Packiam, Vignesh T.

Purpose of review Although radical cystectomy represents the gold standard treatment for patients with high-risk nonmuscle invasive bladder cancer (NMIBC) whose disease does not respond to bacillus Calmette-Guérin (BCG), many patients are unable or unwilling to undergo surgery. The need remains for effective bladder-preserving therapies. This review aims to describe existing treatments, contemporary research in this field and ongoing trials of salvage therapies for patients with BCG-unresponsive NMIBC. Recent findings Intravesical chemotherapy has been utilized frequently in this setting. Emerging data on combination regimens such as intravesical gemcitabine and docetaxel and intravesical cabazitaxel, gemcitabine and cisplatin are promising; nevertheless, larger, prospective trials are needed. Meanwhile, the intravenous checkpoint inhibitor pembrolizumab was recently FDA-approved for patients BCG-unresponsive NMIBC. Encouraging clinical trial results for intravesical nadofaragene firadenovec, oportuzumab monatox and ALT-803 + BCG have been released, while data from trials of other treatment strategies, including novel chemotherapy and drug delivery, augmented BCG immunotherapy, adenoviral and gene therapy, targeted therapy, and combination systemic immunotherapy with intravesical agents, are eagerly awaited. Summary Several novel salvage therapies offer promise for patients with BCG-unresponsive NMIBC. Patient selection, efficacy, safety, cost and ease of administration must be carefully considered to determine the optimal treatment approach.

395 Background: Patients with BCG-unresponsive carcinoma in situ (CIS) are treated with radical cystectomy (RCx) or salvage intravesical chemotherapy (SIC). Recently, the FDA approved pembrolizumab for BCG-unresponsive CIS +/- papillary tumors. Given the costs and toxicities of pembrolizumab, it remains unclear whether its benefits are sufficient to warrant widespread use for BCG-unresponsive CIS. To that end, we conducted a cost-effectiveness analysis comparing pembrolizumab with RCx and SIC (using gemcitabine-docetaxel as the prototypical regimen) for patients with BCG-unresponsive CIS. Methods: A decision-analytic Markov model compared pembrolizumab, SIC (with gemcitabine-docetaxel), and RCx for patients with BCG-unresponsive CIS +/- papillary tumors who are RCx candidates (index patient 1) or are unwilling/unable to undergo RCx (index patient 2). Each treatment option was a Markov node containing distinct variations of the following health states: surveillance, recurrence, progression to MIBC, progression to metastasis, treatment toxicity, and death. Incremental Cost-Effectiveness Ratios (ICERs) were compared using a willingness-to-pay threshold of $100,000/Quality-adjusted life year (QALY). The model used a US Medicare perspective with a 5-year time horizon for the base case. One-way and probabilistic sensitivity analyses were performed for all model parameters. Results: For index patient 1, pembrolizumab was not cost-effective vs. RCx (ICER $1,403,008) or SIC (ICER $2,011,923). One-way sensitivity analysis revealed that pembrolizumab only became cost-effective relative to RCx with a > 93% price reduction. Relative to RCx, SIC was cost-effective for time horizons < 5 years and nearly cost-effective at 5 years (ICER $118,324). One-way sensitivity analysis revealed that SIC became cost-effective relative to RCx if its risk of recurrence or metastasis at 2 years was less than 55% or 5.9%, respectively. For index patient 2, pembrolizumab required > 90% price reduction to be cost-effective vs. RCx (ICER $1,073,240). Probabilistic sensitivity analyses revealed that pembrolizumab was unlikely to be cost-effective even at high willingness-to-pay thresholds. Further sensitivity analyses found that no two-way combination of extrapolated values resulted in pembrolizumab being favored over RCx or SIC for either index patient. Conclusions: Based on decision-analytic Markov modeling of treatment options for patients with BCG-unresponsive CIS, pembrolizumab was unlikely to be cost-effective without a > 90% price reduction. While both RCx and SIC were more cost-effective than pembrolizumab, further studies may validate the cost-effectiveness of gemcitabine-docetaxel relative to RCx if the recurrence and metastasis thresholds are met. Overall, our model supports the preferential use of RCx and SIC over pembrolizumab for BCG-unresponsive CIS.

TPS594 Background: The standard treatment for upper tract urothelial carcinoma (UTUC) is radical nephroureterectomy (RNU) with bladder cuff resection. Subsequent intravesical recurrence is common and results in patient morbidity and increased healthcare cost. Level 1 evidence has demonstrated reduction of intravesical recurrence with instillation of intravesical Mitomycin C at 10 days following RNU. However, there has been limited adoption of Mitomycin C due to concerns for toxicity and logistics of postoperative drug delivery. Meanwhile, immediate intravesical gemcitabine has been shown to reduce intravesical recurrence following transurethral resection of bladder cancers without increasing toxicity compared to placebo. Moreover, small series have suggested improved efficacy of intraoperative intravesical chemotherapy for RNU. The purpose of the GEMINI trial, therefore, is to prospectively establish the safety and efficacy of intraoperative instillation of intravesical gemcitabine in patients undergoing RNU for UTUC. Methods: GEMINI is a multi-center open-label, single-arm, Phase II study that aims to enroll 90 patients with cTa-T4N0M0 UTUC. Patients receive intraoperative intravesical instillation of gemcitabine at the beginning of RNU, to be held in the bladder for at least 1 hour. The instilled drug will be drained prior to resection of the bladder cuff. Patients will undergo standard of care postoperative surveillance, including cystoscopy at 3, 6, 12, 18, and 24 months. The primary endpoint is 1-year intravesical recurrence-free survival. The historical event rate for no treatment is 30%, and we estimated a 40% relative reduction in event rate with gemcitabine. The study is powered to provide 80% power to detect this difference based on a one-sided exact test of proportions with alpha level 0.05. Secondary endpoints include time to recurrence and stratification of recurrence free survival by tumor grade, tumor stage, neoadjuvant chemotherapy, ureteral tumor location, and history of bladder cancer. Safety and adverse event endpoints will be evaluated. Complete accrual is expected within 3 years.

725 Background: The impact of surgical resection of renal tumors on peripheral immune related cells is not well characterized, and has potential implications as biomarkers for systemic immune therapy are being developed. We sought to assess the effect of surgical resection on circulating cytotoxic T-cells (CTLs) for patients with renal tumors. Methods: We prospectively enrolled 40 patients undergoing partial, radical, or cytoreductive nephrectomy (PN, RN, CN) for unilateral primary renal tumors between 2016 and 2018. Blood draws were performed pre-op, 1 day post-op, and 3 months post-op. Flow cytometry was performed on peripheral blood mononuclear cells (PBMCs). The % of PBMCs expressing CD11a/CD8 (CTLs) were assessed. The % of CTLs expressing PD-1, Bim (a downstream PD-1 pathway pro-apoptotic mediator), CX3CR1/GZMB (an effector memory T-cell phenotype), and Ki67 (a proliferation marker) were assessed. Median changes in % of CTLs were evaluated with the Wilcoxon signed rank test. Comparisons between aggressive (pT3-4, N1, M1, or aggressive histology (high-grade, coagulative necrosis, sarcomatoid dedifferentiation, or specific RCC-variant histologies)) versus indolent tumors were assessed using the Wilcoxon rank sum test. Results: Twenty, 12, and 8 patients underwent RN, PN, and CN, respectively. Thirty, 7, and 3 patients had clear-cell RCC, non-clear cell RCC, and oncocytoma, respectively. Twenty-three and 17 patients had aggressive and indolent tumors, respectively. While there was no significant change at 1 day, by 3 months there were significantly increased CTLs among PBMCs (+1.3%; p=0.004). There was significant decrease in CX3CR1+GZMB+ CTLs (-2.9%; p<0.001) and significant increase in Bim+ CTLs (+3.0%; p=0.03) at 1 day but not 3 months. Interestingly, Ki67+ CTLs increased at day 1 (+0.6%; p<0.001) but decreased by 3 months (-0.6%; p=0.001). There were no significant changes in PD-1+ CTLs at either time point. There were no significant changes in any CTL characteristics at 1 day or 3 months between aggressive and indolent tumors. Conclusions: These findings characterize changing CTL profiles over time with surgical resection of renal tumors which may help guide biomarker development.

483 Background: We evaluate the impact of salvage intravesical therapy on survival in patients with NMIBC previously treated with BCG who ultimately underwent radical cystectomy (RC). Methods: We retrospectively identified patients with NMIBC who received at least 1 complete induction course of BCG and subsequently underwent RC for bladder cancer between 2000-2018. Patients were stratified by receipt of salvage intravesical therapy following BCG prior to RC. Oncologic outcomes were compared using Cox proportional hazards regression analysis and the Kaplan-Meier method. Results: We identified 371 patients who underwent RC after receiving BCG, of whom 55 (15%) received salvage intravesical therapy, most commonly Mitomycin C (n = 26), Valrubicin (n = 8), Gemcitabine (n = 7), and CG0070 (n = 6). Median follow-up among survivors was 1.1 (IQR 0-4.3) years. Patients who received salvage intravesical therapy were more likely to initially present with CIS (27% vs 17%) and less likely to present with T1 disease (33% vs 50%, both p < 0.05). Receipt of salvage intravesical therapy was not associated with increased risk of adverse pathology (≥pT2 or pN+) at RC (33% vs 41%, p = 0.27). Furthermore, on Kaplan-Meier analysis, receipt of salvage intravesical therapy was not associated with cancer-specific or overall survival. On multivariable Cox proportional hazards regression, clinical stage prior to RC, but not receipt of salvage intravesical therapy, was associated with inferior cancer-specific survival and overall survival. Conclusions: Our results suggest that RC following carefully managed salvage intravesical therapy after BCG is not associated with inferior oncologic outcomes, which can improve patient counseling. [Table: see text]

Abstract Background Immunosuppressive regimens associated with organ transplantation increase the risk of developing cancer. Transplant candidates and recipients with prostate cancer are often treated, even if low-risk features would ordinarily justify active surveillance. Methods Using SEER-Medicare, we identified 163 676 men aged 66 years and older diagnosed with nonmetastatic prostate cancer. History of solid organ transplant was identified using diagnosis or procedure codes. A propensity score-matched cohort was identified by matching transplanted men to nontransplanted controls by age, race, region, year, T-stage, grade, comorbidity, and cancer therapy. Fine-Gray competing risk models assessed associations between transplant status and prostate cancer-specific mortality (PCSM) and overall mortality (OM). Results We identified 620 men (0.4%) with transplant up to 10 years before (n = 320) or 5 years after (n = 300) prostate cancer diagnosis and matched them to 3100 men. At 10 years, OM was 55.7% and PCSM was 6.0% in the transplant cohort compared with 42.4% (P &lt; .001) and 7.6% (P = .70) in the nontransplant cohort, respectively. Adjusted models showed no difference in PCSM for transplanted men (hazard ratio = 0.88, 95% confidence interval = 0.61 to 1.27, P = .70) or differences by prostate cancer therapy. Among 334 transplanted men with T1-2N0, well or moderately differentiated “low-risk” prostate cancer, PCSM was similar for treated and untreated men (hazard ratio = 0.92, 95% confidence interval = 0.47 to 1.81). Conclusions Among men aged 66 years and older with prostate cancer, an organ transplant is associated with higher OM but no observable difference in PCSM. These findings suggest men with prostate cancer and previous or future organ transplantation should be managed per usual standards of care, including consideration of active surveillance for low-risk cancer characteristics.

617 Background: Anxiety and depression are psychosocial factors which have been demonstrated to have mixed interactions with mortality across various malignancies. While these variables have been associated with poor overall survival for patients with metastatic RCC, the influence on outcomes for localized RCC has been poorly studied. We evaluated the association of anxiety or depression with survival in patients with surgically treated localized clear cell RCC (ccRCC). Methods: We performed retrospective review of our institutional nephrectomy registry to identify 1,990 patients who underwent radical or partial nephrectomy for unilateral, sporadic, non-metastatic ccRCC between 1995- 2011. Baseline anxiety and depression were identified using ICD-9 codes. Associations of anxiety or depression with outcomes of interest were evaluated using Cox proportional hazards models. Two propensity score (PS) techniques were used: adjusting for PS quintile and re-weighting by stabilized inverse probability weights. Results: A total of 197 (10%) patients had diagnoses of anxiety or depression (57 had anxiety alone, 107 had depression alone, and 33 had both anxiety and depression). Median follow-up among survivors was 10.0 (IQR 7.3-13.6) years, during which time 864 died, including 363 from RCC. Patients with anxiety or depression were younger (mean age 59 vs 62 years, p < 0.001) and had more recent operations (75% vs 47% in 2005-2011, p < 0.001) compared to those with neither diagnosis. After PS adjustment, all clinical and pathologic features were well balanced between groups. After PS adjustment, there were no significant differences in time to local ipsilateral recurrence, distant metastases, and death from RCC between groups. We did note a trend to poorer overall survival in patients with anxiety or depression (HR 1.29, 95%CI = 0.98-1.69, p = 0.065). Conclusions: Our results suggest that neither anxiety nor depression is significantly associated with oncologic outcomes among patients with localized surgically treated ccRCC. The trend toward worse overall survival among patients with anxiety or depression warrants further investigation.