Citations

74 Background: Nearly all men that experience recurrence of prostate cancer after radical prostatectomy are placed on salvage androgen deprivation therapy (sADT) in an attempt to control the disease. Yet, little is known regarding the efficacy of the treatment, the therapeutic duration or the predictors of treatment failure. Therefore, we examined our experience with sADT after radical prostatectomy in a cohort of patients with no evidence of systemic disease. Methods: We identified 1,373 patients that were treated with sADT after radical prostatectomy prior to the development of systemic disease. Clinical and pathologic variables predicting systemic progression and cancer death were evaluated using the Kaplan-Meier method and compared using the log rank test. Multivariate Cox proportional hazard regression models were used to analyze the impact of these variables on disease progression and survival. Results: Patients were treated with sADT at a median of 4.2 years after surgery. The median PSA at initiation of sADT was 1.6 ng/mL. The majority (1,234, 90%) of patients had a calculable PSA doubling time prior to the initiation of sADT. 275 patients (20.0%) experienced systemic progression at a median of 3.1 years after the start of sADT. 175 patients (12.7%) died of prostate cancer at a median of 4.7 years after the start of sADT. Factors that predicted disease progression after sADT on multivariate analysis included either neoadjuvant or adjuvant ADT (HR - 2.0, p<0.0001), increasing pathologic Gleason Score (HR - 1.18, p=0.009), increasing pathologic stage (HR - 1.3, p<0.0001), PSA at start of sADT (HR - 1.3, p<0.0001) and PSA doubling time (1.65, p<0.0001). Conclusions: Most men treated with sADT after radical prostatectomy prior to the development of systemic progression experience a lengthy disease-free interval. Multivariate predictors of treatment failure include prior adjuvant or neoadjuvant ADT, pathologic Gleason Score, pathologic stage, PSA level at initiation of sADT and PSA doubling time before sADT. No significant financial relationships to disclose.

44 Background: We investigated the association of germline genetic variation in hormone biosynthesis and metabolism genes with prostate cancer specific mortality in a cohort of advanced prostate cancer patients. Methods: We successfully genotyped 852 single nucleotide polymorphisms (SNPs) from 97 genes in a cohort of 267 advanced prostate cancer patients at the time of progression to castration recurrence (CRPC) during on-going androgen ablation. Tagging SNPs with minor allele frequency (MAF) of >5% and r2 ≥0.8 were selected from HapMap, NIEHS and Seattle SNP databases. Medical records were queried for cause of death. The primary endpoint of time to prostate cancer specific mortality (PCSM), was pre-defined as time from development of CRPC to death from prostate cancer progression. Principle components analysis was used for gene-levels tests, and to account for multiple testing, we calculated the false discovery rate (FDR). For SNP level results, hazard ratios (HR) and 95% confidence intervals (CI) were estimated using cox regression. Results: The median age of the cohort was 72 years at CRPC. 43% had a Gleason score (GS)=8-10, 33% a GS=7, and 24% a GS<7. After a median follow-up of 1.8 years (IQ range: 0.8–3.3 years), 139 patients died, of which 107 were due to prostate cancer progression. In unadjusted gene level analyses, UGT1A7 (p=0.0059; FDR=0.19), UGT1A10 (p=0.0017; FDR=0.17) and UGT1A3 (p=0.0037; FDR=0.18) were associated with PCSM. After adjusting for age and GS, SNPs strongly associated with PCSM are listed in the Table . Conclusions: Variation in UGT genes involved in hormone metabolism yield prognostic information in CRPC. Further validation is needed to develop these as prognostic biomarkers. [Table: see text] No significant financial relationships to disclose.

354 Background: Partial nephrectomy (PN) has demonstrated equivalent cancer control to radical nephrectomy (RN) and has been associated with lower rates of all-cause mortality. Nevertheless, there continues to be wide variability in practice pattern in the treatment of renal masses. Specifically, the decision to perform PN or RN often depends on patient, surgeon and renal mass characteristics. By quantifying the renal tumor using the R.E.N.A.L. nephrometry scoring system, collecting surgeon information, and providing defined clinical scenarios we attempt to evaluate factors important in surgeon decision-making. Methods: In June 2009, all members of the American Urological Association with a listed email address were invited to participate in a survey evaluating the management of renal masses. Respondents were asked their preferred treatment for 8 clinical scenarios. Each of these renal masses was given a nephrometry score (NS). The propensity to offer PN was evaluated by NS and surgical volume. High volume was defined as > 50 renal cases per year and low volume was defined as £ 10 cases per year. Results: 764 attending level urologic surgeons responded to each of the 8 scenarios providing 6112 evaluable clinical scenarios. NS ranged from 4-10; each unit increase was associated with 2-fold increased odds of a surgeon offering radical nephrectomy (OR 1.99, 95% CI: 1.93,2.06). PN was the preferred treatment for approximately 95% of patients with low complexity tumors (NS < 8) regardless of surgical volume. However, proposed treatment of high complexity tumors (NS ³ 8) demonstrated considerable heterogeneity in treatment choice. Controlling for all patient characteristics, high surgical volume significantly predicted whether PN would be offered to patients with high complexity tumors (OR 3.04 95% CI: 2.34,9.95), but not those with low complexity tumors (OR 1.95 95% CI: 0.87,4.38) compared to low volume surgeons. Conclusions: Increasing NS correlated with increased use of radical nephrectomy, particularly after a score of 8 among all surgeons. As renal surgical volume increased, surgeons were more willing to offer PN in high complexity tumors. No significant financial relationships to disclose.

348 Background: While the initial natural history after surgical resection for localized renal cell carcinoma (RCC) has been well-characterized, recurrence patterns for patients who experience late recurrence of disease continue to be defined. Here, we evaluated the clinical characteristics and survival of patients who experienced disease recurrence > 5 years following nephrectomy. Methods: We identified 1,454 patients who were treated with radical nephrectomy (RN) or nephron-sparing surgery (NSS) for unilateral, sporadic pT1-4NxM0 RCC between 1970-2000 and who had remained free of disease for 5 years after surgery. Late (> 5 years) recurrence was then recorded and was classified as renal (ipsilateral/contralateral kidney) recurrence and distant (all other sites) recurrence. The incidence of late recurrence was estimated using the Kaplan Meier method, and clinicopathological variables subsequent disease relapse were analyzed using Cox proportional hazard regression models. Results: Median follow-up after nephrectomy in the cohort here was 13.9 years (range 5.1-38.9). In total, 63 patients experience a late recurrence in the ipsilateral/contralateral kidney, at a median of 9.3 years (range 5.1-25.3) after surgery. 172 (11.8%) patients developed late distant metastases, at a median of 9.6 years (range: 5.1-26.6). Estimated recurrence-free survival at 10 and 15 years following nephrectomy was 97.3% and 95.2% for renal recurrence and 93.1% and 85.9% for distant recurrence, respectively. Increased tumor size (HR 1.1; p<0.001) was associated with a higher rate of late renal recurrence, while increased tumor size (HR 1.1; p=0.018), clear cell or collecting duct histology (HR 3.7; p<0.001), and tumor stage pT1b (HR 2.8; p<0.001), pT2a (HR 4.5; p<0.001), pT2b (HR 3.4; p=0.007), and pT3/4 (HR 5.1; p<0.001) were predictive of the development of late distant metastasis. Conclusions: Patients undergoing surgery for localized RCC remain at life-long risk of disease recurrence. Approximately 5% experience renal recurrence and 15% demonstrate distant relapse, during the ensuing 10 years. Continued investigation to identify potential site-specific predictors of late recurrence is necessary to guide postoperative surveillance regimens. No significant financial relationships to disclose.

324 Background: The indications for the removal of the ipsilateral adrenal gland in patients with renal cell cancer (RCC) have not been well defined. Most continue to advocate ipsilateral adrenalectomy in patients with risky features such as a tumor thrombus, large, locally advanced tumors, and/or upper pole tumors. We evaluated the oncologic outcomes of concurrent adrenalectomy with either partial (PN) or radical nephrectomy (RN) in a large single institution cohort. Methods: From 1970–2006, 4,019 consecutive patients with RCC treated by RN (n=3,107) or PN (n=912) from Mayo Clinic were studied for adrenal involvement. Risk of asynchronous adrenal metastasis and cancer specific survival (CS) were also compared between those who underwent concomitant adrenalectomy (n=1,464) and those who did not (n=2,555) using multivariate cox models. Results: Median postoperative follow-up was 6 years. Synchronous ipsilateral adrenal involvement was rare even for those with large (>7cm) tumors (2.5%), upper pole (1.3%), and locally advanced (pT3/4) tumors (3.5%). The development of asynchronous adrenal metastasis occurred in 109 patients (2.7%) at a median of 3.7 years after initial surgery. The risk of developing an ipsilateral (1.4% 95% CI 0.8, 2.0) vs. contralateral (1.8% 95% CI 1.0, 2.6) asynchronous adrenal metastasis was equivalent at 10 years, in those who did not undergo adrenalectomy at initial surgery. At 10 years, 7.3% (99% CI: 4.4, 10.2) of patients with higher stage tumors (pT3/4) are predicted to develop a contralateral adrenal metastasis. On multivariate analysis, routine adrenalectomy was associated with a decreased risk of subsequent adrenal metastasis (HR 0.88: 99% CI 0.81, 0.95), but did not significantly impact CS (HR 1.15: 99% CI 0.99, 1.34). Conclusions: Asynchronous metastasis can usually be salvaged without apparent effect on CS. Ipsilateral adrenal involvement from RCC was uncommon even in large, locally advanced, and/or upper pole tumors. Routine adrenalectomy in these high risk patients may lead to an unacceptably high rate of adrenal insufficiency when a significant subset develops a contralateral adrenal metastasis. No significant financial relationships to disclose.

321 Background: Factors that determine renal function after partial nephrectomy (PN) are not well defined, including the impact of cold vs. warm ischemia and the relative importance of modifiable and non-modifiable factors. We studied these determinants in a large cohort of patients with a solitary functioning kidney undergoing PN. Methods: In 1980–2009, 660 PN were performed at 4 centers for tumor in a solitary-functioning kidney under cold (n=300) or warm (n=360) ischemia. Data were collected in IRB-approved registries; follow- up averaged 4.5 years. Pre- and postoperative glomerular filtration rates (GFR) were estimated via CKD-EPI equation. Results: At 3 months after PN, median GFR decreased by equivalent amounts with cold or warm ischemia (21% vs. 22%, respectively, p=0.7) although median cold ischemic times were much longer (45 vs. 22 min. respectively, p<0.001). In multivariable analyses, increasing age, larger tumor size, lower preoperative GFR, and longer ischemia time were associated with decreased postoperative GFR (p<0.05). When percentage of parenchyma spared was incorporated into the analysis, this factor and preoperative GFR proved to be the primary determinants of ultimate renal function, and duration of ischemia lost statistical significance. Conclusions: This non-randomized comparative study suggests that long-term renal function after PN is determined primarily by the quantity and quality of renal parenchyma that can be preserved. Within the relatively strict parameters of conventional practice, i.e. predominantly short ischemic intervals and liberal use of hypothermia, ischemia time was not an independent predictor of ultimate renal function after PN. Nevertheless, type and duration of ischemia remain the most important modifiable factors during PN, and mandate further study. [Table: see text]

290 Background: Previous studies have shown robot assisted radical cystectomy (RARC) to have equivalent perioperative outcomes to open radical cystectomy. There are few reports that have examined the oncologic results of RARC specifically with respect to node-positive patients. We report the outcomes of node-positive patients who have undergone RARC with medium-term (at least 1 year) follow-up. Methods: A total of 275 patients underwent RARC at two institutions for invasive bladder cancer between 2005-present. We examined the 50 patients with node-positive disease that had a minimum of one year follow-up. Oncologic outcomes, recurrence free survival (RFS), and disease specific survival (DSS) were analyzed and compared to the open literature. Results: Mean clinical follow up in this case series was 29 months (range 12–64 months). The mean number of lymph nodes removed was 18 (range 5–35), and mean number of positive LNs was 3.1 (range 1–12). Overall rate of LN positivity was 26%. Mean LN density was 18%. Seventeen (34%) patients had ≤ pT2 disease and 33 (66%) pT3/T4 disease. At this follow-up, 29 patients have recurred, 21 patients died of disease, giving a RFS and DSS of 42% and 58%, respectively. Mean (median) time to recurrence was 10.2 months (9 months). A total of 60% of patients received peri-operative chemotherapy in this cohort. These findings are consistent with prior reports of such oncologic outcomes in node-positive patients in open series. Conclusions: The oncologic follow-up of patients undergoing RARC with LN positive disease appears to have acceptable outcomes during medium term (mean 29 months) follow-up. As our follow-up increases, we expect to continue to accurately define the long-term clinical suitability and oncologic success of this procedure in this high-risk population. No significant financial relationships to disclose.

288 Background: We report our experience with robot assisted radical cystectomy (RARC) with regard to medium-term (at least 2 year) oncologic outcomes. Methods: A total of 275 patients have undergone RARC and urinary diversion at two institutions for invasive bladder cancer between 2005-present. We performed a retrospective analysis of the 139 patients who underwent RARC with a minimum of 2 years follow-up. Medium term oncologic outcomes including recurrence rates, time to recurrence, recurrence free survival (RFS), disease specific survival (DSS) were analyzed. Follow-up was measured from time of surgery to time of most recent clinical follow-up. Results: This cohort of patients consisted of 108 men (78%) and 31 women (22%) at a mean age of 67.3 years (range 45-86 years). Sixty-one (44%) patients had ≤ pT2 disease, 38 (27%) pT3/T4 disease, and 40 (29%) N+ disease. The mean number of lymph nodes removed was 18 (range 3-41). The average clinical follow up in this case series was nearly 3 years with a mean of 35.9 months (range 24-64 months). At this follow-up, 39 patients have recurred, 27 patients died of disease, and 5 patients died of other causes giving an overall RFS, DSS, and OS rates of 80%, 71%, and 68%, respectively. The mean (median) time to recurrence was 12.3 months (10 months). These findings are consistent with prior reports of the oncologic outcomes for open radical cystectomy. Conclusions: The oncologic follow-up of patients undergoing RARC appears to be favorable with acceptable outcomes in the medium-term (mean – 3 years). As our follow-up increases, we should expect to truly define the long-term clinical appropriateness and oncologic success of this procedure. No significant financial relationships to disclose.

277 Background: For patients (pts) with LRR or advanced primary tumors of the UB or ureter, limited therapeutic options exist. Outcomes of combined SR and IOERT are reported here. Methods: From 1983 to 2009, a total of 17 pts with urothelial (16 pts) or squamous cell carcinoma (1 pt) of the UB (n=13) or ureter (n=4) were treated with SR and IOERT. Pts had LRR after radical cystoprostatectomy or nephroureterectomy (n=15) or advanced primary tumor (n=2). Extent of SR was R0 (microscopic negative margins), R1 (microscopic positive margins), and R2 (gross residual tumor) in 7, 1, and 9 pts, respectively. After maximal SR, IOERT was delivered to the tumor bed. Median IOERT dose and energy delivered were 12.5 Gy (range; 10-20) and 9 MeV (range; 6-18), respectively, with 1 (n=15), 2 (n=1), or 3 (n=1) IOERT fields. Sixteen pts also received perioperative external beam radiotherapy (EBRT) with a median dose of 50.4 Gy (range; 21.6- 60). Five pts received concurrent chemotherapy (CT) with perioperative EBRT. Overall (OS), disease-free survival (DFS) and relapse patterns were estimated from the date of SR and IOERT using the Kaplan-Meier method. Results: The median pt age was 63 years (yrs) (range; 51-76). The median follow-up of surviving pts was 3.6 yrs (range; 1.1-10.0). OS and DFS at 1, 2, and 5 yrs were 53%, 31%, and 16%, and 24%, 18%, and 18%, respectively. Central (within the IOERT field), locoregional (tumor bed or first echelon draining lymphatics), and distant relapse at 2 yrs were 15%, 49%, and 67%, respectively. Seven pts received systemic CT after relapse. Mortality within 30 days of SR and IOERT was 0%. Two pts (12%) experienced grade 4-5 (NCI-CTCAE v. 4) toxicity potentially related to the multimodality therapy. Conclusions: For pts with LRR or advanced primary tumor of the UB or ureter, this multimodality therapy including SR and IOERT resulted in durable OS and DFS in a small but significant number of pts. Both LRR and distant relapse were common, indicating a need for more effective systemic therapy along with more refined locoregional therapy. No significant financial relationships to disclose.

259 Background: Vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) are produced by bladder cancer cell lines in vitro and expressed in human tumor tissues. Preclinical studies have also shown that bladder cancer cell lines express VEGF receptor 1 and 2 on their surface membrane. Pazopanib is a vascular endothelial receptor tyrosine kinase inhibitor with anti-angiogenesis and antitumor activity in several preclinical models. A two-stage phase II study was conducted to assess the activity and toxicity profile of pazopanib administered to patients with metastatic, urothelial carcinoma. Methods: Patients with one prior systemic therapy for recurrent, metastatic urothelial carcinoma were eligible. Patients received pazopanib at a dose of 800 mg orally daily for 4 week cycle. Results: Nineteen patients were enrolled. Median age was 66 years, with > 89% of patients presenting poorly differentiated bladder cancer. Adverse event data is available on 18 patients. No grade 4 or 5 events have been experienced. Nine patients have experienced 11 grade 3 adverse events of which 7 were deemed at least possibly related to treatment. Most common toxicities were anemia, thrombocytopenia, leucopenia and fatigue. For stage 1, none of the first 16 evaluable patients were deemed success (CR or PR) by the RECIST criteria during the first four 4-week cycles of treatment. Median progression- free survival was 1.9 months. This met the futility stopping rule of interim analysis, and therefore, the trial was recommended to be permanently closed. Correlative studies including measurement of VEGF levels in archived tissues and blood are pending. Conclusions: Pazopanib did not show activity in urothelial carcinoma patients. The role of anti-VEGF therapies in urothelial carcinoma may need further evaluation in rational combination strategies. [Table: see text]