Publications by authors named "Andrew J Stephenson"

153 Publications

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

BJU Int 2020 Nov 5. Epub 2020 Nov 5.

Division of Urology, Department of Surgical Sciences, Torino School of Medicine, Torino, Italy.

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 (
Conclusions: In patients with cT2N0 BCa and no preoperative hydronephrosis, NAC increased the rate of pathological complete response and downstaging.
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http://dx.doi.org/10.1111/bju.15289DOI Listing
November 2020

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

BJU Int 2020 Sep 27. Epub 2020 Sep 27.

Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.

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.
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http://dx.doi.org/10.1111/bju.15253DOI Listing
September 2020

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

J Urol 2020 10 7;204(4):748-753. Epub 2020 Apr 7.

University of Texas M.D. Anderson Cancer Center, Houston, Texas.

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.
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http://dx.doi.org/10.1097/JU.0000000000001074DOI Listing
October 2020

Impact of sex on response to neoadjuvant chemotherapy in patients with bladder cancer.

Urol Oncol 2020 07 11;38(7):639.e1-639.e9. Epub 2020 Feb 11.

Department of Urology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria; Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX; Departments of Urology, Weill Cornell Medical College, New York, New York; Department of Urology, Second Faculty of Medicine, Charles University, Prague, Czech Republic; Institute for Urology and Reproductive Health, I.M. Sechenov First Moscow State Medical University, Moscow, Russia. Electronic address:

Objective: To assess the effect of patient's sex on response to neoadjuvant chemotherapy (NAC) in patients with clinically nonmetastatic muscle-invasive bladder cancer (MIBC).

Methods: Complete pathologic response, defined as ypT0N0 at radical cystectomy, and downstaging were evaluated using sex-adjusted univariable and multivariable logistic regression modeling. We used interaction terms to account for age of menopause and smoking status. The association of sex with overall survival and cancer-specific survival was evaluated using Cox regression analyses.

Results: A total of 1,031 patients were included in the analysis, 227 (22%) of whom were female. Female patients had a higher rate of extravesical disease extension (P = 0.01). After the administration of NAC, ypT stage was equally distributed between sexes (P = 0.39). On multivariable logistic regression analyses, there was no difference between the sexes or age of menopause with regards to ypT0N0 rates or downstaging (all P > 0.5). On Cox regression analyses, sex was associated with neither overall survival (hazard ratio 1.04, 95% confidence interval 0.75-1.45, P = 0.81) nor cancer-specific survival (hazard ratio 1.06, 95% confidence interval 0.71-1.58, P = 0.77).

Conclusion: Our study generates the hypothesis that NAC equalizes the preoperative disparity in pathologic stage between males and females suggesting a possible differential response between sexes. This might be the explanation underlying the comparable survival outcomes between sexes despite females presenting with more advanced tumor stage.
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http://dx.doi.org/10.1016/j.urolonc.2020.01.010DOI Listing
July 2020

Association of Baseline Prostate-Specific Antigen Level With Long-term Diagnosis of Clinically Significant Prostate Cancer Among Patients Aged 55 to 60 Years: A Secondary Analysis of a Cohort in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial.

JAMA Netw Open 2020 01 3;3(1):e1919284. Epub 2020 Jan 3.

Department of Surgery, Division of Urology, Rush Medical College, Chicago, Illinois.

Importance: The use of prostate-specific antigen (PSA) screening for prostate cancer is controversial because of the risk of overdiagnosis and overtreatment of indolent cancers. Optimal screening strategies are highly sought.

Objective: To estimate the long-term risk of any prostate cancer and clinically significant prostate cancer based on baseline PSA levels among men aged 55 to 60 years.

Design, Setting, And Participants: This secondary analysis of a cohort in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial uses actuarial analysis to analyze the association of baseline PSA levels with long-term risk of any prostate cancer and of clinically significant prostate cancer among men aged 55 to 60 years enrolled in the screening group of the trial between 1993 and 2001.

Exposure: Single PSA measurement at study entry.

Main Outcomes And Measures: Long-term risk of any prostate cancer and clinically significant prostate cancer diagnoses.

Results: There were 10 968 men aged 55 to 60 years (median [interquartile range] age, 57 [55-58] years) at study enrollment in the screening group of the PLCO Cancer Screening Trial who had long-term follow-up. Actuarial 13-year incidences of clinically significant prostate cancer diagnosis among participants with a baseline PSA of 0.49 ng/mL or less was 0.4% (95% CI, 0%-0.8%); 0.50-0.99 ng/mL, 1.5% (95% CI, 1.1%-1.9%); 1.00-1.99 ng/mL, 5.4% (95% CI, 4.4%-6.4%); 2.00-2.99 ng/mL, 10.6% (95% CI, 8.3%-12.9%); 3.00-3.99 ng/mL, 15.3% (95% CI, 11.4%-19.2%); and 4.00 ng/mL and greater, 29.5% (95% CI, 24.2%-34.8%) (all pairwise log-rank P ≤ .004). Only 15 prostate cancer-specific deaths occurred during 13 years of follow-up, and 9 (60.0%) were among men with a baseline PSA level of 2.00 ng/mL or higher.

Conclusions And Relevance: In this secondary analysis of a cohort from the PLCO Cancer Screening Trial, baseline PSA levels among men aged 55 to 60 years were associated with long-term risk of clinically significant prostate cancer. These findings suggest that repeated screening can be less frequent among men aged 55 to 60 years with a low baseline PSA level (ie, <2.00 ng/mL) and possibly discontinued among those with baseline PSA levels of less than 1.00 ng/mL.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.19284DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6991265PMC
January 2020

The prognostic value of the neutrophil-to-lymphocyte ratio in patients with muscle-invasive bladder cancer treated with neoadjuvant chemotherapy and radical cystectomy.

Urol Oncol 2020 01 31;38(1):3.e17-3.e27. Epub 2019 Oct 31.

Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada. Electronic address:

Introduction: The neutrophil-to-lymphocyte ratio (NLR) is an attractive marker because it is derived from routine bloodwork. NLR has shown promise as a prognostic factor in muscle invasive bladder cancer (MIBC) but its value in patients receiving neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) is not yet established. Since NLR is related to an oncogenic environment and poor antitumor host response, we hypothesized that a high NLR would be associated with a poor response to NAC and would remain a poor prognostic indicator in patients receiving NAC.

Methods: A retrospective analysis was performed on patients with nonmetastatic MIBC (cT2-4aN0M0) who received NAC prior to RC between 2000 and 2013 at 1 of 19 centers across Europe and North America. The pre-NAC NLR was used to split patients into a low (NLR ≤ 3) and high (NLR > 3) group. Demographic and clinical parameters were compared between the groups using Student's t test, chi-squared, or Fisher's exact test. Putative risk factors for disease-specific and overall survival were analyzed using Cox regression, while predictors of response to NAC (defined as absence of MIBC in RC specimen) were investigated using logistic regression.

Results: Data were available for 340 patients (199 NLR ≤ 3, 141 NLR > 3). Other than age and rate of lymphovascular invasion, demographic and pretreatment characteristics did not differ significantly. More patients in the NLR > 3 group had residual MIBC after NAC than the NLR ≤ 3 group (70.8% vs. 58.3%, P = 0.049). NLR was the only significant predictor of response (odds ratio: 0.36, P = 0.003) in logistic regression. NLR was a significant risk factor for both disease-specific (hazard ratio (HR): 2.4, P = 0.006) and overall survival (HR:1.8, P = 0.02).

Conclusion: NLR > 3 was associated with a decreased response to NAC and shorter disease-specific and overall survival. This suggests that NLR is a simple tool that can aid in MIBC risk stratification in clinical practice.
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http://dx.doi.org/10.1016/j.urolonc.2019.09.023DOI Listing
January 2020

The Role of Imaging in the Diagnosis, Staging, Response to Treatment, and Surveillance of Patients with Germ Cell Tumors of the Testis.

Urol Clin North Am 2019 Aug;46(3):315-331

Urology Department, Glickman Urologic and Kidney Institute, Cleveland Clinic, Glickman Tower, Q10. 9500 Euclid Avenue, Cleveland, OH 44108, USA; Center for Urologic Oncology, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address:

Germ cell tumors (GCTs) of the testis are cured with the successful integration of surgery, chemotherapy, and/or radiation therapy in most cases. The favorable results are a consequence of improved risk stratification, risk-adapted chemotherapy, reduced morbidity of treatment, and appropriate integration of multimodal therapy. The success of these approaches depends on accurate staging with imaging studies of the testis, retroperitoneum, and thorax. This article reviews the indications for imaging and performance characteristics of modalities in the diagnosis, staging, surveillance, and follow-up of patients with GCTs. We also highlight the current guideline recommendations for imaging in treatment of patients with GCTs.
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http://dx.doi.org/10.1016/j.ucl.2019.05.001DOI Listing
August 2019

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

Invest New Drugs 2019 12 24;37(6):1231-1238. Epub 2019 Jun 24.

Cleveland Clinic, Glickman Urological and Kidney Institute, 9500 Euclid Avenue/R35, Cleveland, OH, 44195, USA.

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.
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http://dx.doi.org/10.1007/s10637-018-00716-wDOI Listing
December 2019

Heterogeneity in Definitions of High-risk Prostate Cancer and Varying Impact on Mortality Rates after Radical Prostatectomy.

Eur Urol Oncol 2018 06 15;1(2):143-148. Epub 2018 May 15.

Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Dana Farber Cancer Institute, Boston, MA, USA.

Background: Multiple definitions of high-risk prostate cancer (PC) exist in clinical practice. Prior studies have primarily evaluated the variability in prediction of biochemical recurrence.

Objective: To examine the impact of different definitions on mortality after radical prostatectomy (RP).

Design, Setting, And Participants: Retrospective study of 6477 men with clinically localized disease undergoing RP at Barnes-Jewish Hospital (St. Louis, MO, USA) and Cleveland Clinic (Cleveland, OH, USA) between 1995 and 2007.

Outcome Measurements And Statistical Analysis: Seven pretreatment definitions of high-risk PC (prostate-specific antigen [PSA] ≥20ng/ml, biopsy Gleason score 8-10, clinical stage ≥T2c, cT3, D'Amico definition, National Comprehensive Cancer Network definition, Kattan nomogram) were evaluated. The Kaplan-Meier method was used to generate unadjusted survival estimates. Multivariable Cox proportional hazard regression models (controlling for age) were used to estimate the hazard ratio (HR) for PC-specific mortality (PCSM) and overall mortality (OM) in the high-risk group compared to men with lower risk not meeting that definition.

Results And Limitations: 6477 men were treated with RP from 1995 to 2007 and were followed for a median of 67 mo. Depending on the definition, patients with high-risk PC comprised between 0.7% (when using cT3 as the criterion) and 8.2% (when using the D'Amico criterion) of the population. The 10-yr PC survival estimates varied from 89.7% (PSA ≥20ng/ml) to 69.7% (cT3) and overall survival ranged from 83.4% to 58.1%. On multivariable analysis, all high-risk definitions were associated with a higher risk of PCSM compared to lower risk (HR ranging from 4.38 for PSA ≥20ng/ml to 19.97 for cT3; all p<0.001). All definitions of high risk except for preoperative PSA ≥20ng/ml were associated with a higher risk of OM (HR 1.72 for D'Amico to 3.31 for cT3; all p<0.01).

Conclusions: Heterogeneity in outcomes existed, depending on the pretreatment definition of high-risk PC. Clinical stage T3 and Gleason score 8-10 were most strongly associated with PCSM and OM.

Patient Summary: There is variability in prostate cancer outcomes after surgery, depending on the definition of pretreatment high-risk disease used. Clinical stage T3 and high Gleason score were most strongly associated with prostate cancer-specific mortality and overall mortality.
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http://dx.doi.org/10.1016/j.euo.2018.02.004DOI Listing
June 2018

Optimizing the Timing of Salvage Postprostatectomy Radiotherapy and the Use of Concurrent Hormonal Therapy for Prostate Cancer.

Eur Urol Oncol 2018 05 15;1(1):3-18. Epub 2018 May 15.

Department of Radiotherapy, Centre Léon Bérard, Lyon, France.

Context: Currently, salvage radiotherapy (SRT) is the only known curative intervention for men with recurrent disease following prostatectomy. Critical issues in the optimal selection and management of men being considered for SRT include the threshold prostate-specific antigen (PSA) value at which to initiate treatment (ie, pre-SRT PSA) and the role of concurrent hormonal therapy (HT).

Objective: To review the published evidence pertaining to the optimal timing for SRT and the role of concurrent HT.

Evidence Acquisition: MEDLINE (via PubMed), EMBASE, the Cochrane Central Register of Controlled Trials, and guideline statements from professional organizations were queried from January 1, 2000 through January 10, 2018.

Evidence Synthesis: Thirty-three independent reports, including two randomized trials evaluating HT with SRT, were identified. Retrospective data suggest that SRT initiation at lower pre-SRT PSA levels is associated with better clinical outcomes. Prospective data suggest an overall survival benefit with concurrent HT that manifests during long-term follow-up, with the caveat that hypothesis-generating subgroup analyses suggest that this benefit may be limited to patients with higher pre-SRT PSA levels. Patients with adverse risk factors, such as Gleason grade group 4-5 disease, are likely to benefit the most from earlier SRT initiation and/or the use of HT.

Conclusions: Given the limitations of the available data, it is imperative that physicians participate in shared decision-making, with the recommendation tailored for each man's desire to maximize oncologic benefit (with a risk of overtreatment) versus potential quality-of-life optimization (with a risk of undertreatment). Within that framework, a significant body of retrospective data supports initiation of SRT at low pre-SRT PSA values, without an arbitrary absolute threshold. Prospective data suggest a benefit of HT, but this benefit may be greatest in patients with a pre-SRT PSA that is higher than the typical level in most patients receiving "early" SRT. Further research is necessary before absolute recommendations can be made.

Patient Summary: Two ways to potentially improve outcomes following salvage radiotherapy for prostate cancer that recurs after prostatectomy are to start treatment at a lower prostate-specific antigen level and to use concurrent hormonal therapy. Our review suggests that the available evidence is imperfect, but highlights that both measures are likely to improve clinical outcomes in general, but perhaps not uniformly and/or consistently for all patients. Physician-patient shared decision-making and further research are critical.
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http://dx.doi.org/10.1016/j.euo.2018.02.008DOI Listing
May 2018

Older Age at Diagnosis and Initial Disease Volume Predict Grade Reclassification Risk on Confirmatory Biopsy in Patients Considered for Active Surveillance.

Urology 2019 08 7;130:106-112. Epub 2019 May 7.

Lerner College of Medicine, Cleveland Clinic, Cleveland, OH; Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH. Electronic address:

Objective: To identify which active surveillance candidates benefit most from confirmatory biopsies to exclude grade underclassification.

Materials And Methods: This observational study includes 556 men diagnosed between 2002 and 2015 with Gleason 3 + 3 (GG1) disease on initial diagnostic biopsy, of whom 406 received a confirmatory biopsy within 12 months for active surveillance. Multivariable logistic regression analysis was performed to determine clinicopathologic features associated with Gleason 7 or higher (GG2+) on a confirmatory biopsy. Regression tree analysis was employed to stratify patients into select risk groups.

Results: Eighty-five of 406 patients (20.9%) with initially GG1 disease were reclassified to GG2+ on a confirmatory biopsy. On multivariable analysis, increasing age (per year odds ratio 1.07; 95% confidence interval 1.02-1.12; P <.01) and more positive cores at diagnosis (per core, odds ratio 1.37, 95% confidence interval 1.09-1.72; P <.01) were significantly associated with reclassification, independent of prostate volume, clinical stage, initial PSA, or confirmatory biopsy type (including magnetic resonance imaging-targeted approaches or transrectal saturation random sampling). Recursive partitioning demonstrated that age over 73 and 5 or more positive cores were factors associated with the greatest reclassification risk.

Conclusion: In our cohort, both advancing age and additional positive cores were associated with increased odds of reclassification to GG2+ on confirmatory biopsy. In men over age 73 or with 5 or more positive cores, a repeat biopsy within 12 months may be particularly beneficial to minimize tumor grade underclassification.
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http://dx.doi.org/10.1016/j.urology.2019.02.050DOI Listing
August 2019

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

Invest New Drugs 2019 06 30;37(3):559-566. Epub 2019 Apr 30.

Department of Solid Tumor Oncology and Urology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA.

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 .
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http://dx.doi.org/10.1007/s10637-019-00778-4DOI Listing
June 2019

Assessing the relationship between statin use and oncologic outcomes among men electing active surveillance for localized prostate cancer.

Prostate Cancer Prostatic Dis 2019 12 17;22(4):617-623. Epub 2019 Apr 17.

Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA.

Background: This study aims to assess the effect of statin therapy on outcomes among men managed with active surveillance.

Methods: This is a retrospective cohort study evaluating 635 men managed with active surveillance from 2005 to 2015 at a large, academic medical center. The primary endpoints of analyses are disease reclassification (i.e., change in volume or grade of cancer on subsequent biopsies after diagnosis), progression to definitive therapy with curative intent (i.e., surgery or radiotherapy), and surveillance failure-defined as the development of either biochemical failure after definitive therapy, metastases, or prostate cancer-specific mortality-among statin and non-statin users. Secondary analyses were performed to assess the effect of statin use on outcomes among men who progressed to definitive treatment.

Results: Three hundred fifty-six (56.1%) patients in the cohort were on statin therapy at the initiation of surveillance. The median age was 66.7 and 63.3 years among statin and non-statin users, respectively. On univariate analysis, there were no differences in the rates of disease reclassification, progression to definitive treatment, and surveillance failure between the statin and non-statin users in the cohort (all p > 0.05). There was no difference in the rate of biochemical failure among men who progressed to definitive therapy when stratified by statin use (p = 0.89). Pathologic data were available for 105 men who progressed to radical prostatectomy while on surveillance at our institution. Duration of statin use (months) was inversely correlated with adverse pathology for radical prostatectomy on both univariate (OR: 0.99; 95% CI 0.98, 0.99; p = 0.03) and multivariate analysis (OR: 0.98; 95% CI 0.97, 0.99; p = 0.02).

Conclusion: Statin use was not associated with any clinical benefit with regard to disease reclassification, progression to definitive treatment, or surveillance failure among men selecting active surveillance at our institution. There was a 2% decrease in the odds of adverse pathology for each month of statin use among the men who progressed to radical prostatectomy while on active surveillance, but it is unclear at this time if this association has any durable impact on surveillance outcomes among men with favorable risk prostate cancer.
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http://dx.doi.org/10.1038/s41391-019-0147-0DOI Listing
December 2019

Prostate-only Versus Whole-pelvis Radiation with or Without a Brachytherapy Boost for Gleason Grade Group 5 Prostate Cancer: A Retrospective Analysis.

Eur Urol 2020 01 13;77(1):3-10. Epub 2019 Apr 13.

Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address:

Background: The role of elective whole-pelvis radiotherapy (WPRT) remains controversial. Few studies have investigated it in Gleason grade group (GG) 5 prostate cancer (PCa), known to have a high risk of nodal metastases.

Objective: To assess the impact of WPRT on patients with GG 5 PCa treated with external-beam radiotherapy (EBRT) or EBRT with a brachytherapy boost (EBRT+BT).

Design, Setting, And Participants: We identified 1170 patients with biopsy-proven GG 5 PCa from 11 centers in the United States and one in Norway treated between 2000 and 2013 (734 with EBRT and 436 with EBRT+BT).

Outcome Measurements And Statistical Analysis: Biochemical recurrence-free survival (bRFS), distant metastasis-free survival (DMFS), and prostate cancer-specific survival (PCSS) were compared using Cox proportional hazards models with propensity score adjustment.

Results And Limitations: A total of 299 EBRT patients (41%) and 320 EBRT+BT patients (73%) received WPRT. The adjusted 5-yr bRFS rates with WPRT in the EBRT and EBRT+BT groups were 66% and 88%, respectively. Without WPRT, these rates for the EBRT and EBRT+BT groups were 58% and 78%, respectively. The median follow-up was 5.6yr. WPRT was associated with improved bRFS among patients treated with EBRT+BT (hazard ratio [HR] 0.5, 95% confidence interval [CI] 0.2-0.9, p=0.02), but no evidence for improvement was found in those treated with EBRT (HR 0.8, 95% CI 0.6-1.2, p=0.4). WPRT was not significantly associated with improved DMFS or PCSS in the EBRT group (HR 1.1, 95% CI 0.7-1.7, p=0.8 for DMFS and HR 0.7, 95% CI 0.4-1.1, p=0.1 for PCSS), or in the EBRT+BT group (HR 0.6, 95% CI 0.3-1.4, p=0.2 for DMFS and HR 0.5 95% CI 0.2-1.2, p=0.1 for PCSS).

Conclusions: WPRT was not associated with improved PCSS or DMFS in patients with GG 5 PCa who received either EBRT or EBRT+BT. However, WPRT was associated with a significant improvement in bRFS among patients receiving EBRT+BT. Strategies to optimize WPRT, potentially with the use of advanced imaging techniques to identify occult nodal disease, are warranted.

Patient Summary: When men with a high Gleason grade prostate cancer receive radiation with external radiation and brachytherapy, the addition of radiation to the pelvis results in a longer duration of prostate-specific antigen control. However, we did not find a difference in their survival from prostate cancer or in their survival without metastatic disease. We also did not find a benefit for radiation to the pelvis in men who received radiation without brachytherapy.
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http://dx.doi.org/10.1016/j.eururo.2019.03.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521828PMC
January 2020

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

J Urol 2019 06;201(6):1115-1120

Cleveland Diagnostics, Inc. , Cleveland , Ohio.

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.
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http://dx.doi.org/10.1097/JU.0000000000000185DOI Listing
June 2019

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

BJU Int 2019 08 10;124(2):282-289. Epub 2019 Feb 10.

University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.

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.
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http://dx.doi.org/10.1111/bju.14671DOI Listing
August 2019

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

Cancer 2019 02 13;125(3):391-397. Epub 2018 Nov 13.

Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

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.
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http://dx.doi.org/10.1002/cncr.31833DOI Listing
February 2019

Transcriptomic and Protein Analysis of Small-cell Bladder Cancer (SCBC) Identifies Prognostic Biomarkers and DLL3 as a Relevant Therapeutic Target.

Clin Cancer Res 2019 01 16;25(1):210-221. Epub 2018 Oct 16.

Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, Ohio.

Purpose: Transcriptomic profiling can shed light on the biology of small-cell bladder cancer (SCBC), nominating biomarkers, and novel therapeutic targets.

Experimental Design: Sixty-three patients with SCBC had small-cell histology confirmed and quantified by a genitourinary pathologist. Gene expression profiling was performed for 39 primary tumor samples, 1 metastatic sample, and 6 adjacent normal urothelium samples (46 total) from the same cohort. Protein levels of differentially expressed therapeutic targets, DLL3 and PDL1, and also CD56 and ASCL1, were confirmed by IHC. A SCBC PDX model was utilized to assess efficacy of DLL3-targeting antibody-drug conjugate (ADC).

Results: Unsupervised hierarchical clustering of 46 samples produced 4 clusters that correlated with clinical phenotypes. Patients whose tumors had the most "normal-like" pattern of gene expression had longer overall survival (OS) compared with the other 3 clusters while patients with the most "metastasis-like" pattern had the shortest OS ( = 0.047). Expression of DLL3, PDL1, ASCL1, and CD56 was confirmed by IHC in 68%, 30%, 52%, and 81% of tissue samples, respectively. In a multivariate analysis, DLL3 protein expression on >10% and CD56 expression on >30% of tumor cells were both prognostic of shorter OS ( = 0.03 each). A DLL3-targeting ADC showed durable antitumor efficacy in a SCBC PDX model.

Conclusions: Gene expression patterns in SCBC are associated with distinct clinical phenotypes ranging from more indolent to aggressive disease. Overexpression of mRNA and protein is common in SCBC and correlates with shorter OS. A DLL3-targeted ADC demonstrated efficacy superior to chemotherapy in a PDX model of SCBC.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333466PMC
January 2019

Impact of Neoadjuvant Chemotherapy on Pathologic Response in Patients With Upper Tract Urothelial Carcinoma Undergoing Extirpative Surgery.

Clin Genitourin Cancer 2018 12 22;16(6):e1237-e1242. Epub 2018 Aug 22.

Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH; University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA (current). Electronic address:

Background: Neoadjuvant chemotherapy (NAC) has been increasingly adopted in the management of high-grade upper tract urothelial carcinoma (UTUC), largely extrapolating from level I evidence in urothelial carcinoma of the bladder. Studies examining pathologic outcomes in patients with UTUC receiving NAC are mostly limited to retrospective, single-center studies with limited sample size, with results of a phase II trial recently presented. Hypothesizing that NAC is associated with improved pathologic response (PR), we compared pathologic outcomes in patients with high-grade UTUC who did and did not receive NAC before extirpative surgery.

Patients And Methods: A total of 6174 patients with nonmetastatic, high-grade UTUC who underwent extirpative surgery from 2006 to 2014 were identified from the National Cancer Database. Patients were stratified by NAC status. PR was defined as pathologic stage less than clinical stage. Univariate and multivariable logistic regression analysis was employed to identify predictors of PR.

Results: Two hundred sixty (4.2%) patients received NAC. A higher incidence of PR was observed in patients receiving NAC (25.2% vs. 1.8%; P < .001), with complete PR observed in 6.1% of patients receiving NAC and 0.4% of patients undergoing surgery alone. NAC (odds ratio [OR], 19.8; 95% confidence interval [CI], 11.8-33.5), nonwhite race (OR, 3.2; 95% CI, 1.7-6.3), and ureteral tumor location (OR, 1.6; 95% CI, 1.02-2.6) were independently associated with PR.

Conclusions: Examining a large national cancer registry, we observed a higher incidence of PR in patients with UTUC receiving NAC, validating findings of prior studies. Our findings support consideration of NAC in high grade UTUC. Prospective trials will better define the impact of NAC on pathologic and survival outcomes.
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http://dx.doi.org/10.1016/j.clgc.2018.08.003DOI Listing
December 2018

Testing of a Tool for Prostate Cancer Screening Discussions in Primary Care.

Front Oncol 2018 28;8:238. Epub 2018 Jun 28.

Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, United States.

Background: As prostate cancer (PCa) screening decisions often occur in outpatient primary care, a brief tool to help the PCa screening conversation in busy clinic settings is needed.

Methods: A previously created 9-item tool to aid PCa screening discussions was tested in five diverse primary care clinics. Fifteen providers were recruited to use the tool for 4 weeks, and the tool was revised based upon feedback. The providers then used the tool with a convenience sample of patients during routine clinic visits. Pre- and post-visit surveys were administered to assess patients' knowledge of the option to be screened for PCa and of specific factors to consider in the decision. McNemar's and Stuart-Maxwell tests were used to compare pre-and post-survey responses.

Results: 14 of 15 providers completed feedback surveys and had positive responses to the tool. All 15 providers then tested the tool on 95 men aged 40-69 at the five clinics with 2-10 patients each. The proportion of patients who strongly agreed that they had the option to choose to screen for PCa increased from 57 to 72% ( = 0.018) from the pre- to post-survey, that there are factors in the personal or family history that may affect PCa risk from 34 to 47% ( = 0.012), and that their opinions about possible side effects of treatment for PCa should be considered in the decision from 47 to 61% ( = 0.009).

Conclusion: A brief conversation tool for the PCa screening discussion was well received in busy primary-care settings and improved patients' knowledge about the screening decision.
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http://dx.doi.org/10.3389/fonc.2018.00238DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6031706PMC
June 2018

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

Curr Opin Urol 2018 09;28(5):448-453

Cleveland Clinic Glickman Urological and Kidney Institute, Cleveland, Ohio, USA.

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.
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http://dx.doi.org/10.1097/MOU.0000000000000525DOI Listing
September 2018

Clinical Outcomes for Patients With Gleason Score 10 Prostate Adenocarcinoma: Results From a Multi-institutional Consortium Study.

Int J Radiat Oncol Biol Phys 2018 07 5;101(4):883-888. Epub 2018 Apr 5.

Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, California. Electronic address:

Purpose: Gleason score (GS) 10 disease is the most aggressive form of clinically localized prostate adenocarcinoma (PCa). The long-term clinical outcomes and overall prognosis of patients presenting with GS 10 PCa are largely unknown because of its rarity.

Methods And Materials: The study included 112 patients with biopsy-determined GS 10 PCa who received treatment with radical prostatectomy (RP, n = 26), external beam radiation therapy (EBRT, n = 48), or EBRT with a brachytherapy boost (EBRT-BT, n = 38) between 2000 and 2013. Propensity scores were included as covariates for comparative analysis. Overall survival, prostate cancer-specific survival, and distant metastasis-free survival (DMFS) were estimated by the Kaplan-Meier method with inverse probability of treatment weighting to control for confounding.

Results: The median follow-up period was 4.9 years overall (3.9 years for RP, 4.8 years for EBRT, and 5.7 years for EBRT-BT). Significantly more EBRT patients than EBRT-BT patients received upfront androgen deprivation therapy (98% vs 79%, P < .01 by χ test), though the durations were similar (median, 24 months vs 22.5 months). Of the RP patients, 34% received postoperative EBRT, and 35% received neoadjuvant systemic therapy. The propensity score-adjusted 5-year overall survival rate was 80% for the RP group, 73% for the EBRT group, and 83% for the EBRT-BT group. The corresponding adjusted 5-year prostate cancer-specific survival rates were 87%, 75%, and 94%, respectively. The EBRT-BT group trended toward superior DMFS when compared with the RP group (hazard ratio, 0.3; 95% confidence interval 0.1-1.06; P = .06) and had superior DMFS when compared with the EBRT group (hazard ratio, 0.4; 95% confidence interval 0.1-0.99; P = .048).

Conclusions: To our knowledge, this is the largest series ever reported on the clinical outcomes of patients with biopsy-determined GS 10 PCa. These data provide useful prognostic benchmark information for physicians and patients. Aggressive therapy with curative intent is warranted, as >50% of patients remain free of systemic disease 5 years after treatment.
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http://dx.doi.org/10.1016/j.ijrobp.2018.03.060DOI Listing
July 2018

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

BJU Int 2018 12 22;122(6):1003-1009. Epub 2018 Jun 22.

Glickman Urological and Kidney Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.

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.
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http://dx.doi.org/10.1111/bju.14418DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737926PMC
December 2018

Feasibility of Cisplatin-Based Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer Patients With Diminished Renal Function.

Clin Genitourin Cancer 2018 08 22;16(4):e879-e892. Epub 2018 Feb 22.

Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH. Electronic address:

Background: Cisplatin-based neoadjuvant chemotherapy (NAC) before radical cystectomy is the standard of care in muscle-invasive bladder cancer. There are limited data regarding chemotherapy tolerability and outcomes for patients with low glomerular filtration rate (GFR) who receive cisplatin-based NAC.

Patients And Methods: A retrospective analysis of patients who received cisplatin-based NAC at Cleveland Clinic (2005-2016) was undertaken. Patients with pre-NAC GFR < 60 mL/min by either Cockcroft-Gault (CG) or Modification of Diet in Renal Disease (MDRD) formula were compared to patients with GFR ≥ 60 mL/min for NAC tolerability, pathologic complete and partial response (pPR), and the ability to undergo radical cystectomy.

Results: Thirty patients with low GFR (34-59 mL/min) and 94 patients with normal GFR (≥ 60 mL/min) were identified. Low GFR patients were older (median, 71 vs. 65 years), but other demographic and transurethral resection of bladder tumor characteristics were comparable. Low GFR patients more frequently had early NAC discontinuation (30% vs. 13%), NAC modifications (delays, dose reduction, or discontinuation, 66% vs. 40%), and cisplatin-based NAC administered in split doses (37% vs. 16%). No differences in NAC tolerability or outcomes were noted among low GFR patients receiving split-dose versus standard regimens. No differences were noted between low and normal GFR patients in NAC cycles (median, 3 for each), cystectomy rates (93% for each), time to cystectomy, and GFR change from baseline to after NAC. Pathologic complete response was higher among normal GFR patients (24% vs. 14%).

Conclusion: Patients with low GFR had more NAC discontinuations and modifications, but most completed planned NAC cycles. For carefully selected patients with GFR < 60 mL/min, cisplatin-based NAC remains a treatment option.
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http://dx.doi.org/10.1016/j.clgc.2018.02.002DOI Listing
August 2018

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.

JAMA 2018 03;319(9):896-905

Department of Radiation Oncology, University of California, Los Angeles.

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.
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http://dx.doi.org/10.1001/jama.2018.0587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885899PMC
March 2018

Comparison Between Adjuvant and Early-Salvage Postprostatectomy Radiotherapy for Prostate Cancer With Adverse Pathological Features.

JAMA Oncol 2018 05 10;4(5):e175230. Epub 2018 May 10.

Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.

Importance: Prostate cancer with adverse pathological features (ie, pT3 and/or positive margins) after prostatectomy may be managed with adjuvant radiotherapy (ART) or surveillance followed by early-salvage radiotherapy (ESRT) for biochemical recurrence. The optimal timing of postoperative radiotherapy is unclear.

Objective: To compare the clinical outcomes of postoperative ART and ESRT administered to patients with prostate cancer with adverse pathological features.

Design, Setting, And Participants: This multi-institutional, propensity score-matched cohort study involved 1566 consecutive patients who underwent postprostatectomy ART or ESRT at 10 US academic medical centers between January 1, 1987, and December 31, 2013. Propensity score 1-to-1 matching was used to account for covariates potentially associated with treatment selection. Data were collected from January 1 to September 30, 2016. Data analysis was conducted from October 1, 2016, to October 21, 2017.

Main Outcomes And Measures: Freedom from postirradiation biochemical failure, freedom from distant metastases, and overall survival. All outcomes were measured from date of surgery to address lead-time bias.

Results: Of 1566 patients, 1195 with prostate-specific antigen levels of 0.1 to 0.5 ng/mL received ESRT and 371 patients with prostate-specific antigen levels lower than 0.1 ng/mL received ART. The median age (interquartile range) was 60 (55-65) years. After propensity score matching, the median (interquartile range) follow-up after surgery was similar between the ESRT and ART groups (73.3 [44.9-106.6] months vs 65.8 [40-107] months; P = .22). Adjuvant RT, compared with ESRT, was associated with higher freedom from biochemical failure (12-year actuarial rates: 69% [95% CI, 60%-76%] vs 43% [95% CI, 35%-51%]; effect size, 26%), freedom from distant metastases (95% [95% CI, 90%-97%] vs 85% [95% CI, 76%-90%]; effect size, 10%), and overall survival (91% [95% CI, 84%-95%] vs 79% [95% CI, 69%-86%]; effect size, 12%). Adjuvant RT, lower Gleason score and T stage, nodal irradiation, and postoperative androgen deprivation therapy were favorable prognostic features on multivariate analysis for biochemical failure. Sensitivity analysis demonstrated that the decreased risk of biochemical failure associated with ART remained significant unless more than 56% of patients in the ART group were cured by surgery alone. This threshold is greater than the estimated 12-year freedom from biochemical failure rate of 33% to 52% after radical prostatectomy alone, as determined by a contemporary dynamic nomogram.

Conclusions And Relevance: Adjuvant RT, compared with ESRT, was associated with reduced biochemical recurrence, distant metastases, and death for high-risk patients, pending prospective validation. These findings suggest that a greater proportion of patients with prostate cancer who have adverse pathological features may benefit from postprostatectomy ART rather than surveillance followed by ESRT.
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http://dx.doi.org/10.1001/jamaoncol.2017.5230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885162PMC
May 2018

Seminal vesicle schwannoma presenting as rectal pain: successful robotic-assisted excision.

Transl Androl Urol 2017 Dec;6(6):1184-1186

Department of Urology, Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA.

Schwannomas, not uncommon in the head and neck, rarely occur in the pelvis. Here we describe a seminal vesicle schwannoma, the first of its kind successfully excised via robotic surgery. An otherwise well 62 year-old male presented with a complaint of rectal pain. Colonoscopy identified a mass effect on the rectum, suggesting an external lesion. A computed tomography scan revealed a right seminal vesicle mass. Transrectal ultrasound guided biopsy returned a tissue diagnosis of schwannoma. To aid in operative planning, magnetic resonance imaging of the prostate and pelvis was obtained with and without contrast. This defined a 5 × 4 × 4 cm mass abutting the right seminal vesicle without evidence of invasion into adjacent structures. The patient underwent an elective robotic-assisted laparoscopic resection of the mass. Final pathology demonstrated a completely excised schwannoma arising from the soft tissue adherent to the right seminal vesicle.
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http://dx.doi.org/10.21037/tau.2017.10.03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5760379PMC
December 2017

Reducing Overutilization of Preoperative Medical Referrals Among Patients Undergoing Radical Cystectomy Using an Evidence-based Algorithm.

Urology 2018 Apr 2;114:71-76. Epub 2018 Jan 2.

Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH. Electronic address:

Objective: To evaluate the frequency with which preoperative medical evaluations lead to changes in perioperative management of patients undergoing radical cystectomy and to examine the impact of an evidence-based algorithm on referral utilization.

Materials And Methods: A retrospective review of 176 patients undergoing radical cystectomy in 2013-2014 was conducted. Patients referred for additional preoperative medical or cardiology evaluation were identified and the incidence of diagnostic testing or management changes resulting from such evaluations were determined. The impact of an evidence-based algorithm on referral utilization and identification of patients undergoing changes in perioperative management was examined.

Results: Of 176 patients, 111 underwent additional preoperative medical evaluation, with 2.7% undergoing additional diagnostic testing and 8.1% experiencing resultant changes in medical management. Perioperative management changes were minor in scope, with the majority (65%) involving management of hypertension or hypokalemia. Perioperative outcomes were similar between patients undergoing urologic evaluation alone and patients referred for additional preoperative medical evaluation. Applying a referral algorithm incorporating the American College of Cardiology guidelines would have avoided 72% of all medical referrals and reduced direct hospital costs of preoperative evaluations by 74%, while still capturing 94% of all patients who underwent perioperative management changes and all patients with diagnostic findings necessitating surgical delay.

Conclusion: Preoperative medical evaluation of patients undergoing radical cystectomy infrequently yields perioperative management changes. The algorithm presented would significantly reduce overutilization and direct hospital costs while capturing patients most likely to benefit from additional medical evaluation.
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http://dx.doi.org/10.1016/j.urology.2017.12.012DOI Listing
April 2018

Multi-institutional Evaluation of Elective Nodal Irradiation and/or Androgen Deprivation Therapy with Postprostatectomy Salvage Radiotherapy for Prostate Cancer.

Eur Urol 2018 07 9;74(1):99-106. Epub 2017 Nov 9.

Cleveland Clinic, Cleveland, OH, USA.

Background: Outcomes with postprostatectomy salvage radiation therapy (SRT) are not ideal. Little evidence exists regarding potential benefits of adding whole pelvic radiation therapy (WPRT) alone or in combination with androgen deprivation therapy (ADT).

Objective: To explore whether WPRT and/or ADT added to prostate bed radiation therapy (PBRT) improves freedom from biochemical failure (FFBF) or distant metastases (DM).

Design, Setting, And Participants: A database was compiled from 10 academic institutions of patients with postprostatectomy prostate-specific antigen (PSA) >0.01 ng/ml; pT1-4, Nx/0, cM0; and Gleason score (GS) ≥7 treated between 1987 and 2013. Median follow-up was 51 mo.

Interventions: WPRT and/or ADT in addition to PBRT.

Outcome Measurements And Statistical Analyses: FFBF and DM were calculated using cumulative incidence estimation. Multivariable analysis (MVA) utilized cumulative incidence regression.

Results And Limitation: Median pre-SRT PSA was 0.5 ng/ml for 1861 patients. Median follow-up for patients not experiencing biochemical failure (BF) was 55 mo. MVA showed increased BF for PBRT versus WPRT (hazard ratio [HR] 1.82, p<0.001) and no ADT versus ADT (HR 1.70, p<0.001). WPRT was associated with a 5-yr FFBF of 62% versus 49% (p<0.001) for PBRT. ADT use was associated with improved 5-yr FFBF (55% vs 50%, p=0.012). No significant differences in DM cumulative incidence were found.

Conclusions: For patients with GS ≥7 receiving SRT, clinicians should weigh FFBF benefits of WPRT and ADT against toxicities. Future studies should explore the impact of WPRT on quality of life, clinical progression, and overall survival.

Patient Summary: We evaluated patients with prostate cancer treated with radiation after surgery to remove the prostate. Both radiation to the pelvic lymph nodes and suppression of testosterone lowered the chance of increasing prostate-specific antigen (a marker for cancer returning).
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http://dx.doi.org/10.1016/j.eururo.2017.10.009DOI Listing
July 2018

Epidural Abscess Following Prostate Biopsy.

Urology 2018 Mar 6;113:1-5. Epub 2017 Nov 6.

Department of Urology, Glickman Urologic and Kidney Institute, Cleveland Clinic, Cleveland, OH; Lerner College of Medicine, Education Institute, Cleveland Clinic, Cleveland, OH.

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http://dx.doi.org/10.1016/j.urology.2017.10.024DOI Listing
March 2018