Impact of Maximal Transurethral Resection on Pathological Outcomes at Cystectomy in a Large, Multi-institutional Cohort.

PURPOSE: While the presence of residual disease at the time of radical cystectomy for bladder cancer is an established prognostic indicator, controversy remains regarding the importance of maximal transurethral resection prior to neoadjuvant chemotherapy. We characterized the influence of maximal transurethral resection on pathological and survival outcomes using a large, multi-institutional cohort. MATERIALS AND METHODS: We identified 785 patients from a multi-institutional cohort undergoing radical cystectomy for muscle-invasive bladder cancer after neoadjuvant chemotherapy. We employed bivariate comparisons and stratified multivariable models to quantify the effect of maximal transurethral resection on pathological findings at cystectomy and survival. RESULTS: Of 785 patients, 579 (74%) underwent maximal transurethral resection. Incomplete transurethral resection was more frequent in patients with more advanced clinical tumor (cT) and nodal (cN) stage (P < .001 and P < .01, respectively), with more advanced ypT stage at cystectomy and higher rates of positive surgical margins (P < .01 and P < .05, respectively). In multivariable models, maximal transurethral resection was associated with downstaging at cystectomy (adjusted odds ratio 1.6, 95% CI 1.1-2.5). In Cox proportional hazards analysis, maximal transurethral resection was not associated with overall survival (adjusted HR 0.8, 95% CI 0.6-1.1). CONCLUSIONS: In patients undergoing transurethral resection for muscle-invasive bladder cancer prior to neoadjuvant chemotherapy, maximal resection may improve pathological response at cystectomy. However, the ultimate effects on long-term survival and oncologic outcomes warrant further investigation.

Identifying the Optimal Number of Neoadjuvant Chemotherapy Cycles in Patients with Muscle Invasive Bladder Cancer.

PURPOSE: We investigated the pathological response rates and survival associated with 3 vs 4 cycles of cisplatin-based neoadjuvant chemotherapy (NAC) in patients with cT2-4N0M0 muscle invasive bladder cancer. MATERIALS AND METHODS: In this cohort study we analyzed clinical data of 828 patients treated with NAC and radical cystectomy between 2000 and 2020. A total of 384 and 444 patients were treated with 3 and 4 cycles of NAC, respectively. Pathological objective response (pOR; ypT0-Ta-Tis-T1 N0), pathological complete response (pCR; ypT0 N0), cancer-specific survival and overall survival were investigated. RESULTS: pOR and pCR were achieved in 378 (45%; 95% CI 42, 49) and 207 (25%; 95% CI 22, 28) patients, respectively. Patients treated with 4 cycles of NAC had higher pOR (49% vs 42%, p=0.03) and pCR (28% vs 21%, p=0.02) rates compared to those treated with 3 cycles. This effect was confirmed on multivariable logistic regression analysis (pOR OR 1.46 p=0.008, pCR OR 1.57, p=0.007). On multivariable Cox regression analysis, 4 cycles of NAC were significantly associated with overall survival (HR 0.68; 95% CI 0.49, 0.94; p=0.02) but not with cancer-specific survival (HR 0.72; 95% CI 0.50, 1.04; p=0.08). CONCLUSIONS: Four cycles of NAC achieved better pathological response and survival compared to 3 cycles. These findings may aid clinicians in counseling patients and serve as a benchmark for prospective trials. Prospective validation of these findings and assessment of cumulative toxicity derived from an increased number of cycles are needed.

Multicenter evaluation of neoadjuvant and induction gemcitabine-carboplatin versus gemcitabine-cisplatin followed by radical cystectomy for muscle-invasive bladder cancer.

PURPOSE: Cisplatin-based chemotherapy followed by radical cystectomy (RC) is recommended in patients with muscle-invasive bladder cancer (MIBC). However, up to 50% of patients are cisplatin ineligible. The aim of this study was to compare clinical outcomes after ≥ 3 cycles of preoperative gemcitabine-carboplatin (gem-carbo) versus gemcitabine-cisplatin (gem-cis). METHODS: We identified 1865 patients treated at 19 centers between 2000 and 2013. Patients were included if they had received ≥ 3 cycles of neoadjuvant (cT2-4aN0M0) or induction (cTanyN + M0) gem-carbo or gem-cis followed by RC. RESULTS: We included 747 patients treated with gem-carbo (n = 147) or gem-cis (n = 600). Patients treated with gem-carbo had a higher Charlson Comorbidity Index (p = 0.016) and more clinically node-positive disease (32% versus 20%; p = 0.013). The complete pathological response (pCR; ypT0N0) rate did not significantly differ between gem-carbo and gem-cis (20.7% versus 22.1%; p = 0.73). Chemotherapeutic regimen was not significantly associated with pCR (OR 0.99 [95%CI 0.61-1.59]; p = 0.96), overall survival (OS) (HR 1.20 [95%CI 0.85-1.67]; p = 0.31), or cancer-specific survival (CSS) (HR 1.35 [95%CI 0.93-1.96]; p = 0.11). Median OS of patients treated with gem-carbo and gem-cis was 28.6 months (95%CI 18.1-39.1) and 45.1 months (95%CI 32.7-57.6) (p = 0.18), respectively. Median CSS of patients treated with gem-carbo and gem-cis was 28.8 months (95%CI 9.8-47.8) and 71.0 months (95%CI median not reached) (p = 0.02), respectively. Subanalyses of the neoadjuvant and induction setting did not show significant survival differences. CONCLUSION: Our results show that a subset of cisplatin-ineligible patients with MIBC achieve pCR on gem-carbo and that survival outcomes seem comparable to gem-cis provided patients are able to receive ≥ 3 cycles and undergo RC.

Comparative effectiveness of neoadjuvant chemotherapy in bladder and upper urinary tract urothelial carcinoma.

OBJECTIVE: To assess the differential response to neoadjuvant chemotherapy (NAC) in patients with urothelial carcinoma of the bladder (UCB) compared to upper tract urothelial carcioma (UTUC) treated with radical surgery. PATIENTS AND METHODS: Data from 1299 patients with UCB and 276 with UTUC were obtained from multicentric collaborations. The association of disease location (UCB vs UTUC) with pathological complete response (pCR, defined as a post-treatment pathological stage ypT0N0) and pathological objective response (pOR, defined as ypT0-Ta-Tis-T1N0) after NAC was evaluated using logistic regression analyses. The association with overall (OS) and cancer-specific survival (CSS) was evaluated using Cox regression analyses. RESULTS: A pCR was found in 250 (19.2%) patients with UCB and in 23 (8.3%) with UTUC (P < 0.01). A pOR was found in 523 (40.3%) patients with UCB and in 133 (48.2%) with UTUC (P = 0.02). On multivariable logistic regression analysis, patients with UTUC were less likely to have a pCR (odds ratio [OR] 0.45, 95% confidence interval [CI] 0.27-0.70; P < 0.01) and more likely to have a pOR (OR 1.57, 95% CI 1.89-2.08; P < 0.01). On univariable Cox regression analyses, UTUC was associated with better OS (hazard ratio [HR] 0.80, 95% CI 0.64-0.99, P = 0.04) and CSS (HR 0.63, 95% CI 0.49-0.83; P < 0.01). On multivariable Cox regression analyses, UTUC remained associated with CSS (HR 0.61, 95% CI 0.45-0.82; P < 0.01), but not with OS. CONCLUSIONS: Our present findings suggest that the benefit of NAC in UTUC is similar to that found in UCB. These data can be used as a benchmark to contextualise survival outcomes and plan future trial design with NAC in urothelial cancer.

Neoadjuvant chemotherapy plus radical cystectomy versus radical cystectomy alone in clinical T2 bladder cancer without hydronephrosis.

OBJECTIVES: To assess the efficacy of neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) in a retrospective multicentre cohort of patients with cT2N0M0 bladder cancer (BCa) without preoperative hydronephrosis. PATIENTS AND METHODS: This was a propensity-based analysis of 619 patients. Of these, 316 were treated with NAC followed by RC and 303 with upfront RC. After multiple imputations, inverse probability of treatment weighting (IPTW) was used to account for potential selection bias. Multivariable logistic regression analysis was performed to evaluate the impact of NAC on pathological complete response and downstaging at RC, while IPTW-adjusted Kaplan-Meier curves and Cox regression models were built to evaluate the impact of NAC on overall survival (OS). RESULTS: After IPTW-adjusted analysis, standardised differences between groups were <15%. A complete response (pT0N0) at final pathology was achieved in 94 (30%) patients receiving NAC and nine (3%) undergoing upfront RC. Downstaging to non-muscle-invasive disease (

Association of age with response to preoperative chemotherapy in patients with muscle-invasive bladder cancer.

PURPOSE: To assess the association of patient age with response to preoperative chemotherapy in patients with muscle-invasive bladder cancer (MIBC). MATERIALS AND METHODS: We analyzed data from 1105 patients with MIBC. Patients age was evaluated as continuous variable and stratified in quartiles. Pathologic objective response (pOR; ypT0-Ta-Tis-T1N0) and pathologic complete response (pCR; ypT0N0), as well survival outcomes were assessed. We used data of 395 patients from The Cancer Genome Atlas (TCGA) to investigate the prevalence of TCGA molecular subtypes and DNA damage repair (DDR) gene alterations according to patient age. RESULTS: pOR was achieved in 40% of patients. There was no difference in distribution of pOR or pCR between age quartiles. On univariable logistic regression analysis, patient age was not associated with pOR or pCR when evaluated as continuous variables or stratified in quartiles (all p > 0.3). Median follow-up was 18 months (IQR 6-37). On Cox regression and competing risk regression analyses, age was not associated with survival outcomes (all p > 0.05). In the TCGA cohort, patient with age ≤ 60 years has 7% less DDR gene mutations (p = 0.59). We found higher age distribution in patients with luminal (p < 0.001) and luminal infiltrated (p = 0.002) compared to those with luminal papillary subtype. CONCLUSIONS: While younger patients may have less mutational tumor burden, our analysis failed to show an association of age with response to preoperative chemotherapy or survival outcomes. Therefore, the use of preoperative chemotherapy should be considered regardless of patient age.

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

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

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

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

Clinical Validation of IsoPSA™, a Single Parameter, Structure Based Assay for Improved Detection of High Grade Prostate Cancer.

PURPOSE: Current prostate specific antigen markers to detect prostate cancer are limited by low specificity for high grade disease. IsoPSA™ is a blood based, structure focused assay which predicts risk by partitioning the isoforms of prostate specific antigen that are linked to cancer in an aqueous 2-phase reagent system. We validated the clinical performance of this assay for identifying high grade disease in a new contemporary biopsy cohort. MATERIALS AND METHODS: We performed a multicenter prospective validation in 271 men scheduled for prostate biopsy at a total of 7 academic and community centers who were enrolled between May 2017 and March 2018. Blood samples were obtained for assay prior to biopsy. The discrimination power of the assay to detect high grade prostate cancer (Gleason 7 or greater) was evaluated by ROC analysis and compared to prior results. Clinical performance was further improved by comparison with multiparametric magnetic resonance imaging-ultrasound vs transrectal ultrasound guided biopsies. RESULTS: The assay AUC was 0.784 for high grade vs low grade cancer/benign histology, which was superior to the AUCs of total prostate specific antigen and percent free prostate specific antigen. If 1,000 patients were biopsied, the assay would have reduced the number of unnecessary biopsies from 705 to 402 (43%) with only 22 missed high grade cancers, of which 7 would have been Gleason sum 4 + 3 or higher. Subset analysis of multiparametric magnetic resonance imaging guided biopsy produced a substantial improvement of the AUC to 0.831. CONCLUSIONS: Validation of the structure based IsoPSA assay demonstrated statistical concordance with previously reported results and verified its superior performance vs concentration based prostate specific antigen and the free-to-total prostate specific antigen ratio. The assay improvement in detecting high grade prostate cancer using multiparametric magnetic resonance imaging-ultrasound guided biopsy may help define a new diagnostic paradigm.

Phase II trial of continuous treatment with sunitinib in patients with high-risk (BCG-refractory) non-muscle invasive bladder cancer.

Purpose Sunitinib is a vascular endothelial growth factor receptor (VEGFR) inhibitor with antitumor activity against bladder cancer. We hypothesized that treatment with sunitinib may decrease progression or recurrence in non-muscle invasive bladder cancer (NMIBC) refractory to intra-vesical BCG. Patients and Methods This is a single-arm phase II study of sunitinib in patients (pts) with NMIBC who progressed after BCG. Treatment included sunitinib 37.5 g daily for 12 weeks followed by 12± 2-week cystoscopy and surveillance for one year. The primary endpoint was the complete response rate at 12 months. Secondary endpoints included recurrence free survival (RFS), progression free survival (PFS), overall survival (OS), and safety of sunitinib. Correlative studies on effects of sunitinib on myeloid derived suppressor cells (MDSC) and humoral immune responses were also performed. This trial was registered on ClinicalTrials.gov, number NCT01118351. Results Between June 2011 and September 2011, 15/19 pts. completed 12 weeks of therapy. The remaining 4 pts. had treatment related adverse events leading to discontinuation of sunitinib with one patient withdrawing consent. On the 12-week cystoscopy, 44% (8/18) of the pts. showed remission, 50% (9/18) progression and 1/18 recurrence. Overall, 22% (4/18) of pts. remained free of progression for >12 months. Grade (G) 4 toxicities were noted in 2 pts. (anemia and thrombocytopenia) while G3 were noted in 58%. Sunitinib resulted in reversal of MDSC mediated immunosuppression. Conclusions In NMIBC refractory to BCG, treatment with sunitinib was safe but not associated with improved clinical outcomes. The immune effects of sunitinib deserve further investigation.

Randomized phase II trial of neoadjuvant everolimus in patients with high-risk localized prostate cancer.

Background Despite definitive local therapy, patients with high-risk prostate cancer have a significant risk for local and distant failure. To date, no systemic therapy given prior to surgery has been shown to improve outcomes. The phosphatidilinositol 3-kinase/AKT/mTOR pathway is commonly dysregulated in men with prostate cancer. We sought to determine the clinical efficacy and safety of the mTOR/TORC1 inhibitor everolimus in men with high-risk prostate cancer undergoing radical prostatectomy. Methods This is a randomized phase II study of everolimus at two different doses (5 and 10 mg daily) given orally for 8 weeks before radical prostatectomy in men with high-risk prostate cancer. The primary endpoint was the pathologic response (histologic P0, margin status, extraprostatic extension) and surgical outcomes. Secondary endpoints included changes in serum PSA level and treatment effects on levels of expression of mTOR, p4EBP1, pS6 and pAKT. Results Seventeen patients were enrolled: nine at 10 mg dose and eight at 5 mg dose. No pathologic complete responses were observed and the majority of patients (88%) had an increase in their PSA values leading to this study being terminated early due to lack of clinical efficacy. Treatment-related adverse events were similar to those previously reported with the use of everolimus in other solid tumors and no additional surgical complications were observed. A significant decrease in the expression of p4EBP1 was noted in prostatectomy samples following treatment. Conclusions Neoadjuvant everolimus given at 5 mg or 10 mg daily for 8 weeks prior to radical prostatectomy did not impact pathologic responses and surgical outcomes of patients with high-risk prostate cancer. Trial registration NCT00526591 .

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

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

Genomic Scores are Independent of Disease Volume in Men with Favorable Risk Prostate Cancer: Implications for Choosing Men for Active Surveillance.

PURPOSE: We sought to determine whether disease volume at prostate biopsy would correlate with genomic scores among men with favorable risk prostate cancer. MATERIALS AND METHODS: We identified all men with NCCN® (National Comprehensive Cancer Network®) very low and low risk disease who underwent Oncotype DX® prostate testing at our institution from 2013 to 2016. Disease volume was characterized as the percent of positive cores, the number of cores with greater than 50% involvement, the largest involvement of any single core and prostate specific antigen density. Nonparametric testing was performed to compare the median Genomic Prostate Score™ and the likelihood of favorable pathology findings between quartiles of disease volume. RESULTS: We identified 112 (37.8%) and 184 men (62.2%) at NCCN very low and low risk, respectively. Median scores did not differ significantly between disease volume quartiles (all p >0.05). However, the median likelihood of favorable pathology findings statistically differed between volume quartiles (all <0.05). Seven of the 105 men (6.3%) with very low risk disease were reclassified at low risk and 13 of 181 (7.2%) with low risk disease were reclassified at intermediate risk. Genomic disease reclassification did not depend on biopsy tumor volume. CONCLUSIONS: In patients with NCCN very low and low risk prostate cancer genomic scores did not demonstrate meaningfully significant differences by volume based on clinically established cutoff points. Moreover, genomic scores identified and reclassified men with higher risk disease despite generally acceptable surveillance characteristics in this group according to grade and volume. This suggests that in patients at low risk the tumor biological potential measured by genomics rather than by volume should inform decisions on active surveillance candidacy.

Impact of 5α-Reductase Inhibitors on Disease Reclassification among Men on Active Surveillance for Localized Prostate Cancer with Favorable Features.

PURPOSE: We determined the effect of 5α-reductase inhibitors on disease reclassification in men with prostate cancer optimally selected for active surveillance. MATERIALS AND METHODS: In this retrospective review we identified 635 patients on active surveillance between 2002 and 2015. Patients with favorable cancer features on repeat biopsy, defined as absent Gleason upgrading, were included in the cohort. Patients were stratified by those who did or did not receive finasteride or dutasteride within 1 year of diagnosis. The primary end point was grade reclassification, defined as any increase in Gleason score or predominant Gleason pattern on subsequent biopsy. This was assessed by multivariable Cox proportional hazards regression analysis. RESULTS: At diagnosis 371 patients met study inclusion criteria, of whom 70 (19%) were started on 5α-reductase inhibitors within 12 months. Median time on active surveillance was 53 vs 35 months in men on vs not on 5α-reductase inhibitors (p <0.01). Men on 5α-reductase inhibitors received them for a median of 23 months (IQR 6-37). On actuarial analysis there was no significant difference in grade reclassification for 5α-reductase inhibitor use in patients overall or in the very low/low risk subset. The overall percent of patients who experienced grade reclassification was similar at 13% vs 14% (p = 0.75). After adjusting for baseline clinicopathological features 5α-reductase inhibitors were not significantly associated with grade reclassification (HR 0.80, 95% CI 0.31-1.80, p = 0.62). Furthermore, no difference in adverse features on radical prostatectomy specimens was observed in treated patients (p = 0.36). CONCLUSIONS: Among our cohort of men on active surveillance 5α-reductase inhibitor use was not associated with a significant difference in grade reclassification with time.

Effects of pathological upstaging or upgrading on metastasis and cancer-specific mortality in men with clinical low-risk prostate cancer.

OBJECTIVES: To determine if the presence of adverse pathological features in patients eligible for active surveillance (AS) are prognostic of poor oncological outcomes, independent of pretreatment risk. PATIENTS AND METHODS: A retrospective analysis was performed on patients who underwent radical prostatectomy (RP) at two institutions (Cleveland Clinic Foundation and Memorial Sloan Kettering Cancer Center) between 1987 and 2008, and who had subsequent follow-up. Rates of biochemical recurrence, metastasis and death from prostate cancer were compared amongst patients with adverse pathological features (Gleason score ≥7, ≥pT3, or lymph node invasion) based on D'Amico clinical risk (low vs intermediate/high). We also compared survival outcomes between patients with and without pathological upgrading/upstaging amongst D'Amico low-risk patients. Univariate and multivariable Cox regression models were used to assess the association between clinical risk, pathological reclassification, and oncological outcomes. RESULTS: We identified 16 341 patients who underwent RP, of whom 6 371 were clinically low-risk. Adverse outcomes in men with adverse pathological features were significantly lower in those with low clinical risk, with an ~50% and ~70% reduction in the risk of metastasis and death, respectively. Only pathological upgrading/upstaging to Gleason score ≥8, seminal vesicle invasion, and lymph node invasion from clinical low-risk disease, were associated with adverse outcomes. However, these types of reclassification were rare. CONCLUSION: Clinical low-risk patients with pathological upgrading/upstaging have substantially lower rates of important oncological outcomes compared to those with higher pretreatment risk and not substantially different than low-risk patients without pathological upgrading/upstaging. These results call into question the use of this endpoint to counsel patients about the merits and risks of AS.

Prognostic markers in clinical stage I seminoma and nonseminomatous germ cell tumours.

PURPOSE OF REVIEW: Testicular germ cell tumour (TGCT) is a common malignancy among young men. There is controversy regarding the best approach for patients with clinical stage I disease due to rates of relapse with active surveillance in contrast to overtreatment with adjuvant therapy. The aim of this review is to describe the role of prognostic factors in this setting. RECENT FINDINGS: Molecular prognostic factors have been described as a possible future aid to clinical and histologic features in the approach of patients with clinical stage I germ cell tumours. SUMMARY: Prognostic factors currently available are not accurate enough and may lead to overtreatment. However, though active surveillance has shown long-term survival near to 100% in the management of clinical stage I germ cell tumours, there is a significant percentage of patients with occult metastatic disease, who benefit from adjuvant therapy. In light of these data, future research is needed to better define high-risk patients for relapse, taking into account molecular markers recently reported.

Radical Prostatectomy, External Beam Radiotherapy, or External Beam Radiotherapy With Brachytherapy Boost and Disease Progression and Mortality in Patients With Gleason Score 9-10 Prostate Cancer.

Importance: The optimal treatment for Gleason score 9-10 prostate cancer is unknown. Objective: To compare clinical outcomes of patients with Gleason score 9-10 prostate cancer after definitive treatment. Design, Setting, and Participants: Retrospective cohort study in 12 tertiary centers (11 in the United States, 1 in Norway), with 1809 patients treated between 2000 and 2013. Exposures: Radical prostatectomy (RP), external beam radiotherapy (EBRT) with androgen deprivation therapy, or EBRT plus brachytherapy boost (EBRT+BT) with androgen deprivation therapy. Main Outcomes and Measures: The primary outcome was prostate cancer-specific mortality; distant metastasis-free survival and overall survival were secondary outcomes. Results: Of 1809 men, 639 underwent RP, 734 EBRT, and 436 EBRT+BT. Median ages were 61, 67.7, and 67.5 years; median follow-up was 4.2, 5.1, and 6.3 years, respectively. By 10 years, 91 RP, 186 EBRT, and 90 EBRT+BT patients had died. Adjusted 5-year prostate cancer-specific mortality rates were RP, 12% (95% CI, 8%-17%); EBRT, 13% (95% CI, 8%-19%); and EBRT+BT, 3% (95% CI, 1%-5%). EBRT+BT was associated with significantly lower prostate cancer-specific mortality than either RP or EBRT (cause-specific HRs of 0.38 [95% CI, 0.21-0.68] and 0.41 [95% CI, 0.24-0.71]). Adjusted 5-year incidence rates of distant metastasis were RP, 24% (95% CI, 19%-30%); EBRT, 24% (95% CI, 20%-28%); and EBRT+BT, 8% (95% CI, 5%-11%). EBRT+BT was associated with a significantly lower rate of distant metastasis (propensity-score-adjusted cause-specific HRs of 0.27 [95% CI, 0.17-0.43] for RP and 0.30 [95% CI, 0.19-0.47] for EBRT). Adjusted 7.5-year all-cause mortality rates were RP, 17% (95% CI, 11%-23%); EBRT, 18% (95% CI, 14%-24%); and EBRT+BT, 10% (95% CI, 7%-13%). Within the first 7.5 years of follow-up, EBRT+BT was associated with significantly lower all-cause mortality (cause-specific HRs of 0.66 [95% CI, 0.46-0.96] for RP and 0.61 [95% CI, 0.45-0.84] for EBRT). After the first 7.5 years, the corresponding HRs were 1.16 (95% CI, 0.70-1.92) and 0.87 (95% CI, 0.57-1.32). No significant differences in prostate cancer-specific mortality, distant metastasis, or all-cause mortality (≤7.5 and >7.5 years) were found between men treated with EBRT or RP (cause-specific HRs of 0.92 [95% CI, 0.67-1.26], 0.90 [95% CI, 0.70-1.14], 1.07 [95% CI, 0.80-1.44], and 1.34 [95% CI, 0.85-2.11]). Conclusions and Relevance: Among patients with Gleason score 9-10 prostate cancer, treatment with EBRT+BT with androgen deprivation therapy was associated with significantly better prostate cancer-specific mortality and longer time to distant metastasis compared with EBRT with androgen deprivation therapy or with RP.

Outcomes of Active Surveillance after Initial Surveillance Prostate Biopsy.

PURPOSE: We analyzed the rates of disease reclassification at initial and subsequent surveillance prostate biopsy as well as the treatment outcomes of deferred therapy among men on active surveillance for prostate cancer. MATERIALS AND METHODS: From a prospective database we identified 300 men on active surveillance who had undergone initial surveillance prostate biopsy, with or without confirmatory biopsy, within 1 year of diagnosis. Of these men 261 (87%) were classified as having NCCN very low or low risk disease at diagnosis. Disease reclassification on active surveillance was defined as the presence of 50% or more positive cores and/or surveillance prostate biopsy Gleason score upgrading. Patients with type I disease reclassification included those with any surveillance prostate biopsy Gleason score upgrading, while patients with type II reclassification had to have primary Gleason pattern 4-5 disease on surveillance prostate biopsy. Outcomes after initial surveillance prostate biopsy were evaluated using actuarial analyses. RESULTS: At the time of initial surveillance prostate biopsy 49 (16%) and 19 (6%) patients had type I and type II disease reclassification, respectively. Those who underwent confirmatory biopsy had significantly reduced rates of type I (9% vs 23%, p=0.001) and type II (3% vs 9%, p=0.01) reclassification at initial surveillance prostate biopsy. For the 251 patients without disease reclassification at initial surveillance prostate biopsy the 2-year rates of subsequent type I and II reclassification were 17% (95% CI 0-24) and 3% (95% CI 0.1-7), respectively. For the 93 patients who received deferred therapy the 5-year biochemical progression-free probability was 89% (95% CI 79-98), including 95%, 82% and 70% among those without, and those with type I and type II disease reclassification, respectively. CONCLUSIONS: Patients on active surveillance with stable disease at the time of initial surveillance prostate biopsy may be appropriate candidates for less intensive surveillance prostate biopsy schedules.

Do Renin-Angiotensin Blockers Affect Renal Function and Cardiac Outcomes in Patients Undergoing Partial Nephrectomy?

PURPOSE: Currently no data exist to guide renal surgeons on the perioperative use of renin-angiotensin blockers despite potential cardiorenal benefits. We aimed to assess the impact of resuming renin-angiotensin blockers on postoperative renal function and adverse cardiac events following partial nephrectomy. MATERIALS AND METHODS: This is an observational analysis of patients who underwent robot-assisted laparoscopic partial nephrectomy from 2006 to 2014 at a single institution. The Wilcoxon rank sum and chi-square tests, and logistic regression were used to assess the risk of adverse renal and cardiac events stratified by history and pattern of renin-angiotensin blockade perioperatively. RESULTS: We identified 900 patients with a median followup of 16.3 months (IQR 1.4-39.1). There were no significant differences in severe renal dysfunction at last followup on univariate analysis or adverse cardiac events at 30 days on multivariate analysis in patients stratified by a history of renin-angiotensin blockade. Of the 338 patients 137 (41.9%) resumed renin-angiotensin blockade immediately after surgery, which did not result in any significant difference in the postoperative glomerular filtration rate (p >0.05). Resuming renin-angiotensin blockade at discharge home was associated with a decreased risk of heart failure within 30 days of surgery (0.3% vs 11.8% of cases) and stage IV/V chronic kidney disease at last followup (2.6% vs 25.5%, each p <0.001). CONCLUSIONS: Renin-angiotensin blockers appear safe to continue immediately after renal surgery. Discharge home with angiotensin converting enzyme inhibitors/angiotensin receptor blockers was associated with a decreased risk of heart failure and severe renal dysfunction. However, this risk may be overstated as a result of the small number of patients discharged without resuming the home medication.