Advanced age is an independent prognostic factor of disease progression in high-risk prostate cancer: results in 180 patients treated with robot-assisted radical prostatectomy and extended pelvic lymph node dissection in a tertiary referral center.

OBJECTIVES: This study aimed to assess more clinical and pathological factors associated with prostate cancer (PCa) progression in high-risk PCa patients treated primarily with robot-assisted radical prostatectomy (RARP) and extended pelvic lymph node dissection (ePLND) in a tertiary referral center. MATERIALS AND METHODS: In a period ranging from January 2013 to October 2020, RARP and ePLND were performed on 180 high-risk patients at Azienda Ospedaliera Universitaria Integrata of Verona (Italy). PCa progression was defined as biochemical recurrence/persistence and/or local recurrence and/or distant metastases. Statistical methods evaluated study endpoints, including Cox's proportional hazards, Kaplan-Meyer survival curves, and binomial logistic regression models. RESULTS: The median age of included patients was 66.5 [62-71] years. Disease progression occurred in 55 patients (30.6%), who were more likely to have advanced age, palpable tumors, and unfavorable pathologic features, including high tumor grade, stage, and pelvic lymph node invasion (PLNI). On multivariate analysis, PCa progression was predicted by advanced age (≥ 70 years) (HR = 2.183; 95% CI = 1.089-4377, p = 0.028), palpable tumors (HR = 3.113; 95% CI = 1.499-6.465), p = 0.002), and PLNI (HR = 2.945; 95% CI = 1.441-6.018, p = 0.003), which were associated with clinical standard factors defining high-risk PCa. Age had a negative prognostic impact on elderly patients, who were less likely to have palpable tumors but more likely to have high-grade tumors. CONCLUSIONS: High-risk PCa progression was independently predicted by advanced age, palpable tumors, and PLNI, which is associated with standard clinical prognostic factors. Consequently, with increasing age, the prognosis is worse in elderly patients, who represent an unfavorable age group that needs extensive counseling for appropriate and personalized management decisions.

Advanced age portends poorer prognosis after radical prostatectomy: a single center experience.

INTRODUCTION AND OBJECTIVE: Although advanced age doesn't seem to impair oncological outcomes after robot-assisted radical prostatectomy (RARP), elderly patients have increased rates of prostate cancer (PCa) related deaths due to a higher incidence of high-risk disease. The potential unfavorable impact of advanced age on oncological outcomes following RARP remains an unsettled issue. We aimed to evaluate the oncological outcome of PCa patients > 69 years old in a single tertiary center. MATERIALS AND METHODS: 1143 patients with clinically localized PCa underwent RARP from January 2013 to October 2020. Analysis was performed on 901 patients with available follow-up. Patients ≥ 70 years old were considered elderly. Unfavorable pathology included ISUP grade group > 2, seminal vesicle, and pelvic lymph node invasion. Disease progression was defined as biochemical and/or local recurrence and/or distant metastases. RESULTS: 243 cases (27%) were classified as elderly patients (median age 72 years). Median (IQR) follow-up was 40.4 (38.7-42.2) months. Disease progression occurred in 159 cases (17.6%). Elderly patients were more likely to belong to EAU high-risk class, have unfavorable pathology, and experience disease progression after surgery (HR = 5.300; 95% CI 1.844-15.237; p = 0.002) compared to the younger patients. CONCLUSIONS: Elderly patients eligible for RARP are more likely to belong to the EAU high-risk category and to have unfavorable pathology that are independent predictors of disease progression. Advanced age adversely impacts on oncological outcomes when evaluated inside these unfavorable categories. Accordingly, elderly patients belonging to the EAU high-risk should be counseled about the increased risk of disease progression after surgery.

The Influence of Endogenous Testosterone Density on Unfavorable Disease and Tumor Load at Final Pathology in Intermediate-Risk Prostate Cancer: Results in 338 Patients Treated with Radical Prostatectomy and Extended Pelvic Lymph Node Dissection.

OBJECTIVE: The aim of this study is to evaluate the influence of endogenous testosterone density (ETD) on features of aggressive prostate cancer (PCa) in intermediate-risk disease treated with radical prostatectomy and extended pelvic lymph node dissection. MATERIALS AND METHODS: Density measurements included the ratio of endogenous testosterone (ET), prostate-specific antigen (PSA), and percentage of biopsy positive cores (BPC) on prostate volume (ETD, PSAD, and BPCD, respectively). The ratio of percentage of cancer invading the gland (tumor load, TL) on prostate weight (TLD) was also calculated. Unfavorable disease (UD) was defined as tumor upgrading (ISUP >3) and/or upstaging (pT >2) and/or lymph node invasion (LNI). Associations of ETD with features of aggressive PCa, including UD and TLD, were evaluated by logistic and linear regression models. RESULTS: Evaluated cases were 338. Subjects with upgrading, upstaging, and LNI were 61/338 (18%), 73/338 (21%), and 25/338 (7.4%), respectively. TLD correlated with UD (Pearson's correlation coefficient, r = 0.204; p < 0.0001), PSAD (r = 0.342; p < 0.0001), BPCD (r = 0.364; p < 0.0001), and ETD (r = 0.214; p < 0.0001), which also correlated with BMI (r = -0.223; p < 0.0001), PSAD (r = 0.391; p < 0.0001), and BPCD (r = 0.407; p < 0.0001). TLD was the strongest independent predictor of UD (OR = 2.244; 95% CI = 1.146-4.395; p = 0.018). In the multivariate linear regression model predicting BPCD, ETD was an independent predictor (linear regression coefficient, b = 0.026; 95% CI: 0.016-0.036; p < 0.0001) together with PSAD (b = 1.599; 95% CI: 0.863-2.334; p < 0.0001) and TLD (b = 0.489; 95% CI: 0.274-0.706; p < 0.0001). According to models, TLD increased as ETD increased accordingly, but mean ET levels were significantly lower for patients with UD. CONCLUSIONS: As ETD measurements incremented, the risk of large tumors extending beyond the prostate increased accordingly, and patients with lower ET levels were more likely to occult UD. The influence of ETD on PCa biology should be addressed by prospective studies.

Positive independent association between preoperative endogenous testosterone density and tumor load density in surgical specimen of patients undergoing radical prostatectomy.

OBJECTIVE: To evaluate the influence of endogenous testosterone density (ETD) and tumor load density (TLD) in the surgical specimen of prostate cancer (PCa) patients. METHODS: ETD was assessed as the ratio of endogenous testosterone (ET) to prostate volume (PV). TLD was calculated as the ratio of tumor load (TL) to prostate weight. Preoperative prostate-specific antigen relative densities (PSAD) and percentage of biopsy-positive cores (BPCD) were also assessed. The association of high TLD (above the first quartile) with clinical and pathological factors was assessed by the logistic regression model (univariate and multivariate analysis). RESULTS: Between November 2014 and December 2019, ET was measured in 805 cases treated with radical prostatectomy (RP). Median (IQR) of ET and ETD was 412 (321.4-519 ng/dL) and 9.8 (6.8-14.4 ng/(dLxmL)) as well as for TL and TLD was 20 (10-30%) and 0.33 (0.17-0.58%/gr), respectively. As a result, high TLD was detected in 75% of cases. A positive independent association was found between high TLD and ETD. Accordingly, as ETD levels increased, the risk of detecting high TLD in the surgical specimen increased, regardless of PSAD and BPCD. CONCLUSIONS: At diagnosis of PCa, a positive independent association was found between ETD and risk of high TLD. Subjects with increasing ETD levels were more likely to have high TLD, associated with unfavorable pathology features. The positive association between ETD and TLD in the prostate microenvironment might adversely influence PCa's natural history.

High-volume surgeons decrease operating time in robot-assisted radical prostatectomy: results in 1229 patients.

BACKGROUND: The aim is to evaluate factors impacting operating time (OT) during robot-assisted radical prostatectomy (RARP) with or without extended pelvic lymph node dissection (ePLND) for prostate cancer. METHODS: Overall, 1289 patients underwent RARP from January 2013 to December 2021. ePLND was performed in 825 cases. Factors potentially associated with OT variations were assessed. Three low-volume (LVS) and two high-volume surgeons (HVS) performed the procedures. A linear regression model was computed to assess associations with OT variations. RESULTS: When RARP was performed by HVS an OT decrease was observed independently by significant clinical (Body Mass Index [BMI]; prostate volume [PV]) and anatomical/perioperative features (prostate weight [PW]; intraoperative blood loss [BL]) both in clinical (change in OT: -42.979 minutes; 95% CI: -51.789; -34.169; P<0.0001) and anatomical/perioperative models (change in OT: -40.020 minutes; 95% CI: -48.494; -31.587; P<0.0001). A decreased OT was observed in clinical (change in OT: -27.656 minutes; 95% CI: -33.449; -21.864; P<0.0001) and anatomical/perioperative (change in OT: -24.935 minutes; 95% CI: -30.562; -19.308; P<0.0001) models also in case of RARP with ePLND performed by HVS, independently by BMI, PV, PSA as well as for PW, seminal vesicle invasion, positive surgical margins, and BL. CONCLUSIONS: In a tertiary academic referral center, OT decreased when RARP was performed by HVS, independently of adverse clinical and anatomical/perioperative factors. Available OT loads can be planned to optimize waiting lists, teaching tasks, operative costs, and surgeon's volume.

The impact of prognostic group classification on prostate cancer progression in intermediate-risk patients according to the European Association of Urology system: results in 479 patients treated with robot-assisted radical prostatectomy at a single tertiary referral center.

Background: Treatment outcomes in intermediate-risk prostate cancer (PCa) may be impaired by adverse pathology misclassification including tumor upgrading and upstaging. Clinical predictors of disease progression need to be improved in this category of patients. Objectives: To identify PCa prognostic factors to define prognostic groups in intermediate-risk patients treated with robot-assisted radical prostatectomy (RARP). Design: Data from 1143 patients undergoing RARP from January 2013 to October 2020 were collected: 901 subjects had available follow-up, of whom 479 were at intermediate risk. Methods: PCa progression was defined as biochemical recurrence and/or local recurrence and/or distant metastases. Study endpoints were evaluated by statistical methods including Cox's proportional hazards, Kaplan-Meyer survival curves, and binomial and multinomial logistic regression models. Results: After a median (interquartile range) of 35 months (15-57 months), 84 patients (17.5%) had disease progression, which was independently predicted by the percentage of biopsy-positive cores ⩾ 50% and the International Society of Urological Pathology (ISUP) grade group 3 for clinical factors and by ISUP > 2, positive surgical margins and pelvic lymph node invasion for pathological features. Patients were classified into clinical and pathological groups as favorable, unfavorable (one prognostic factor), and adverse (more than one prognostic factor). The risk of PCa progression increased with worsening prognosis through groups. A significant positive association was found between the two groups; consequently, as clinical prognosis worsened, the risk of detecting unfavorable and adverse pathological prognostic clusters increased in both unadjusted and adjusted models. Conclusion: The study identified factors predicting disease progression that allowed the computation of highly correlated prognostic groups. As the prognosis worsened, the risk of PCa progression increased. Intermediate-risk PCa needs more prognostic stratification for appropriate management.

A study on 479 patients looked at how prognostic group classification affects progression in patients with intermediate-risk prostate cancer treated with robot-assisted radical prostatectomy Prostate cancer is a serious health concern in men, and those with intermediate-risk prostate cancer may experience disease progression. Urologists use various methods to predict the risk of progression in these patients. However, sometimes the predictions are not accurate. Therefore, researchers conducted a study to identify factors that could help predict disease progression in patients with intermediate-risk prostate cancer who underwent robot-assisted surgery. This study on 479 patients found that a percentage of biopsy-positive cores ⩾ 50% and the International Society of Urological Pathology (ISUP) grade group 3 were predictive factors of disease progression. Additionally, factors like ISUP > 2, positive surgical margins, and pelvic lymph node invasion also predicted disease progression. Patients were classified into three groups based on their clinical and pathological features: favorable, unfavorable (one negative prognostic factor), and adverse (more than one negative prognostic factor). The risk of prostate cancer progression increased as the prognosis worsened through these groups. The study concluded that a more accurate stratification of intermediate-risk prostate cancer patients is needed to manage the disease effectively.

Tumor upgrading among very favorable intermediate-risk prostate cancer patients treated with robot-assisted radical prostatectomy: how can it impact the clinical course?

PURPOSE: We sought to investigate predictors of unfavorable tumor upgrading in very favorable intermediate-risk (IR) prostate cancer (PCa) patients treated with robot-assisted radical prostatectomy, in addition to evaluate how it may affect the risk of disease progression. METHODS: A very favorable subset of IR PCa patients presenting with prostate-specific antigen (PSA) < 10 ng/mL, percentage of biopsy positive cores (BPC) < 50%, and either International Society of Urological Pathology (ISUP) grade group 1 and clinical stage T2b or ISUP grade group 2 and clinical stage T1c-2b was identified. Unfavorable pathology at radical prostatectomy was defined as the presence of ISUP grade group > 2 (unfavorable tumor upgrading), extracapsular extension (ECE), and seminal vesicle invasion (SVI). Disease progression was defined as the event of biochemical recurrence and/or local recurrence and/or distant metastases. Associations were evaluated by Cox regression and logistic regression analyses. RESULTS: Overall, 210 patients were identified between January 2013 and October 2020. Unfavorable tumor upgrading was detected in 71 (33.8%) cases, and adverse tumor stage, including ECE or SVI in 18 (8.6%) and 11 (5.2%) patients, respectively. Median (interquartile range) follow-up was 38.5 (16-61) months. PCa progression occurred in 24 (11.4%) patients. Very favorable IR PCa patients with unfavorable tumor upgrading at final pathology showed a persistent risk of disease progression, which hold significance after adjustment for all factors (Hazard Ratio [HR]: 5.95, 95% Confidence Interval [CI]: 1.97-17.92, p = 0.002) of which PSA was an independent predictor (HR: 1.52, 95% CI 1.12-2.08, p = 0.008). Moreover, these subjects were more likely to belong to the biopsy ISUP grade group 2. CONCLUSIONS: Very favorable IR PCa patients hiding unfavorable tumor upgrading were more likely to experience disease progression. Unfavorable tumor upgrading involved about one-third of cases and was less likely to occur in patients presenting with biopsy ISUP grade group 1. Tumor misclassification is an issue to discuss, when counseling this subset of patients for active surveillance because of the risk of delayed active treatment.

Preoperative endogenous testosterone density predicts disease progression from localized impalpable prostate cancer presenting with PSA levels elevated up to 10 ng/mL.

OBJECTIVE: To investigate endogenous testosterone density (ETD) predicting disease progression from clinically localized impalpable prostate cancer (PCa) presenting with prostate-specific antigen (PSA) levels elevated up to 10 ng/mL and treated with radical prostatectomy. MATERIALS AND METHODS: In a period ranging from November 2014 to December 2019, 805 consecutive PCa patients who were not under androgen blockade had endogenous testosterone (ET, ng/dL) measured before surgery. ETD was evaluated as the ratio of ET on prostate volume (PV). Unfavorable disease was defined as including ISUP ≥ 3 and/or seminal vesicle invasion in the surgical specimen. The risk of disease progression was evaluated by statistical methods. RESULTS: Overall, the study selected 433 patients, of whom 353 (81.5%) had available follow-up. Unfavorable disease occurred in 46.7% of cases and was predicted by tumor quantitation features that were positively associated with ETD. Disease progression, which occurred for 46 (13%) cases, was independently predicted only by ETD (hazard ratio, HR = 1.037; 95% CI 1.004-1.072; p = 0.030) after adjusting for unfavorable disease. According to a multivariate model, ETD above the third quartile was confirmed to be an independent predictor for PCa progression (HR = 2.479; 95% CI 1.355-4.534; p = 0.003) after adjusting for unfavorable disease. The same ETD measurements, ET mean levels were significantly lower in progressing cancers. CONCLUSIONS: In this particular subset of patients, increased ETD with low ET levels, indicating androgen independence, resulted in a more aggressive disease with poorer prognosis.

Normal preoperative endogenous testosterone levels predict prostate cancer progression in elderly patients after radical prostatectomy.

Background: The impact of senior age on prostate cancer (PCa) oncological outcomes following radical prostatectomy (RP) is controversial, and further clinical factors could help stratifying risk categories in these patients. Objective: We tested the association between endogenous testosterone (ET) and risk of PCa progression in elderly patients treated with RP. Design: Data from PCa patients treated with RP at a single tertiary referral center, between November 2014 and December 2019 with available follow-up, were retrospectively evaluated. Methods: Preoperative ET (classified as normal if >350 ng/dl) was measured for each patient. Patients were divided according to a cut-off age of 70 years. Unfavorable pathology consisted of International Society of Urologic Pathology (ISUP) grade group >2, seminal vesicle, and pelvic lymph node invasion. Cox regression models tested the association between clinical/pathological tumor features and risk of PCa progression in each age subgroup. Results: Of 651 included patients, 190 (29.2%) were elderly. Abnormal ET levels were detected in 195 (30.0%) cases. Compared with their younger counterparts, elderly patients were more likely to have pathological ISUP grade group >2 (49.0% versus 63.2%). Disease progression occurred in 108 (16.6%) cases with no statistically significant difference between age subgroups. Among the elderly, clinically progressing patients were more likely to have normal ET levels (77.4% versus 67.9%) and unfavorable tumor grades (90.3% versus 57.9%) than patients who did not progress. In multivariable Cox regression models, normal ET [hazard ratio (HR) = 3.29; 95% confidence interval (CI) = 1.27-8.55; p = 0.014] and pathological ISUP grade group >2 (HR = 5.62; 95% CI = 1.60-19.79; p = 0.007) were independent predictors of PCa progression. On clinical multivariable models, elderly patients were more likely to progress for normal ET levels (HR = 3.42; 95% CI = 1.34-8.70; p = 0.010), independently by belonging to high-risk category. Elderly patients with normal ET progressed more rapidly than those with abnormal ET. Conclusion: In elderly patients, normal preoperative ET independently predicted PCa progression. Elderly patients with normal ET progressed more rapidly than controls, suggesting that longer exposure time to high-grade tumors could adversely impact sequential cancer mutations, where normal ET is not anymore protective on disease progression.

Clinical implications of endogenous testosterone density on prostate cancer progression in patients with very favorable low and intermediate risk treated with radical prostatectomy.

We tested the association between endogenous testosterone density (ETD; the ratio between endogenous testosterone [ET] and prostate volume) and prostate cancer (PCa) aggressiveness in very favorable low- and intermediate-risk PCa patients who underwent radical prostatectomy (RP). Only patients with prostate-specific antigen (PSA) within 10 ng ml -1 , clinical stage T1c, and International Society of Urological Pathology (ISUP) grade group 1 or 2 were included. Preoperative ET levels up to 350 ng dl -1 were classified as abnormal. Tumor quantitation density factors were evaluated as the ratio between percentage of biopsy-positive cores and prostate volume (biopsy-positive cores density, BPCD) and the ratio between percentage of cancer invasion at final pathology and prostate weight (tumor load density, TLD). Disease upgrading was coded as ISUP grade group >2, and progression as recurrence (biochemical and/or local and/or distant). Risk associations were evaluated by multivariable Cox and logistic regression models. Of 320 patients, 151 (47.2%) had intermediate-risk PCa. ET (median: 402.3 ng dl -1 ) resulted abnormal in 111 (34.7%) cases (median ETD: 9.8 ng dl -1 ml -1 ). Upgrading and progression occurred in 109 (34.1%) and 32 (10.6%) cases, respectively. Progression was predicted by ISUP grade group 2 (hazard ratio [HR]: 2.290; P = 0.029) and upgrading (HR: 3.098; P = 0.003), which was associated with ISUP grade group 2 (odds ratio [OR]: 1.785; P = 0.017) and TLD above the median (OR: 2.261; P = 0.001). After adjustment for PSA density and body mass index (BMI), ETD above the median was positively associated with BPCD (OR: 3.404; P < 0.001) and TLD (OR: 5.238; P < 0.001). Notably, subjects with abnormal ET were more likely to have higher BPCD (OR: 5.566; P = 0.002), as well as TLD (OR: 14.998; P = 0.016). Independently by routinely evaluated factors, as ETD increased, BPCD and TLD increased, but increments were higher for abnormal ET levels. In very favorable cohorts, ETD may further stratify the risk of aggressive PCa.

Preoperative endogenous total testosterone predicts prostate cancer progression: results in 580 consecutive patients treated with robot assisted radical prostatectomy for clinically localized disease.

PURPOSE: To test the role of endogenous total testosterone (ETT) as a predictor of prostate cancer (PCa) progression in patients treated with robot assisted radical prostatectomy for clinically localized disease. METHODS: Between November 2014 and December 2019, 580 consecutive patients were evaluated. Preoperative ETT levels were classified as ≤ 350 ng/dL vs. > 350 ng/dL. The associations between ETT levels and the risk of PCa progression, defined as any event of biochemical recurrence and/or local recurrence and/or distant metastases, or other clinical and pathological factors were evaluated by regression analyses. RESULTS: Preoperative ETT levels resulted ≤ 350 ng/dL in 173 (29.8%) patients. Disease progression occurred in 101 (17.1%) cases. Progressing patients were more likely to present with PSA levels > 10 ng/mL, as well as with unfavorable tumor grade (ISUP 4-5) and stage (pT3b) at final pathology, but less likely to have ETT levels ≤ 350 ng/mL. On clinical multivariable Cox regression models, ETT ≤ 350 ng/mL exhibited a statistically significant protective effect on tumor progression (hazard ratio: 0.57, p = 0.013). Subjects presenting with ETT levels ≤ 350 ng/mL were less likely to harbor ISUP 4-5 tumor grade either at biopsy (odds ratio [OR]: 0.46, p = 0.028) or final pathology (OR: 0.45, p = 0.032). CONCLUSIONS: At PCa diagnosis, ETT, which associates with ISUP tumor grade, is an independent predictor of disease progression. Accordingly, as ETT decreases to levels ≤ 350 ng/dL, the risk of unfavorable tumor grade decreases, and a more favorable prognosis is expected. Preoperative ETT levels may allow further patient stratification along prognostic risk groups.

Prognostic Impact and Clinical Implications of Unfavorable Upgrading in Low-Risk Prostate Cancer after Robot-Assisted Radical Prostatectomy: Results of a Single Tertiary Referral Center.

Objective: to evaluate predictors and the prognostic impact of favorable vs. unfavorable tumor upgrading among low-risk prostate cancer (LR PCa) patients treated with robot-assisted radical prostatectomy (RARP). Methods: From January 2013 to October 2020, LR PCa patients treated with RARP at our institution were identified. Unfavorable tumor upgrading was defined as the presence of an International Society of Urological Pathology (ISUP) grade group at final pathology > 2. Disease relapse was coded as biochemical recurrence and/or local recurrence and/or presence of distant metastases. Regression analyses tested the association between clinical and pathological features and the risk of unfavorable tumor upgrading and disease relapse. Results: Of the 237 total LR PCa patients, 60 (25.3%) harbored unfavorable tumor upgrading. Disease relapse occurred in 20 (8.4%) patients. Unfavorable upgrading represented an independent predictor of disease relapse, even after adjustment for other clinical and pathological variables. Conversely, favorable tumor upgrading did not show any statistically significant association with PCa relapse. Unfavorable tumor upgrading was associated with tumors being larger (OR: 1.03; p = 0.031), tumors extending beyond the gland (OR: 8.54, p < 0.001), age (OR: 1.07, p = 0.009), and PSA density (PSAD) ≥ 0.15 ng/mL/cc (OR: 1.07, p = 0.009). Conclusions: LR PCa patients with unfavorable upgrading at final pathology were more likely to be older, to have PSAD ≥ 0.15 ng/mL/cc, and to experience disease relapse. Unfavorable tumor upgrading is an issue to consider when counseling these patients to avoid delayed treatments, which may impair cancer-specific survival.