our institution's ambulatory surgery center. We retrospectively reviewed patients treated with minimally invasive RP who were sent a daily questionnaire completed using a web interface until postoperative day 10. Severe symptoms automatically generate a "yellow alert," which messages the clinic, while very severe symptoms generate a "red alert," additionally prompting the patient to call. We summarized rates of moderate-to-very severe symptoms and fit local polynomial regressions. We compared rates of 30-day or 90-day complications (grade ≥2) based on the presence of alert symptoms. RESULTS: Of 2,266 men undergoing RP, 1,942 (86%) completed surveys. Among moderate-to-very severe symptom levels, pain (72%) and dyspnea (11%) were most common. Pain, nausea and dyspnea consistently decreased over time; fever and vomiting had a flat pattern. In patients experiencing red-alert symptoms, we observed a higher risk of 30-day complications, but rates were low and differences between groups were nonsignificant (2.9% vs 1.9%; difference 1.1%; 95% CI -1.3-3.5; p=0.3). Results were similar examining 90-day complications. CONCLUSIONS: While symptoms are common after RP, substantial improvements occur over the first 10 days. Severe or very severe symptoms conferred at most a small absolute increase in complication risk, which should be reassuring to patients and clinicians.

Clinical utility of subclassifying positive surgical margins at radical prostatectomy.

OBJECTIVE: To determine whether subclassification of positive surgical margins (PSMs) increases predictive ability for biochemical recurrence (BCR) and aids clinical decision-making in patients undergoing radical prostatectomy. PATIENTS AND METHODS: We studied 2147 patients with pT2 and pT3a prostate cancer with detailed surgical margin parameters and BCR status. We compared a base model, a linear predictor calculated from the Memorial Sloan Kettering Cancer Center postoperative nomogram (prostate-specific antigen, pathological tumour grade and stage), with the addition of surgical margin status to five additional models (base model plus surgical margin subclassifications) to evaluate enhancement in predictive accuracy. Decision curve analysis (DCA) was performed to determine the clinical utility of parameters that enhanced predictive accuracy. RESULTS: Among 2147 men, 205 had PSMs, and 231 developed BCR. Discrimination for the base model with addition of surgical margin status was high (c-index = 0.801) and not meaningfully improved by adding surgical margin subclassification in the full cohort. In analyses considering only men with PSMs (N = 55 with BCR), adding surgical margin subclassification to the base model increased discrimination for total length of all PSMs - alone or with maximum Gleason grade at the margin (c-index improvement = 0.717 to 0.752 and 0.753, respectively). DCA demonstrated a modest benefit to clinical utility with the addition of these parameters. CONCLUSIONS: Specific subclassification parameters add predictive accuracy for BCR and may aid clinical utility in decision-making for patients with PSMs. These findings may be useful for patient counselling and future adjuvant therapy trial design.

Validation of the cell cycle progression score to differentiate indolent from aggressive prostate cancer in men diagnosed through transurethral resection of the prostate biopsy.

BACKGROUND: Validation of biomarker-based prognostic models to improve risk stratification in men with localized prostate cancer (PrCa) remains a clinical need. It has previously been shown that the cell cycle progression (CCP) test provides significant, independent prognostic information for men who were incidentally diagnosed with PrCa after transurethral resection of the prostate (TURP) and were conservatively managed. AIM: The results have been extended in a newly analyzed retrospective cohort of UK men diagnosed through TURP biopsy (TURP1B; N = 305). METHODS AND RESULTS: The CCP score was derived from TURP biopsy tissue and combined with a modified UCSF Cancer of the Prostate Risk Assessment score (CAPRA) to generate the clinical cell-cycle risk score (CCR). The primary endpoint was PrCa-specific mortality (PSM). Hazard ratios (HR) were calculated for a one-unit change in score. Median follow-up was 9.6 (IQR: 5.4, 14.1) years, and 67 (22%) men died from PrCa within 10 years of diagnosis. The median CCP score was 1.1 (IQR: 0.6, 1.7). In univariate analyses, CCR proved a significant prognosticator of PSM (HR per unit score change = 2.28; 95% CI: 1.89, 2.74; P = 1.0 × 10-19 ). In multivariate analyses, CCR remained a significant prognosticator of PSM after adjusting for CAPRA (HR per unit score change = 4.36; 95% CI: 2.65, 7.16; P = 1.3 × 10-8 ), indicating that its molecular component, CCP, provides significant, independent prognostic information. CONCLUSION: These findings validate a combined clinicopathologic and molecular prognostic model for conservatively managed men who are diagnosed through TURP, supporting the use of CCR to inform clinical management.

Have urinary function outcomes after radical prostatectomy improved over the past decade?

BACKGROUND: Changes in surgical technique and postoperative care that target improvements in functional outcomes are widespread in the literature. Radical prostatectomy (RP) is one such procedure that has seen multiple advances over the past decade. The objective of this study was to leverage RP as an index case to determine whether practice changes over time produced observable improvements in patient-reported outcomes. METHODS: This study analyzed patients undergoing RP by experienced surgeons at a tertiary care center with prospectively maintained patient-reported outcome data from 2008 to 2019. Four patient-reported urinary function outcomes at 6 and 12 months after RP were defined with a validated instrument: good urinary function (domain score ≥ 17), no incontinence (0 pads per day), social continence (≤1 pad per day), and severe incontinence (≥3 pads per day). Multivariable logistic regressions evaluated changes in outcomes based on the surgical date. RESULTS: Among 3945 patients meeting the inclusion criteria, excellent urinary outcomes were reported throughout the decade but without consistent observable improvements over time. Specifically, there were no improvements in good urinary function at 12 months (P = .087) based on the surgical date, and there were countervailing effects on no incontinence (worsening; P = .005) versus severe incontinence (improving; P = .003). Neither approach (open, laparoscopic, or robotic), nor nerve sparing, nor membranous urethral length mediated changes in outcomes. CONCLUSIONS: In a decade with multiple advances in surgical and postoperative care, there was evidence of improvements in severe incontinence, but no measurable improvements across 3 other urinary outcomes. Although worsening disease factors could contribute to the stable observed outcomes, a more systematic approach to evaluating techniques and implementing patient selection and postoperative care advances is needed. LAY SUMMARY: Although there have been advances in radical prostatectomy over the past decade, consistent observable improvements in postoperative incontinence were not reported by patients. To improve urinary function outcomes beyond the current high standard, the approach to studying innovations in surgical technique needs to be changed, and further development of other aspects of prostatectomy care is needed.

Independent validation of a pre-specified four-kallikrein marker model for prediction of adverse pathology and biochemical recurrence.

BACKGROUND: Accurate markers for prostate cancer (PC) risk stratification could aid decision-making for initial management strategies. The 4Kscore has an undefined role in predicting outcomes after radical prostatectomy (RP). METHODS: We included 1476 patients with 4Kscore measured prior to RP at two institutions. The 4Kscore was assessed for prediction of adverse pathology at RP and biochemical recurrence (BCR) relative to a clinical model. We pre-specified that all analyses would be assessed in biopsy Grade Group 1 (GG1) or 2 (GG2) PC patients, separately. RESULTS: The 4Kscore increased discrimination for adverse pathology in all patients (delta area under the receiver operative curve (AUC) 0.009, 95% confidence interval (CI) 0.002, 0.016; clinical model AUC 0.767), driven by GG1 (delta AUC 0.040, 95% CI 0.006, 0.073) rather than GG2 patients (delta AUC 0.005, 95% CI -0.012, 0.021). Adding 4Kscore improved prediction of BCR in all patients (delta C-index 0.014, 95% CI 0.007, 0.021; preop-BCR nomogram C-index 0.738), again with larger changes in GG1 than in GG2. CONCLUSIONS: This study validates prior investigations on the use of 4Kscore in men with biopsy-confirmed PC. Men with GG1 PC and a high 4Kscore may benefit from additional testing to guide treatment selection. Further research is warranted regarding the value of the 4Kscore in men with biopsy GG2 PC.

Addition of Prostate Volume and Prostate-specific Antigen Density to Memorial Sloan Kettering Cancer Center Prostate Cancer Nomograms.

Prostate-specific antigen (PSA) density is an established prognostic marker for prostate cancer. We investigated whether the inclusion of PSA density or prostate volume in the Memorial Sloan Kettering Cancer Center nomograms improves the prediction of biochemical recurrence (BCR) after radical prostatectomy (RP). Among the 11 725 men included, 2140 developed BCR. Neither PSA density nor prostate volume was associated with BCR when added to either the pre-RP or post-RP model (all p values ≥0.10) and changes in the C index were very small (largest change, 0.002). The results were robust to exclusion of outlying prostate volumes and restriction to patients treated after 2005. There is no justification for adding prostate volume or PSA density to BCR nomograms. PATIENT SUMMARY: Addition of prostate volume or prostate-specific antigen density to Memorial Sloan Kettering Cancer Center prediction schemes did not improve the prediction of recurrence of prostate cancer after removal of the prostate.

Limited versus Extended Pelvic Lymph Node Dissection for Prostate Cancer: A Randomized Clinical Trial.

BACKGROUND: Pelvic lymph node dissection (PLND) is the most reliable procedure for lymph node staging. However, the therapeutic benefit remains unproven; although most radical prostatectomies at academic centers are accompanied by PLND, there is no consensus regarding the optimal anatomical extent of PLND. OBJECTIVE: To evaluate whether extended PLND results in a lower biochemical recurrence rate. DESIGN, SETTING, AND PARTICIPANTS: We conducted a single-center randomized trial. Patients, enrolled between October 2011 and March 2017, were scheduled to undergo radical prostatectomy and PLND. Patients were assigned to limited or extended PLND by cluster randomization. Specifically, surgeons were randomized to perform limited or extended PLND for 3-mo periods. INTERVENTION: Randomization to limited (external iliac nodes) or extended (external iliac, obturator fossa and hypogastric nodes) PLND. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was the rate of biochemical recurrence. RESULTS AND LIMITATIONS: Of 1440 patients included in the final analysis, 700 were randomized to limited PLND and 740 to extended PLND. The median number of nodes retrieved was 12 (interquartile range [IQR] 8-17) for limited PLND and 14 (IQR 10-20) extended PLND; the corresponding rate of positive nodes was 12% and 14% (difference -1.9%, 95% confidence interval [CI] -5.4% to 1.5%; p = 0.3). With median follow-up of 3.1 yr, there was no significant difference in the rate of biochemical recurrence between the groups (hazard ratio 1.04, 95% CI 0.93-1.15; p = 0.5). Rates for grade 2 and 3 complications were similar at 7.3% for limited versus 6.4% for extended PLND; there were no grade 4 or 5 complications. CONCLUSIONS: Extended PLND did not improve freedom from biochemical recurrence over limited PLND for men with clinically localized prostate cancer. However, there were smaller than expected differences in nodal count and the rate of positive nodes between the two templates. A randomized trial comparing PLND to no node dissection is warranted. PATIENT SUMMARY: In this clinical trial we did not find a difference in the rate of biochemical recurrence of prostate cancer between limited and extended dissection of lymph nodes in the pelvis. This study is registered on ClinicalTrials.gov as NCT01407263.

Preoperative exercise interventions to optimize continence outcomes following radical prostatectomy.

Urinary incontinence is a common and predictable consequence among men with localized prostate cancer who have undergone radical prostatectomy. Despite advances in the surgical technique, urinary continence recovery time remains variable. A range of surgical and patient-related risk factors contributing to urinary incontinence after radical prostatectomy have been described, including age, BMI, membranous urethral length and urethral sphincter insufficiency. Physical activity interventions incorporating aerobic exercise, resistance training and pelvic floor muscle training programmes can positively influence the return to continence in men after radical prostatectomy. Traditional approaches to improving urinary continence after radical prostatectomy have typically focused on interventions delivered during the postoperative period (rehabilitation). However, the limited efficacy of these postoperative approaches has led to a shift from the traditional reactive model of care to more comprehensive interventions incorporating exercise-based programmes that begin in the preoperative period (prehabilitation) and continue after surgery. Comprehensive prehabilitation interventions include appropriately prescribed aerobic exercise, resistance training and specific pelvic floor muscle instruction and exercise training programmes. Transperineal ultrasonography is a non-invasive and validated method for the visualization of the action of the pelvic floor musculature, providing real-time visual biofeedback to the patient during specific pelvic floor muscle instruction and training. Importantly, the waiting time before surgery can be used for the delivery of comprehensive prehabilitation exercise-based interventions to increase patient preparedness in the lead-up to surgery and optimize continence and health-related quality-of-life outcomes following radical prostatectomy.