Igor Frank

High grade neuroendocrine carcinoma of the urinary bladder treated by radical cystectomy: a series of small cell, mixed neuroendocrine and large cell neuroendocrine carcinoma

Summary High grade neuroendocrine carcinomas (HGNEC) treated by cystectomy often carry an original diagnosis of typical urothelial carcinoma (UC). The correct diagnosis of HGNEC is critical in influencing the decision for early chemotherapy, potentially followed by cystectomy. The objective of this study was to characterise the features of HGNEC treated by radical cystectomy. The study consisted of 79 patients with HGNEC including small cell (68 patients), large cell neuroendocrine (LCNEC) (5 patients) and mixed neuroendocrine (mixed-NEC) carcinoma (6 patients) matched with 122 patients with UC, treated at our institution between 1987 and 2014. Morphometric analysis for cell and nuclear size as well as immunophenotyping for neuroendocrine markers and cell-cycle regulators were applied to tissue microarrays. Small cell, LCNEC and mixed-NEC are a morphological spectrum of high grade neuroendocrine carcinoma with overlapping histological features, identical immunophenotype, Ki-67 proliferative rate and patient outcomes. Finally, the nuclear size criteria is misleading as HGNEC, particularly cases of LCNEC and mixed-NEC, may have enlarged nuclei compared to small cell carcinomas and are more prone to be misdiagnosed as UC, thereby preventing appropriate management.

MP77-17 IMPACT OF TIME FROM BIOPSY TO SURGERY ON COMPLICATIONS, FUNCTIONAL AND ONCOLOGIC OUTCOMES FOLLOWING RADICAL PROSTATECTOMY

on AS must undergo PSA testing and repeated biopsies over time in all proposed protocols and patients are subjected to discomfort and anxiety as well as to the complications of repeated biopsies. We tried to identify the predictors of progression-free survival (PFS) at a single institution AS program in order to identify patients in whom repeated biopsies could be avoided or reduced in frequency. METHODS: Between 2009 and 2016, 235 consecutive patients affected by low-risk PCa according to PRIAS criteria (cT1/T2a; PSA<10 ng/ml; PSA density <0.2; Gleason score <7; <3 positive cores) were enrolled in our AS program. Tumor progression was defined as pathological upgrading (Gleason >6 or >2 positive cores) at repeated yearly biopsies. First, Kaplan-Meier analyses were used to quantify progression-free survival at 1, 3 and 5 years, respectively. Second, we identified patients who were progression-free at 3 years of follow-up. Finally, univariable and multivariable logistic regression analyses were used to predict 3-year PFS. Covariates consisted of age, total PSA, clinical stage (cT) and number of positive cores at the time of enrolment as well as negative (no cancer) 1-year biopsy. RESULTS: Progression-free survival rate was 85%, 55%, and 40% at 1, 3 and 5 years, respectively. Median follow-up was 19 months. Overall, 56 (23.8%) patients were progression-free at 3 years of followup. Median number of cores at enrolment in AS program was 16 (IQR: 14-20), while median number of cores at first-year biopsy was 18 (IQR: 14-20). At univariable analyses, total PSA and negative 1-year biopsy were significant predictors of 3-year PFS (all p<0.05). Patients with negative biopsy at 1 year had a 3-year PFS of 75.8 vs. 29.0% in those with positive biopsy at 1-year. These results were confirmed at multivariable analyses, where a negative 1-year biopsy represented the only independent predictor of 3-year PFS (OR: 2.47; p1⁄40.04). CONCLUSIONS: The first biopsy after enrolment in AS program is an important predictor of PCa progression in the first 3 years in men on AS. Negative findings at 1-year biopsy suggest a high chance of 3-year PFS. Patients with negative 1-year biopsy could be followedup with less stringent biopsy protocol, in order to reduce possible biopsy-related side effects and discomfort.

PD67-10 INCIDENCE AND RISK FACTORS FOR PERITONEAL CARCINOMATOSIS FOLLOWING OPEN RADICAL CYSTECTOMY

lymph node dissection, and number of lymph nodes removed. Perioperative outcomes measured included length of stay (LOS), 30-day and 90-day postoperative mortality rates, as well as 30-day readmission following surgery. To minimize selection bias, observed differences in baseline characteristics between patients who received RARC vs. ORC were controlled for using a weighted propensity score analysis. Using weighted data, all endpoints were assessed using propensity-adjusted logistic regression analyses. RESULTS: Of 9,561 patients who underwent RC, 2,048 (21.4%) and 7,513 (78.6%) underwent RARC and ORC, respectively. The use of RARC has increased over time, from 16.7% in 2010 to 25.3% in 2013. With regard to oncologic outcomes, RARC was associated with similar positive surgical margins (9.4% vs. 10.7% OR:0.86, 95%CI 0.72-1.04, p1⁄40.12), higher rates of lymphadenectomy (96.4% vs. 92.0%, OR: 2.31, 95%CI 1.68-3.19, p<0.001), higher median lymph node count (17 vs. 12, p<0.001) and higher rates of lymph node count above the median (56.8% vs. 40.4%, OR: 1.95, 95%CI 1.56-2.43, p<0.001). With regard to postoperative outcomes, receipt of RARC was associated with a shorter median LOS (7 vs. 8, p<0.001), lower rates of pLOS (45.1% vs. 54.8%, OR: 0.68, 95%CI 0.58-0.79, p<0.001), lower 30-day (1.5% vs. 2.8%, OR: 0.49, 95%CI 0.29-0.82, p1⁄40.007) and 90day postoperative mortality (5.0% vs. 6.8%, OR: 0.72, 95%CI 0.54-0.95, p1⁄40.023). CONCLUSIONS: Our large contemporary study shows the increased adoption of RARC between 2010 and 2013, with currently more than 1 out of 4 patients undergoing RARC. RARC was associated with higher LN counts, shorter LOS and lower postoperative mortality.

MP53-16 LONG-TERM ONCOLOGIC OUTCOMES OF ADDING RADICAL PROSTATECTOMY TO CASTRATION FOR PATHOLOGICAL NODE-POSITIVE PROSTATE CANCER

any urinary leak) after RP and post IMRT was achieved in 29 (69%) and 27 (64.3%), respectively. After a median follow up of 3.4 years, a PSA recurrence and clinical recurrence were observed in 7 (16.7%) and 4 (9.5%) patients. A 5-year biochemical and clinical recurrencefree survival rate were 70.7% and 84.0%, respectively. 5-year overall free survival was 93.6%. None of patients died for prostate cancer during follow up. CONCLUSIONS: This phase II trial test a novel multimodal treatment paradigm for high-risk prostate cancer. Toxicity was acceptably low and long term oncological outcomes were good. Further studies are needed to compare this novel treatment paradigm to the standard of care.

MP78-19 SURGICAL MANAGEMENT OF UROTHELIAL CARCINOMA IN PATIENTS WITH UPPER TRACT AND LOWER TRACT UROTHELIAL CARCINOMA: IMPACT OF SURGICAL SEQUENCE

RESULTS: The 26 (5.3%) patients who developed UUT-SPTs requiring surgical treatment after RC had predominantly invasive cancers (Ta 1⁄4 23.1%, Tis 1⁄4 11.5%, T1 1⁄4 26.9%, T2 1⁄4 19.2%, T31⁄4 15.4%, T4 1⁄4 3.9%) which were also predominantly high grade (G31⁄4 88.5%, G2 1⁄4 7.7 %, G1 1⁄4 3.8). The mean time from RC to the development of SPT was 33.8 months. In a linear regression analysis that controlled for age, bladder pathologic tumor stage was significantly associated with decreased time to SPT (p1⁄4 0.030). Neoadjuvant CBT was given to 11.5 % of bladder UC patients prior to RC and 19.2% received adjuvant CBT after RC . Mean eGFR decreased from 69.3 prior to RC to 55.7 prior to UUT-SPT surgical treatment. UUT-SPTs were managed with nephroureterectomy (92.3%) or ureterectomy (7.7%), and ipsilateral lymphadenectomy (77%). Neoadjuvant CBT prior to UUT surgery was administered to 15.4% of patients. Mean eGFR further decreased after UUT-SPT surgery to 39.5, and 23.1% of patients received adjuvant CBT following UUT surgery. Patient were followed for a mean of 76.1 months and 38.5% of patients died of disease, 29.9% died of unknown/other causes, and 34.6% are alive with no evidence of disease. CONCLUSIONS: UUT-SPTs manifest as more advanced disease after RC. Decreased renal function occurs frequently post RC and may impair the use of peri-operative CBT for patients with high grade SPTs of the UUT. This warrants further studies to develop novel nonnephrotoxic targeted therapies in the peri-operative setting of surgery for SPTs.

MP34-03 ONCOLOGIC OUTCOMES FOR PATIENTS WITH RESIDUAL CANCER AT CYSTECTOMY FOLLOWING PREOPERATIVE CHEMOTHERAPY: A PATHOLOGIC STAGE-MATCHED COMPARATIVE ANALYSIS

INTRODUCTION AND OBJECTIVES: While neoadjuvant chemotherapy prior to radical cystectomy (RC) has been demonstrated to improve survival compared to RC alone for urothelial carcinoma of the bladder (UCB), the bulk of this survival benefit has been attributed to patients who achieve ypT0 status at RC. The implications of having residual UCB (rUCB) at RC after preoperative chemotherapy (POC) are less clear. As such, we evaluated survival for patients with and without rUCB at RC after POC compared with pathologic stage-matched RC patients who did not receive POC. METHODS: Patients undergoing RC for UCB between 19802010 at Mayo Clinic were identified. All RC pathology was re-reviewed by a single genitourinary pathologist. Patients who received POC for T2-T4 and/or N1-3 M0 UCB were matched 1:2 to patients not exposed to prior chemotherapy based on pT and pN-stage, soft tissue surgical margin status, and year of RC. Kaplan Meier and Cox regression analyses were used to evaluate the associations between POC and cancer-specific (CSS) and overall survival (OS), stratified by presence or absence of rUCB at RC. RESULTS: We matched 111 patients who underwent POC + RC to 222 RC-alone patients. Median age was 68 yrs (IQR 60,74); 59 (18%) were female. Median follow-up was 7.2 yrs (IQR 6,16), during which time a total of 248 patients died, with 148 dying from UCB. In patients without rUCB at RC, there was no difference in 5-yr CSS (86% vs. 90%, p1⁄40.85) or OS (82% vs. 84%, p1⁄40.46) between patients who did versus did not receive POC. Moreover, on multivariable analysis, chemotherapy exposure was not significantly associated with CSS (HR1⁄41.0; 95%CI 0.3-3.1; p1⁄40.9) or OS (HR1⁄40.9; 95%CI 0.4-1.9; p1⁄40.8) in this subgroup. Conversely, among patients with rUCB at RC, receipt of POC was associated with significantly worse 5-yr CSS (32% vs. 56%, p<0.001) and OS (25% vs. 48%, p<0.001). Moreover, on multivariable analysis, chemotherapy exposure remained independently associated with adverse CSS (HR1⁄42.2; 95%CI 1.6-3.1; p<0.001) and OS (HR1⁄42.0; 95%CI 1.5-2.7; p<0.001) among the patients with rUCB. CONCLUSIONS: While patients who achieve a complete response to POC have excellent survival outcomes, patients with residual UCB at RC after POC have a worse prognosis compared to stage-matched RC patients not exposed to chemotherapy. Such patients should be considered for enrollment in novel adjuvant therapy trials, while continued investigation of which patients are most likely to achieve ypT0 status remains warranted.

MP93-16 IMPACT OF OBESITY ON PROSTATE CANCER RECURRENCE AFTER RADICAL PROSTATECTOMY

INTRODUCTION AND OBJECTIVES: When operating deep in the abdomen and pelvis, excess fat can interfere with accessing key anatomical structures and create difficulty in dissection and reconstruction. Since intraperitoneal fat is avoided during extraperitoneal robot assisted radical prostatectomy (eRARP), some Urologists have advocated this approach over its transperitoneal counterpart (tRARP) when operating on morbidly obese men (BMI>40). Herein, we aim to compare outcomes of eRARP vs. tRARP in the morbidly obese. METHODS: A chart review of patients who have undergone robot assisted radical prostatectomy (RARP) at a tertiary care academic center from July 1, 2003 through April 30, 2016 was undertaken. Patients with BMI >40 were identified. Those with concomitant inguinal hernia repair were excluded. The resulting eRARP and tRARP groups were compared for demographic, clinical and pathologic characteristics. Regression analysis was performed between the groups with Age, BMI, ASA score and D’Amico classification as selected covariates. RESULTS: 3168 patients underwent RARP during this time period, of which 82 patients met our inclusion and exclusion criteria; each group comprised 41 patients. No differences were noted in age, BMI, ASA score or pre-operative PSA. The tRARP group had a higher clinical stage (p1⁄40.016), biopsy Gleason score (p1⁄40.007) and D’Amico risk category (p<0.00001). The tRARP group had a higher rate of pelvic lymph node dissection (PLND, p<0.00001). No differences were noted in rate of nerve sparing. No differences were noted in OR time, estimated blood loss (EBL), length of stay (LOS) or time to catheter removal (TCR). No differences were noted in surgical margin status or overall complications (either calculated as binary or total number). On regression analysis, no differences were noted in complications, OR time, LOS, TCR or EBL. CONCLUSIONS: In this cohort, surgical approach (eRARP vs. tRARP) did not affect intraor peri-operative outcomes in morbidly obese men undergoing RARP so surgeons should tailor their approach based on comfort level.

MP72-01 PREDICTING RENAL CELL CARCINOMA PROGRESSION AFTER SURGERY

INTRODUCTION AND OBJECTIVES: Multiple algorithms exist for the prediction of progression after surgical treatment of localized renal cell carcinoma (RCC); however, most are limited to clear cell (ccRCC) only, and have not been updated with contemporary pathologic assessment. We therefore sought to develop predictive models for progression in ccRCC, papillary RCC (papRCC), and chromophobe RCC (chrRCC). METHODS: Binephric patients treated with radical or partial nephrectomy for sporadic, unilateral M0 ccRCC, papRCC, or chrRCC between 1980 and 2010 were identified. All patients had their pathology slides re-reviewed by one pathologist, blinded to patient outcome. Associations with time to progression (defined as local recurrence, distant metastasis, or death from RCC) were evaluated with multivariable Cox proportional hazards regression with stepwise selection using a 500sample bootstrap resampling approach. RESULTS: In total, 3,549 patients were identified: 2,726 (76.8%) with ccRCC, 601 (16.9%) with papRCC, and 222 (6.3%) with chrRCC. For patients with ccRCC, median follow-up was 9.9 years during which time 862 progressed. Features independently associated with ccRCC progression were constitutional symptoms, grade, coagulative necrosis, sarcomatoid differentiation, tumor size, fat invasion, tumor thrombus level, extension beyond Gerota’s fascia, and pN classification. The c-index of this model was 0.83. For papRCC patients, median follow-up was 10.3 years during which time 66 had progressed. Features associated with papRCC progression were grade, fat invasion, and tumor thrombus level, resulting in a c-index of 0.77. For chrRCC patients, median follow-up was 9.1 years during which time 35 had progressed. Features associated with progression included sarcomatoid differentiation, fat invasion, and pN classification, resulting in a c-index of 0.77. Predicted 10-year progression-free survivals for patients without any risk factors were 96%, 96%, and 91% for ccRCC, papRCC, and chrRCC, respectively. CONCLUSIONS: Using routine clinical and pathologic data, we generated 3 histology-specific predictive models for progression after surgical management of RCC. These models have excellent discrimination and may prove important in patient counseling and follow-up planning after surgical intervention. Source of Funding: None

MP20-01 VALIDATION OF THE AMERICAN JOIN COMMITTEE ON CANCER (AJCC) 8TH EDITION PROSTATE CANCER STAGING SYSTEM

INTRODUCTION AND OBJECTIVES: In the recently published 8 edition update of the AJCC staging system for prostate cancer (PCa), pT2a/b/c sub-classifications were consolidated as pT2. Also, serum prostate-specific antigen (PSA) 20ng/ml or Grade Group (GG) 5 now classify patients as Stage III disease. We sought to validate these changes in a large institutional registry with long-term follow-up. METHODS: Men who underwent radical prostatectomy without prior therapy at Mayo Clinic between 1987-2011 were identified. The prognostic significance of a single pT2 designation was compared to previous stratification as unilateral (pT2a-b) versus bilateral (pT2c). Further, 7 edition Stage II patients were then re-categorized based on the presence or absence of PSA 20ng/ml and GG 5. Biochemical recurrence-free (BCR) survival, systemic progression-free survival (sPFS), and cancer-specific survival (CSS) were evaluated using Kaplan Meier analyses and multivariable Cox regression models, adjusting for age, Gleason score, preoperative PSA, and surgical margin status. RESULTS: The overall cohort included 17,846 men with a median follow-up of 11 years (IQR 7,16), during which time 5021 experienced BCR, 1246 progressed systemically, and 641 died from PCa. Among pT2 patients, sub-stratification was not independently associated with BCR-free survival (HR1⁄41.0; 95%CI 0.9-1.1; p1⁄40.69), sPFS (HR1⁄41.0; 95%CI 0.8-1.3; p1⁄40.68), or CSS (HR1⁄40.9; 95%CI 0.61.2; p1⁄40.41). Meanwhile, patients previously classified with Stage II disease who had a preoperative PSA 20ng/ml (now Stage III) had a 15-year CSS that was significantly worse than Stage group II patients with PSA < 20ng/ml (88% vs 94%; p<0.001), but similar to 7 edition Stage III patients (88% vs 86%; p1⁄40.12). On the other hand, Stage II patients now classified as Stage III based on GG 5 had a 15 year CSS that was significantly worse than both 7 edition Stage II patients with GG 1-4 (48% vs 68%; p<0.001) and 7 edition Stage III patients (48% vs 60%; p<0.001). Results for BCR-free survival and sPFS were similar. CONCLUSIONS: We validate the new AJCC pT2 staging classification. Moreover, our data support the designation of patients with a PSA 20ng/ml as Stage III disease. Interestingly, while upstaging GG5 patients from Stage II to III is an improvement, these patients have even worse outcomes than 7 edition Stage III patients, emphasizing the particular prognostic significance of the new GG and the importance of including GG in staging classification.

PD31-01 SURVEILLANCE STRATEGIES IN BLADDER CANCER FOLLOWING RADICAL CYSTECTOMY: A SYSTEMATIC REVIEW AND META-ANALYSIS

INTRODUCTION AND OBJECTIVES: Thereisnoclearguidance on the surveillance of muscle invasive bladder cancer (MIBC) following radical cystectomy (RC) and the effect of surveillance onmortality is debatable. We conducted a systematic review to evaluate the characteristics of availablesurveillanceprotocolsanddeterminetheeffectonmortalitywith the detection of asymptomatic versus symptomatic recurrences. METHODS: An electronic search of PubMed, Medline, Embase and Cochrane Library databases was performed from 1970-2013. Three reviewers independently assessed the 1288 candidate studies for eligibility and abstracted data based on criteria priori established protocol. Outcomes were pooled using random effects meta-analysis. RESULTS: We included 7 retrospective studies with overall good quality. Four studies developed stage stratified surveillance protocols based on stage and recurrence location patterns. All protocols ended surveillance at 5 years and recommended imaging frequencies and techniques that only slightly differed. The detection of asymptomatic recurrences reduced mortality by 22% (RR 0.78, CI 0.58,1.04); this effect was statistically significant only when upper and lower urinary tract recurrences were included in analysis (Figure 1). CONCLUSIONS: Available surveillance protocols for MIBC following RC show several common components. There may be a reduction in mortality with asymptomatic detection that provides a rationale for surveillance.