Sorafenib Versus Observation Following Radical Metastasectomy for Clear-cell Renal Cell Carcinoma: Results from the Phase 2 Randomized Open-label RESORT Study.

BACKGROUND: In selected metastatic renal cell carcinoma (mRCC) patients, radical metastasectomy followed by observation is a potential strategy. It is still to be defined whether systemic therapy should be administered following metastasectomy. OBJECTIVE: To assess the potential benefit of postoperative treatment with sorafenib compared with observation alone after radical metastasectomy in mRCC patients. DESIGN, SETTING, AND PARTICIPANTS: The RESORT trial was a multicenter, randomized, open-label, phase 2 study conducted between November 2012 and November 2017 in Italy. Patients with clear-cell mRCC pretreated with nephrectomy and undergoing radical metastasectomy (three or fewer lesions) were eligible for the study. Patients were randomized (1:1) within 12 wk from metastasectomy to sorafenib (standard dose 400 mg twice daily) or observation for a maximum of 52 wk. Stratification factors were interval from nephrectomy, site, and number of lesions. Overall, 76 patients were screened and 69 were randomized: 33 were assigned to sorafenib and 36 to observation. The primary endpoint was recurrence-free survival (RFS). Secondary endpoints were overall survival and the safety profile. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: RFS curves were estimated with the Kaplan-Meier method, and the log-rank test was used to statistically compare the curves. RESULTS AND LIMITATIONS: At a median follow-up of 38 mo, median RFS was 37 mo (95% confidence interval [CI] 20-not available [NA]) in the observation arm versus 21 mo (95% CI 11-NA) in the sorafenib arm (log-rank test p = 0.404), with 12-, 24-, and 36-mo RFS probability of 74% versus 63%, 59% versus 49%, and 50% versus 41%, respectively, in the observation versus the sorafenib arm. Any-grade adverse event (AE) rates were 84% in the sorafenib arm and 31% in the observation arm; grade ≥3 AE rates were 22% and 3% in the sorafenib and the observation arm, respectively, with a rate of treatment discontinuation for AEs of 19% in the sorafenib arm. CONCLUSIONS: This prospective study showed that systemic treatment with sorafenib did not increase RFS as compared with observation in mRCC patients following radical metastasectomy. PATIENT SUMMARY: This article reports the clinical outcome of patients with metastatic renal cell carcinoma treated with sorafenib or managed with an observation-alone strategy after the radical surgery of metastases. We found that sorafenib did not improve the patient outcome in terms of relapse-free survival in this selected population.

Temporal Trend in Incidental Prostate Cancer Detection at Surgery for Benign Prostatic Hyperplasia.

OBJECTIVE: To assess changes in the rate of incidental prostate cancer (PCa) after benign prostatic hyperplasia (BPH) surgery over the last decade. MATERIALS AND METHODS: We identified 1177 patients surgically treated for BPH (open prostatectomy, transurethral resection or holmium laser enucleation [HoLEP] of the prostate) in 2007-2016 at a single European academic center. Local polynomial regression was used to explore changes in the rate of incidental PCa detected after BPH surgery and of preoperative biopsy performed over time. Logistic regression analyses tested the association of incidental PCa diagnosis with year of surgery and preoperative biopsy. RESULTS: Incidental PCa was found in 6.4% (74) of cases, 67 (91%) with Grade group 1 disease. We observed an increased incidence of PCa diagnosis after BPH surgery over time (odds ratio [OR]: 1.12; 95%confidence interval [CI]: 1.02-1.24, P = .02) along with a concomitant decrease in the rate of preoperative prostate biopsies (OR: 0.83; 95%CI: 0.79-0.88, P < .0001). Patients undergoing a preoperative biopsy showed a lower risk of being diagnosed with PCa after surgery (OR: 0.29; 95% CI: 0.12, 0.72 P = .007). Patients treated with HoLEP had a higher chance of incidental PCa detection (OR: 2.28; 95%CI: 1.30-4.00; P = .004), although this may be related to the significantly higher number of HoLEP performed over the last years. CONCLUSION: The increased rate of low-risk PCa detected after BPH surgery in the last decade reflects the clinical practice changes in PCa screening and diagnosis leading to a reduced number of unnecessary biopsies and indolent cancer diagnosis.

Assessment of the Rate of Adherence to International Guidelines for Androgen Deprivation Therapy with External-beam Radiation Therapy: A Population-based Study.

BACKGROUND: The National Comprehensive Cancer Network and the European Association of Urology guidelines recommend using radiation therapy (RT) with androgen deprivation therapy (ADT) to treat high-risk and locally advanced prostate cancer patients. OBJECTIVE: To evaluate the degree of adherence to these guidelines. DESIGN, SETTING, AND PARTICIPANTS: Between 2003 and 2009, in the Surveillance Epidemiology and End Results (SEER)-Medicare database, 14 180 patients were diagnosed with high-risk (T1-T2 with World Health Organization histologic grade 3) or locally advanced (T3-T4 with any histologic grade) prostatic adenocarcinoma. INTERVENTION: Administration of RT-ADT versus RT alone. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We assessed the rate of adherence to guidelines with respect to use of RT-ADT in the overall population and after stratification according to stage-grade groupings (T1-T2 G3 vs T3-T4 any grade), age (66-69, 70-74, 75-79, ≥80 yr), Charlson Comorbidity Index (CCI) (0, 1, ≥2), and preexisting baseline cardiovascular (CV) disease. We depicted the rate of RT-ADT administration graphically over the study period. Multivariable logistic regression analyses were performed to assess the predictors of RT-ADT use. RESULTS AND LIMITATIONS: RT-ADT rates and guideline adherence were 58-75%, with the highest rate (75%) in 2003 and the lowest (58%) in 2009. When stratified according to stage-grade groupings, age, CCI, and preexisting baseline CV disease, similar results were obtained. In multivariable analyses, year of diagnosis (p<0.001), patient age (p<0.001), stage-grade groupings (p<0.001), CCI (p=0.036), race (p<0.001), marital status (p<0.001), population density (p<0.001), and US regions (p<0.001) were independent predictors of RT-ADT use. The limitations of our study include age >65 yr and exclusive Medicare coverage. CONCLUSIONS: The rate of guideline adherence regarding the use of RT-ADT is suboptimal and decreases with time instead of increasing. PATIENT SUMMARY: This population-based study provides evidence of low adherence to international urologic guidelines regarding the combination of radiation therapy (RT) with androgen deprivation therapy (ADT) for high-risk and locally advanced prostate cancer (PCa) patients. Despite the increasing number of randomized controlled trials over time that showed a survival benefit for patients with high-risk and locally advanced PCa treated with RT-ADT compared with RT alone, the rate of adherence to guidelines decreased with time.

Naftopidil for the treatment of benign prostate hyperplasia: a systematic review.

OBJECTIVES: The aim of the study was to systematically review the effects of the adrenoreceptor A1D antagonist naftopidil in the management of lower urinary tract symptoms (LUTS). METHODS: A structured and comprehensive MEDLINE search was conducted for original articles, reviews, and metanalyses assessing the clinical pharmacology as well as the safety of naftopidil in the treatment of LUTS secondary to BPH. English-language publications dating from 1950 to 2013 were considered. RESULTS: In the considered timeframe, 14 randomized clinical trials (RCT) were reported. Overall, the outcome measures assessed in the various reports included in the present review were changes from baseline in: International Prostate Symptom Score (IPSS), quality of life (QoL) score, maximum urinary flow rate (Qmax), residual volume (PVR), and adverse effects. Although additional well designed, worldwide, placebo-controlled and randomized studies are necessary to confirm the long-term outcomes of naftopidil pharmacotherapy, current data suggest that naftopidil administration in BPH patients provides comparable improvements in total IPSS, QoL, and urinary symptoms from baseline relative to 0.2 mg/d tamsulosin and 8 mg/d silodosin. However, improvements in Qmax are generally less with naftopidil than with tamsulosin. Reported adverse effects related to naftopidil administration are negligible and usually mild. CONCLUSION: It remains unknown whether the data reported on naftopidil in the Japanese population are applicable in symptomatic BPH patients from western countries given that: (1) no English-language clinical trials have compared naftopidil to placebo in Western countries; (2) all clinical trials available were carried out in Japan; (3) in the comparative studies with tamsulosin, the dose of this drug was lower than the recommended dose in Western countries; (4) no data from long-term clinical trials evaluating drug safety beyond 18 weeks.

National Comprehensive Cancer Network practice guidelines 2011: Need for more accurate recommendations for pelvic lymph node dissection in prostate cancer.

PURPOSE: The 2011 NCCN (National Comprehensive Cancer Network) guidelines for prostate cancer recommend pelvic lymph node dissection at radical prostatectomy in all individuals with a nomogram predicted lymph node invasion probability of 2% or greater. We examined the ability of these guidelines to correctly predict lymph node invasion in patients treated with extended pelvic lymph node dissection. MATERIALS AND METHODS: We examined 3,064 consecutive patients treated with radical prostatectomy and extended pelvic lymph node dissection between 2000 and 2010. We formally validated the NCCN guideline nomogram using discrimination, calibration and decision curve analysis as benchmarks. Moreover the performance characteristics of the 2% nomogram cutoff as well as other cutoff values (range 1% to 10%) were tested. RESULTS: Overall 10.0% of patients had lymph node invasion. The discrimination accuracy of the NCCN guideline nomogram was 79.8%, with a maximum underestimation of the lymph node invasion risk of 41.2%. On decision curve analysis the NCCN nomogram fared better than not performing pelvic lymph node dissection in all patients. However, in the prediction range between 0% and 9% the nomogram did not fare better than performing pelvic lymph node dissection in all patients. The use of the 2% cutoff would allow the avoidance of 49.3% of pelvic lymph node dissections, at the cost of missing 20.3% of patients with lymph node invasion. CONCLUSIONS: The NCCN nomogram tends to significantly underestimate the real lymph node invasion rate. Moreover the use of the currently recommended cutoff of 2% to trigger pelvic lymph node dissection might not be appropriate.

Serum sex steroids depict a nonlinear u-shaped association with high-risk prostate cancer at radical prostatectomy.

PURPOSE: To assess the association between preoperative serum total testosterone (tT), 17ß-estradiol (E(2)), sex hormone-binding globulin (SHBG), and tT-E(2) ratio values with high-risk prostate cancer (as defined by the National Comprehensive Cancer Network practice guidelines) at radical prostatectomy. EXPERIMENTAL DESIGN: Serum E(2), tT, and SHBG were dosed the day before surgery (7:00-11:00 am) in a cohort of 724 candidates to radical prostatectomy. Restricted cubic spline functions tested the association between predictors (i.e., model 1: age, body mass index, and serum tT, E(2), and SHBG levels; model 2: tT-E(2) values instead of tT and E(2) levels) and high-risk prostate cancer. RESULTS: Low-, intermediate-, or high-risk prostate cancer was found in 251 (34.7%), 318 (43.9%), and 155 (21.4%) patients, respectively. Patients in the high-risk class showed the lowest tT, E(2), and tT-E(2) ratio values (all P ≤ 0.02). At univariate analysis, only age, tT, E(2), and tT-E(2) ratio values were significantly associated with high-risk prostate cancer (all P ≤ 0.006). At multivariate analyses considering model 1 variables, age (P = 0.03), serum tT (all P < 0.001), and E(2) (all P ≤ 0.01) were associated with high-risk prostate cancer; only tT-E(2) ratios achieved independent predictor status for high-risk prostate cancer (all P < 0.001) when considering model 2. Both the lowest and the highest tT, E(2), and tT-E(2) values depicted a nonlinear U-shaped significant association with high-risk prostate cancer. CONCLUSIONS: These data showed that preoperative serum sex steroids are independent predictors of high-risk prostate cancer, depicting a nonlinear U-shaped association.

Performance characteristics of computed tomography in detecting lymph node metastases in contemporary patients with prostate cancer treated with extended pelvic lymph node dissection.

BACKGROUND: Computed tomography (CT) is a commonly used noninvasive procedure for prostate cancer (PCa) staging. All previous studies addressing the ability of CT scan to predict lymph node invasion (LNI) were based on historical patients treated with limited pelvic lymph node dissection (PLND). OBJECTIVE: Assess the value of CT in predicting LNI in contemporary PCa patients treated with extended PLND (ePLND). DESIGN, SETTING, AND PARTICIPANTS: We evaluated 1541 patients undergoing radical prostatectomy and ePLND between 2003 and 2010 at a single center. All patients were preoperatively staged using abdominopelvic CT scan. All lymph nodes with a short axis diameter ≥ 10 mm were considered suspicious for metastatic involvement. INTERVENTION: All patients underwent preoperative CT scan, radical retropubic prostatectomy, and ePLND, regardless of PCa features at diagnosis. MEASUREMENTS: The performance characteristics of CT scan were tested in the overall patient population, as well as according to the National Comprehensive Cancer Network (NCCN) classification and according to the risk of LNI derived from a nomogram developed on an ePLND series. Logistic regression models tested the relationship between CT scan findings and LNI. Discrimination accuracy was quantified with the area under the curve. RESULTS AND LIMITATIONS: Overall, a CT scan that suggested LNI was found in 73 patients (4.7%). Of them, only 24 patients (32.8%) had histologically proven LNI at ePLND. Overall, sensitivity, specificity, and accuracy of CT scan were 13%, 96.0%, and 54.6%, respectively. In patients with low-, intermediate-, or high-risk PCa according to NCCN classification, sensitivity was 8.3%, 96.3%, and 52.3%, respectively; specificity was 3.6%, 97.3%, and 50.5%, respectively; and accuracy was 17.9%, 94.3%, and 56.1%, respectively. Similarly, in patients with a nomogram-derived LNI risk ≥ 50%, sensitivity, specificity, and accuracy were only 23.9%, 94.7%, and 59.3%, respectively. At multivariable analyses, inclusion of CT scan findings did not improve the accuracy of LNI prediction (81.4% compared with 81.3%; p=0.8). Lack of a central scan review represents the main limitation of our study. CONCLUSIONS: In contemporary patients with PCa, the accuracy of CT scan as a preoperative nodal-staging procedure is poor, even in patients with high LNI risk. Therefore, the need for and the extent of PLND should not be based on the results obtained by CT scan.

Contemporary management of patients with T1a and T1b prostate cancer.

PURPOSE OF REVIEW: Incidental prostate cancer (PCa) - T1a to T1b - still represents a non-negligible clinical entity requiring good decision-making skills to correctly manage patients, most of whom may have insignificant tumours. The aim of the current review is to summarize the available evidence-based information that may be helpful in daily clinical practice. RECENT FINDINGS: Although having major clinical implications, the current TNM staging system for incidental PCa has not been re-evaluated for 20 years. Recently, many reports questioned the accuracy of T1a-T1b classification and strengthened the fact that the decisions to offer further treatment in cases of incidental cancer should be based upon the estimated probability of clinical progression compared to the relative risk of therapy and potential benefit to survival. The use of prostate-specific antigen (PSA) levels before and after transurethral resection of the prostate (TURP) and Gleason score at diagnosis may help in estimating the need for further therapy. SUMMARY: Active surveillance should be recommended for well differentiated incidental cancers in patients with limited life expectancy and low PSA levels after TURP or, alternatively, in patients who are uncomfortable with potential treatment-related complications. In patients with a longer life expectancy - especially for poorly differentiated tumours - radical prostatectomy should be considered. PSA levels before and after TURP increase the accuracy in estimating the need for active management. Further studies focusing on biologic and clinical markers of progression are mandatory to identify those patients who require active treatment after incidental PCa diagnosis.

The role of transrectal saturation biopsy in tumour localization: pathological correlation after retropubic radical prostatectomy and implication for focal ablative therapy.

OBJECTIVE: • To evaluate the accuracy of an initial 24-core prostate biopsy scheme (PBx24) in predicting unilateral prostate cancer (PCa) in radical prostatectomy (RP) specimens. PATIENTS AND METHODS: • Between 2005 and 2008, 203 consecutive patients underwent PBx24 followed by RP for PCa. The area under the curve (AUC) was used to evaluate the accuracy of unilateral PCa on PBx24 to predict unilateral PCa in RP specimens. • The positive predictive value (PPV) and negative predictive value (NPV) were also calculated. Moreover, in patients with unilateral PCa on biopsy, univariable and multivariable logistic regression analyses tested the relationship between the presence of unilateral PCa in an RP specimen and the variables: age, prostate-specific antigen (PSA), total prostate volume, clinical stage, primary Gleason grade, secondary Gleason grade and the number of positive cores. RESULTS: • PCa cores were unilateral in 115 patients (56.7%) on biopsy. Of those, only 26 (22.6%) had unilateral PCa in the RP specimen (AUC, 72.9%; PPV, 22.6%; NPV, 98.8%). In patients with clinically low-risk tumours, only 17 of 63 (27%) had a unilateral PCa on PBx24 and in the RP specimen (AUC, 59.1%; PPV, 27.0%; NPV, 100.0%). • None of the examined variables was an independent predictor of the presence of unilateral PCa in the RP specimen (all P > 0.05). CONCLUSIONS: • Initial PBx24 is not sufficiently accurate to be dependable as a method of predicting tumour laterality in RP specimens. Therefore, the use of PBx24 to guide hemi-ablation therapy of PCa may lead to mistreatment in a considerable proportion of patients. • Moreover, none of the routinely available clinical and pathological characteristics appears to improve the ability of unilateral PCa on biopsy to predict unilateral PCa in the RP specimen.

When to perform bone scan in patients with newly diagnosed prostate cancer: external validation of the currently available guidelines and proposal of a novel risk stratification tool.

BACKGROUND: Several guidelines have indicated that in patients with well-differentiated or moderately well-differentiated prostate cancer (PCa), a staging bone scan may be omitted. However, the guidelines recommendations have not yet been externally validated. OBJECTIVE: The aim of the study was to externally validate the available guidelines regarding the need for a staging bone scan in patients with newly diagnosed PCa. Moreover, we developed a novel risk stratification tool aimed at improving the accuracy of these guidelines. DESIGN, SETTING, AND PARTICIPANTS: The study included 853 consecutive patients diagnosed with PCa between January 2003 and June 2008 at a single centre. All patients underwent bone scan using technetium Tc 99m methylene diphosphonate at diagnosis. MEASUREMENTS: The area under the curve (AUC) of the criteria suggested by the guidelines (European Association of Urology, American Urological Association, National Comprehensive Cancer Network, and American Joint Committee on Cancer) to perform a baseline bone scan was assessed and compared with the accuracy of a classification and regression tree (CART) including prostate-specific antigen (PSA), clinical stage, and biopsy Gleason sum as covariates. RESULTS AND LIMITATIONS: The AUC of the guidelines ranged between 79.7% and 82.6%. However, the novel CART model, which stratified patients into low risk (biopsy Gleason ≤7, cT1-T3, and PSA <10 ng/ml), intermediate risk (biopsy Gleason ≤7, cT2/T3, and PSA >10 ng/ml), and high risk (biopsy Gleason >7) was significantly more accurate (AUC: 88.0%) than all the guidelines (all p≤0.002). The limitation of this study resides in its retrospective design. Moreover, the proposed risk stratification tool can be considered only for patients who are candidates for radical prostatectomy until validated in other clinical settings. CONCLUSIONS: This is the first study aimed at externally validating the available guidelines addressing the need for staging baseline bone scans in PCa patients. All guidelines showed high accuracy. However, their accuracy was significantly lower compared with the accuracy of the novel risk stratification tool. According to this tool, staging bone scans might be considered only for patients with a biopsy Gleason score >7 or with a PSA >10 ng/ml and palpable disease (cT2/T3) prior to treatment. However, before recommending its use in clinical practice, our model needs to be externally validated.

Thirty-day mortality after transurethral resection of the prostate in patients treated with androgen deprivation therapy.

BACKGROUND AND PURPOSE: Seven percent of patients with prostate cancer (PCa) who are exposed to androgen deprivation therapy (ADT) may need transurethral resection of the prostate (TURP). Our objective was to examine the rate and the predictors of 30-day mortality (30dM) after TURP in patients who were exposed to ADT in a large, contemporary Canadian cohort. PATIENTS AND METHODS: We assessed the 30dM rate after TURP in 853 men with the diagnosis of PCa who were treated with primary ADT or radiation therapy followed by ADT. The effect of age, comorbidity (coded according to the Charlson Comorbidity Index [CCI]), number of previous TURP procedures, history of radiation therapy, exposure to antiandrogens, and the type and the duration of ADT before TURP were all tested in univariable and multivariable logistic regression models that predicted 30dM after TURP. RESULTS: During the initial 30 days after TURP, 38 deaths occurred (4.5%, 95% confidence interval: 3.2%-6.2%). Of all variables, the CCI was the only statistically significant (P = 0.001) predictor of 30dM after TURP. The accuracy of CCI in predicting 30dM after TURP in individual patients was 65.1%. Lack of consideration of clinical variables that could predict the 30dM rate after TURP, such as prostate size or prostate-specific antigen level, represents a limitation of this study. CONCLUSIONS: A substantial risk of 30dM is associated with TURP that is performed in patients who are exposed to ADT. Unfortunately, the predictors used in this analysis could not define the individual risk of 30dM with sufficient accuracy. Nonetheless, the average 4.5% risk should be considered at the time of informed consent.

Development and external validation of a highly accurate nomogram for the prediction of perioperative mortality after transurethral resection of the prostate for benign prostatic hyperplasia.

PURPOSE: Benign prostatic hyperplasia affects 60% of men at the age of 60 years. Transurethral resection of the prostate is the gold standard of therapy. We assessed the 30-day mortality rate after transurethral resection of the prostate for benign prostatic hyperplasia, identified risk factors related to 30-day mortality and developed a model that discriminates among individual 30-day mortality risk levels. MATERIALS AND METHODS: We performed development (7,362) and external validation (7,362) of a multivariable logistic regression model predicting the individual probability of 30-day mortality after transurethral resection of the prostate based on an administrative data set (Quebec Health Plan) of 14,724 patients 43 to 99 years old treated between January 1, 1989 and December 31, 2000. RESULTS: Overall 30-day mortality occurred in 58 patients (0.4%) undergoing transurethral resection of the prostate. On univariable analyses increasing age (p <0.001) and increasing Charlson comorbidity index (p <0.001) were statistically significant predictors of 30-day mortality after transurethral resection of the prostate. Conversely annual surgical volume was not. On multivariable analyses age (p <0.001) and Charlson comorbidity index (p <0.001) reached independent predictor status. The accuracy of the age and Charlson comorbidity index based nomogram that predicts the individual probability of 30-day mortality after transurethral resection of the prostate was 83% in the external validation cohort. CONCLUSIONS: Age and Charlson comorbidity index are important determinants of 30-day mortality after transurethral resection of the prostate. The combination of these parameters allows an 83% accurate prediction of individual 30-day mortality risk after transurethral resection of the prostate. Despite limitations such as the need for additional external validations and possibly the need for inclusion of clinical parameters, the use of the current model is warranted for the purpose of informed consent before transurethral resection of the prostate and/or for patient counseling.