Boorjian, Stephen A.

308 Background: Receipt of pelvic radiotherapy (PRT) prior to radical cystectomy (RC) has unclear association on oncologic outcomes. Methods: The Mayo Clinic Cystectomy Registry was queried to review 2139 patients undergoing RC for M0 bladder cancer between 1990 and 2010. We then identified patients receiving PRT prior to RC, and matched these cases to non-radiated controls (~1:2) on the basis of age, sex, receipt of neoadjuvant chemotherapy, and pathologic T and N stages. Cancer-specific survival (CSS), and progression-free survival (PFS) were estimated using the Kaplan-Meier method and compared with the log-rank test. Results: Of 2139 patients undergoing RC, 104 (4.9%) had received PRT prior to surgery. These patients were matched to 191 non-radiated control patients (no PRT). Overall, patients were well-matched on disease and patient characteristics. Median follow-up was 9.6 years (IQR 6.0, 14.8). During this time, 108 patients experienced disease recurrence and 218 died, including 122 who died from bladder cancer. Five-year CSS among patients who did versus did not receive PRT was 55% versus 63% (p=0.10), while the 5-year PFS was 55% versus 61% (p=0.32). Furthermore, the pattern of disease recurrence (abdominal/visceral, urothelial, local/pelvic, thoracic, soft tissue/other) did not differ between the no PRT and PRT groups (all p>0.05). Conclusions: Receipt of PRT prior to RC is not associated with worse oncologic outcomes. While prior PRT may increase surgical complexity, CSS, PFS, and patterns of recurrence are similar to patients who have not received PRT.

279 Background: While bacillus Calmette-Guérin (BCG) is the most effective intravesical treatment for reducing recurrence and progression for high-risk non-muscle invasive bladder cancer (NMIBC), many patients are either refractory to treatment or relapse. We assessed the efficacy and safety of rAd-IFNα/Syn 3 (Instiladrin, FKD Finland), a replication deficient recombinant adenovirus gene transfer vector, for patients with high-grade (HG) BCG refractory or relapsed NMIBC. Methods: In this open-label, US multicenter (n=13), parallel-arm Phase II study (NCT01687244), 43 patients with HG BCG refractory or relapsed NMIBC were randomized 1:1 to receive intravesical rAd-IFNα/Syn3 at 1x1011 or 3x1011viral particles/mL. Patients responding at months 3, 6, and 9 were re-treated at months 4, 7, and 10. Most patients (n=21) had a primary tumor classification of carcinoma in situ (CIS); 9 had both CIS and Ta/T1 disease and 10 had Ta/T1 disease alone. The primary endpoint was 12-month HG recurrence-free survival (RFS). All patients receiving at least one dose were included in efficacy and safety analyses. Results: Forty patients received rAd-IFNα/Syn3 (1 x 1011 vp/mL: n=21; 3 x 1011vp/mL: n=19) between November 2012 and April 2015. Fourteen patients (35.0%; 90% CI 22.6%, 49.2%) remained free of HG tumor recurrence 12 months after initial treatment. Comparable 12 month HG RFS was noted between dosage arms, as well as between patients with refractory and relapsed NMIBC. Interestingly, the 12 month HG recurrence-free survival for patients with Ta/T1-only disease was 50% (5/10). rAd-IFNα/Syn3 was well-tolerated, with no Grade 5 adverse events (AEs), one Grade 4 AE (COPD; unrelated to treatment), and no patient discontinuing treatment due to an adverse event. The most frequently reported AEs were micturition urgency (n=16), dysuria and pollakiuria (n=13 each), fatigue (n=9), and nocturia (n=10). Conclusions: rAd-IFNα/Syn3 was well tolerated and demonstrated promising efficacy for patients with HG NMIBC after BCG therapy who are unable or unwilling to undergo radical cystectomy. A phase III trial utilizing this novel agent is ongoing. Clinical trial information: 01687244.

Objective To evaluate the association between renal tumour complexity and outcomes in a large cohort of patients undergoing percutaneous cryoablation ( PCA ). Patients and Methods Patients with renal tumours treated with PCA were identified using our prospectively maintained ablation registry (2003–2015). Salvage procedures and inherited tumour syndromes were excluded. The associations between R.E.N.A.L. nephrometry score ( NS ) and risk of complications, renal function impairment, local failure and cancer‐specific mortality ( CSM ) were evaluated using univariate and multivariable logistic, linear and Cox regression models. Results The cohort included 618 tumours treated during 580 procedures in 565 patients. The median (interquartile range [ IQR ]) follow‐up was 34 (14.66) months. Complications (any grade) during a procedure ( n [total] = 87, 15%) were more frequent with higher NS ( NS 4–6: 10%; NS 7–9: 14%; NS 10–12: 36%; P < 0.001). Higher NS was independently associated with risk of complications (odds ratio [ OR ; per 1 point] = 1.3; 95% confidence interval [ CI ] 1.2–1.5; P < 0.001). Of all the NS components, tumour size was the most strongly associated with complication risk ( OR 3.4; 95% CI 2.2–5.2; P < 0.001). The median ( IQR ) decline in glomerular filtration rate ( GFR ) from baseline was 9% (0, 22) at last follow‐up. Each additional point in NS was associated with a 1.3% (95% CI 0.4–2.1; P = 0.005) greater GFR decline from baseline. NS was not significantly associated with local failure ( n [total] = 14, 2%; NS 4–6: 2%; NS 7–9: 3%; NS 10–12: 5%; P = 0.32) or CSM ( n [total] = 8, 2%; NS 4–6: 2%; NS 7–9: 3%; NS 10–12: 2%; P = 0.88). Conclusion In high‐complexity tumours PCA was associated with a tumour size‐driven increased risk of post‐procedural complications. Higher NS was associated with a small, clinically minor additional decline in renal function. Risks for local failure and CSM were low, regardless of tumour complexity.

516 Background: The impact of diabetes mellitus (DM) on outcomes in patients with renal cell carcinoma (RCC) is controversial. Herein, we evaluated the association of DM with survival among patients with RCC. Methods: We reviewed 2,589 patients treated with nephrectomy for sporadic, unilateral, M0 RCC between 1990 and 2008 and compared demographic and tumor characteristics in patients with and without DM (nonDM). Patients with DM (n=313) were matched 1:2 to nonDM patients according to date of surgery, age, smoking status, obesity, ECOG performance status (PS), CKD stage, histological subtype, and nuclear grade. Cancer-specific (CSS) and overall survival (OS) were compared by Kaplan-Meier analysis. The association of DM with outcomes was evaluated with Cox proportional hazards regression models. Results: A total of 313 (12%) patients had DM. DM patients were significantly older at RCC diagnosis, more likely to be obese, and had higher Charlson scores, CKD class, rates of smoking, and worse PS at surgery (p<0.001). Patients with DM were also more likely to have ccRCC (83% vs. 76%, p=0.02) and to undergo nephron-sparing surgery (42% vs. 35%, p=0.01), while other pathologic features were similar in DM and nonDM. Among the 939 matched cases and controls, 463 patients died within a median of 5.5 years after nephrectomy. Median follow-up for survivors was 8.6 years. Five-year CSS was not significantly different among DM patients 84% vs. nonDM patients 87% (p=0.11), although 5-year OS was significantly worse among DM patients (66% vs. 75%; p<0.001). Indeed, even after adjusting for Charlson score, DM patients were noted to have a significantly increased risk of all-cause mortality (HR 1.33; p=0.004). In a subanalysis of patients with clear cell RCC, DM patients were more likely to die from RCC compared with nonDM patients after adjusting for the SSIGN (Stage, Size, Grade, Necrosis) score (HR 1.44; p=0.034). Conclusions: In this surgical cohort, DM was independently associated with decreased CSS among patients with ccRCC and with decreased OS in all RCC subtypes. Further studies to determine the potential biologic mechanism for this interaction are warranted.

503 Background: We evaluated temporal patterns in the utilization of systemic therapy among patients undergoing cytoreductive nephrectomy (CN) for metastatic Renal Cell Carcinoma (mRCC) from a large national cancer registry and assessed patient characteristics associated with receipt of systemic treatment. Methods: We reviewed the National Cancer Database to identify patients with stage IV RCC who underwent CN between 1998-2010. Systemic therapy was defined as any treatment with immunotherapy and/or chemotherapy (including targeted agents). We evaluated the association between clinicopathologic features and receipt of systemic therapy using multivariable logistic regression with generalized estimating equations, and assessed the interaction of treatment with time, stratified as immunotherapy (1998-2004) versus targeted-therapy (2005-2010) eras. Results: Of 22,409 patients with mRCC undergoing CN, 8,830 (39%) received systemic therapy. Receipt of systemic therapy increased from 32% in 1998 to 49% in 2010 (p<0.001), largely due to increased utilization of chemotherapy (13.9% vs. 46.7%; p<0.001). Following adjustment, increasing patient age (51-60 years: OR 0.82 [CI 0.73-0.92]; 61-70 years: OR 0.67 [CI 0.59-0.76]; ≥71 years: OR 0.36 [CI 0.31-0.43]), as well as coverage with Medicaid (OR 0.61 [CI 0.5-0.74]), Medicare (OR 0.70 [CI 0.62-0.79]), or no insurance (OR 0.75 [CI 0.63-0.91]) were associated with decreased utilization of systemic therapy. Although use of systemic therapy in the elderly (≥71 years) and in patients with Medicare/Medicaid remained lower throughout the study period, each of these cohorts was significantly more likely to receive systemic treatment in the targeted versus immunotherapy era (all p values <0.05). Conclusions: Utilization of systemic therapy among patients undergoing CN has increased over time, coinciding with the introduction of targeted therapies. Nevertheless, still less than half of such patients receive systemic treatment. While the etiology for lack of treatment is likely multifactorial, the potential health policy implications of continued disparities in care warrant further investigation.

498 Background: Surgery for RCC patients with IVC thrombus above the hepatic veins is complex and associated with an increased risk of perioperative morbidity and mortality. However, minimal data exist that describe contemporary perioperative outcomes at major referral centers or the prognostic factors associated with adverse surgical outcomes. The objective of this study is to determine the preoperative predictors of major complications and 90 day mortality after surgery in RCC patients with IVC thrombus above the hepatic veins. Methods: Records were reviewed of all RCC patients with IVC tumor thrombus above hepatic veins who had surgery from 1/2000 to 12/2012 at Mayo Clinic, MD Anderson, UT Southwestern and the University of Wisconsin. Major complications were recorded were defined as 3A or greater according to the Clavien- Dindo system within 90 days of surgery. Univariate and multivariate (MV) analyses were used to evaluate associations of preoperative clinical, pathological or laboratory variables with risk of major complications or 90-day mortality. Results: A total of 162 patients were identified for study (thrombus level 3,4 in 69 and 93 patients, respectively, according to Neves classification). Cardiopulmonary bypass was used in 60/162 (37.5%), while 40 (24.7%) patients underwent pre-operative angioembolization. Major complications were reported in 55 (34.0%) patients, with the most common being respiratory (12.4%), hematologic (9.2%) and cardiac (8.6%). On MV analysis, preoperative systemic symptoms and level 4 thrombus were independently associated with an increased risk of major complications. Mortality was reported in 17 (10.5%) patients within 90 days after surgery. On MV analysis, ECOG performance status and low serum albumin were independently associated with increased risk of 90 day mortality. Conclusions: Contemporary perioperative mortality and major complication rates for RCC patients with upper level thrombus are 10 and 34%, respectively. ECOG PS >1 and low serum albumin are associated with an increased risk of perioperative mortality, and should be considered when selecting patients for neoadjuvant systemic therapy trials.

402 Background: The American Urological Association (AUA) and the National Comprehensive Cancer Network (NCCN) are highly utilized sources for surveillance strategies following surgical treatment for renal cell carcinoma (RCC). However, the duration of follow-up may be inadequate to capture the majority of recurrences. Herein, we assess the ability of these guidelines to effectively capture recurrences of RCC following primary surgical resection. Methods: We reviewed our institutional database of 3,725 patients treated with radical or partial nephrectomy for M0 sporadic RCC between 1970-2008. For comparison to the AUA guidelines, patients were stratified into low risk following partial nephrectomy (LRp) or radical nephrectomy (LRr) = pT1N0, and moderate/high risk (M/HR) = pT2-4 N0-1. Guideline effectiveness was assessed by calculating the percentage of recurrences detected within the prescribed follow-up periods given for site-specific recurrence: AUA—LRp: 3yrs for all sites; LRr: 1yr for abdominal and 3yrs for chest/bone/other sites; M/HR: 5yrs for all sites; NCCN—6 months for abdominal/chest sites and 5yrs for bone/other sites. Results: Of the 3,725 patients, 2721 (73.1%) underwent radical nephrectomy, 2,210 (59.3%) were classified as pT1 NX-0 and 2,910 (78.1%) as clear cell RCC. Median postoperative follow-up was 8.9yrs (IQR 5.5-14.2) during which 1,114 (29.9%) patients developed recurrence. Of these recurrences, 760 (68.2%) would have been detected using the AUA guidelines and 432 (38.8%) by NCCN recommendations. Within AUA risk groups, 37.2% recurrences were captured in LRp, 31.4% in LRr and 80.2% in M/HR. Capture of 90% of recurrences in the abdomen and chest would require surveillance for 9yrs and 8 yrs, respectively in LRp, 15yrs and 12yrs in LRr and 11yrs and 10yrs in M/HR. Conclusions: Duration of follow-up recommended by current surveillance algorithms by the AUA and NCCN do not adequately capture many recurrences in RCC following radical or partial nephrectomy. Guidelines using risk stratification and site-specific recurrence parameters to assign length of surveillance may allow providers to better individualize surveillance regimens.

310 Background: The European Association of Urology (EAU) and the National Comprehensive Cancer Network (NCCN) provide general guidelines for bladder cancer (BC) surveillance following radical cystectomy (RC). However, it is unclear how well these guidelines capture recurrences after surgery. Herein, we assess the ability of current guidelines to effectively capture BC recurrence following RC and propose a risk stratified and recurrence site-specific surveillance strategy. Methods: We reviewed our institutional database of 1,800 patients who underwent primary RC between 1980-2007. Guideline effectiveness was assessed by calculating the percentage of recurrences detected within the prescribed follow-up periods: EAU—5yrs; NCCN—2yrs. Patients were then stratified according to stage: < = pT1Nx-0, > = pT2Nx-0, pN+, and recurrence site: urothelium, abdomen, chest, other. Recurrence free survival estimates for stage groups and recurrence site were assessed with Kaplan Meier models. Results: Of the 1,800 patients, 634 (35.2%) were classified as > pT2Nx-0 and 234 (13%) as pN+ and overall 228 (12.7%) received perioperative chemotherapy. Median postoperative follow-up was 10.6yrs (IQR 6.8-15.2), during which 716 (39.8%) patients developed recurrence. Of these recurrences, 492 (68.7%) would have been detected using the NCCN guidelines and 644 (89.8%) by EAU recommendations. However, ending oncologic surveillance at 5 years would only capture 81.7% of all recurrences for < = pT1Nx-0 patients and 83% of urothelial specific recurrences across all stage groups. Capture of 90% of recurrences, by stage group, in the urothelium, abdomen and chest would require surveillance for 8yrs, 8yrs and 4yrs, respectively in < = pT1Nx-0, 6yrs, 4yrs and 3yrs in > = pT2Nx-0 and 3yrs, 3yrs and 2yrs for pN+ patients. Conclusions: Duration of surveillance recommended for BC following RC by the EAU and NCCN do not comprehensively capture recurrences seen, specifically, in low risk patients and in cases of urothelial recurrence. Guidelines using risk stratification and site-specific recurrence patterns to assign length of surveillance may allow providers to better individualize surveillance regimens.

359 Background: Sarcomatoid renal cell carcinoma (RCC) is an aggressive form of RCC and is associated with a poor prognosis. Standard therapies tend to be less effective in this subset of patients. Methods: Using the Mayo Clinic Nephrectomy Registry, 206 patients with sarcomatoid RCC treated with partial or radical nephrectomy were identified. These patients were characterized based on extent of disease, treatment response and survival. Results: Of these 206, there was no evidence of distant metastases in 110 patients at the time of surgery and the estimated distant metastases-free survival at one year was 44%. The estimated cancer-specific survival rate at one and five years was 56% and 20%, respectively. Compared to patients with grade 4 RCC without sarcomatoid features, those with sarcomatoid RCC were more likely to develop distant metastases following surgery (hazard ratio 1.49). Considering those with metastatic sarcomatoid RCC, 96 patients had metastases at the time of surgery and 77 with no metastases at the time of surgery subsequently developed distant metastases (n=173). Of these, 156 died at a mean of 1.0 years from time of first evidence of distant metastases with a median cancer-specific survival of 0.6 years. Estimated cancer-specific survival rates from time of first metastases at one year and five years were 34% and 4%, respectively. The most common metastatic sites: lung (46%), bone (15%), liver (13%), non-regional lymph nodes (9%), and brain (5%). Patients who received targeted systemic therapy (10%) with either sunitinib (n=14), sorafenib (2) or pazopanib (1) for their first occurrence of distant metastases had an estimated cancer-specific survival rate at one year of 69%, compared to 30% for patients who did not. Median cancer-specific survival for those receiving targeted therapy as first-line was 2.2 years compared to 0.6 years for those patients who did not. Conclusions: Sarcomatoid RCC is an aggressive subtype of kidney cancer as evidenced by poor survival rates. The patients in this registry with metastatic sarcomatoid RCC who received targeted therapy as first-line treatment had improved cancer-specific survival rates.

494 Background: Renal cell carcinoma (RCC) with rhabdoid differentiation is thought to portend a poor prognosis, similar to RCC with sarcomatoid differentiation. Both rhabdoid and sarcomatoid differentiation are classified as grade 4 RCC based on the most recent International Society of Urological Pathology (ISUP) grading system. We sought to determine the prognostic value of rhabdoid differentiation in comparison to RCC with sarcomatoid differentiation, grade 4 RCC without rhabdoid or sarcomatoid differentiation, and grade 3 RCC. Methods: Using the Mayo Clinic Nephrectomy Registry, we identified 406 patients with ISUP grade 4 RCC and 1,758 patients with grade 3 RCC. A urologic pathologist reviewed all specimens to determine the presence of both rhabdoid and sarcomatoid differentiation. Associations of clinical and pathologic features with death from RCC were evaluated using Cox models. Results: Among the 406 grade 4 RCC tumors, 111 (27%) had rhabdoid differentiation and 189 (47%) had sarcomatoid differentiation, although only 28 (7%) demonstrated both rhabdoid and sarcomatoid differentiation. In multivariable analysis of grade 4 RCC tumors, the presence of rhabdoid differentiation was not associated with death from RCC (HR 0.95, p=0.75); in contrast, sarcomatoid differentiation was significantly associated with death from RCC (HR 1.63, p<0.001). Patients with RCC with rhabdoid differentiation were significantly more likely to die of RCC than patients with grade 3 RCC (HR 2.45, p<0.001) and grade 3 RCC with necrosis (HR 1.62; p<0.001). Conclusions: This study confirms that RCC with rhabdoid differentiation is appropriately classified as grade 4. However, unlike sarcomatoid differentiation, the presence of rhabdoid differentiation in grade 4 RCC is not associated with an increased risk of death from RCC. Therefore, rhabdoid and sarcomatoid differentiation should not be grouped together when assessing risk in a patient with grade 4 RCC.