Frank, Igor

Urinary bladder cancer (UBC) is the most common malignancy of the urinary tract in humans, with an estimated global prevalence of 1.1 million cases over 5 years. Because of its high rates of recurrence and resistance to chemotherapy, UBC is one of the most expensive cancers to treat, resulting in significant health care costs. The development of innovative molecular and cellular tools is necessary to refine patient stratification and help predict response to treatment. Urine is an underused resource of biological components shed from bladder tumors, such as exfoliated cells and extracellular vesicles, that could serve as molecular fingerprints and provide valuable biological insights into tumor phenotype and mechanisms of resistance to chemotherapy. Additionally, characterization of urine-derived extracellular vesicles and cells could be used as reliable biomarkers for prediction of response to neoadjuvant therapy.

e16103 Background: At present, androgen ablation (AA) therapy ± radiation therapy represents a first-line treatment for patients with unresectable locally advanced prostate cancer (CAP), typically resulting in palliative disease control. Immunotherapy, in the form of CTLA-4 blockade, has been shown to potentiate T-cell responses, representing a potential antitumoral immunotherapy for treating CAP. Here, we discuss the outcomes of 5 locally advanced CAP patients treated with the monoclonal antibody MDX-CTLA-4 (MDX-010) + AA who subsequently underwent radical prostatectomy (RP), 2 of whom exhibited striking down-staging of their disease. Methods: A Phase II trial testing AA + MDX-010 therapy for treatment of locally or systemically advanced CAP is currently ongoing at our institution. To date, 5/85 patients have electively opted for off-study RP with extended pelvic lymphadenectomy after documentation of robust treatment response by PSA, staging digital rectal exam, and 3-D imaging. Results: All men had unresectable, locally advanced disease (stage T2c-T4) prior to treatment with AA + MDX-010 and subsequently underwent RP. Median blood loss was 400mL (400–900). All patients had negative surgical margins. Of the 5 patients, 2 exhibited dramatic and indisputable down-staging of their disease. These two patients presented with 80% of biopsies involved with cancer, extraprostatic extension, seminal vesicle (SV) invasion, and bladder base involvement. On final pathology, both exhibited extensive treatment effect, remission of SV involvement, and robust disaggregation of solid tumors resulting in only microscopic, non-contiguous foci of residual intraprostatic cancer. Both had T4 disease pre-treatment, and had stage T2c on final pathology. One patient is free of disease with undetectable PSA for 19 months following adjuvant radiation treatment but no further therapy, while the other patient is awaiting follow-up. Conclusions: We have been able to demonstrate true down-staging of locally advanced prostate cancer with neoadjuvant AA + MDX-010 therapy. This therapeutic modality exhibits significant promise for men with unresectable disease and may provide durable and potentially curative cancer control. No significant financial relationships to disclose.

TPS3172 Background: Bladder cancer is a leading cause of cancer death in the United States. Over 90% of bladder cancer cases are urothelial carcinomas (UC) that may present as a non-muscle-invasive (NMIBC) or muscle-invasive disease (MIBC). Standard of care for NMIBC includes transurethral resection of bladder tumor (TURBT), intravesical chemotherapy and immunotherapy with Bacillus Calmette-Guerin (BCG). Patients (pts) with high-grade BCG-refractory NMIBC or MIBC undergo RC, which involves complete bladder removal and pelvic lymphadenectomy. RC severely impacts quality of life with significant morbidity. Oncolytic viruses are showing promise in UC, and MV-NIS has proven efficacy in other tumor types. MV-NIS is an investigational oncolytic measles virus with an excellent safety profile, irrespective of route of administration (n > 100). MV-NIS-related adverse events are limited to infusion reactions and transient CBC changes, and little local toxicity is anticipated with intravesical therapy. Clinical efficacy of this oncolytic may be related to absence of measles immunity. Based on this, the clinical strategy for MV-NIS is focused on targeting immune-privileged sites via intra-tumoral or intravesical routes, alone or in combination with checkpoint inhibitors. We hypothesize that intravesical therapy with oncolytic MV-NIS can improve clinical outcomes for (a) BCG refractory NMIBC pts to avoid or delay the need for RC; and (b) MIBC pts undergoing RC. Methods: This study is enrolling pts undergoing RC who are ineligible to receive neoadjuvant chemotherapy. The trial has 2 stages to (a) determine the safety and tolerability of intravesical MV-NIS, and (b) assess preliminary efficacy. Part (a) includes 4-24 pts in a timing cohort with doses administered at increasing durations (1-4 weeks) prior to RC to establish safety of a single MV-NIS dose. Part (b) includes an expansion cohort (n = 12) to evaluate the safety and efficacy of 2 intravesical doses of MV-NIS at 2-week intervals prior to RC. Safety is assessed using NCI-CTCAE V5 and Clavien-Dindo grading of operative complications. The efficacy endpoint is pathologic stage at time of RC (pT0 rate), which can be compared to pre-study TURBT stage. Additional exploratory studies include PK and PD analyses in urine, blood and tumor. Enrollment is ongoing at 2 Mayo Clinic sites (Rochester, MN and Jacksonville, FL) and the study has now progressed from the timing cohort into the expansion cohort. Clinical trial information: NCT03171493 .

5117 Background: Prognostic nomograms, scoring tools, and risk tables are rapidly accumulating in the prostate cancer (PCa) literature. It is not always clear to whom these tools should apply and how well they predict the outcomes they were designed to forecast. There is need for independent evaluation of these tools. Methods: We used the Mayo Clinic Radical Prostatectomy Registry, a prospective database of radical prostatectomy (RP) outcomes, to assess tools designed to predict RP outcomes. The validation set included 13,313 RP patients from 1990–2005. There were 3,256 PSA failures, 566 metastases, and 1,599 deaths (301 were due to PCa). We assessed the discrimination, calibration and overall accuracy of prediction tools identified through a structured Pubmed search. Results: Tools varied greatly in terms of complexity, width of prediction interval, and method of presentation. Several tools included non-standard variables and were therefore unevaluable, despite an extensive dataset, leaving the 1999 and 2005 Kattan nomograms, the 1998 and 2001 CDPR scores, and the 2001 GPSM score for analysis. Discrimination (quantitated by the c index) was better for PCa-specific survival and metastases than for PSA failure ( Table ). Kaplan-Meier plots demonstrated clustering of risk groups in most tools, most severely in the higher risk groups of the Kattan nomograms. The calibration plots of most tools (excepting GPSM) had a serious discordance between observed and predicted outcomes in the lower probability ranges. This meant that most tools gravely overestimated the probability of RP failure in high-risk patients, by up to 4- fold. Conclusions: The tools showed moderate discriminatory ability for PSA failure but performed much better for non-surrogate outcomes. Most tools (excepting GPSM) were miscalibrated in high risk patients and dramatically underestimated the efficacy of surgery in this cohort. Prognostic tools may not be as accurate as previously reported. [Table: see text] No significant financial relationships to disclose.

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]

SAGE-Journals-Accessible-Video-Player 10.1089/vid.2018.0051.M1 sj-vid-1-vid-10.1089_vid.2018.0051

Objective To investigate the association between smoking status and pathological response to cisplatin‐based neoadjuvant chemotherapy ( NAC ) and survival outcomes in patients with muscle‐invasive bladder cancer ( MIBC ) treated with radical cystectomy ( RC ). Patients and Methods We reviewed 201 patients treated with NAC and RC for cT 2– cT 4N0M0 BC between 01/1999 and 01/2015. Smoking status was categorised as: ‘never', ‘former', and ‘current' smoker. Pathological response to NAC was defined as: complete (ypT0N0), partial (ypTis/Ta/T1, N0), and no response (ypT2–4 or ypN+). Clinicopathological characteristics were analysed according to smoking status. Logistic regression analyses tested the association between smoking status and pathological response to NAC . Cox regression analyses tested risk factors associated with recurrence, overall ( OM ) and cancer‐specific mortality ( CSM ). Results Overall, there were 58 (28.9%) never smokers, 87 (43.3%) former smokers, and 56 (27.9%) current smokers. No response to NAC was more frequently noted in current smokers (73.2%; P = 0.007). Former smoker ( odds ratio [OR] 2.28; P = 0.024) and current smoker statuses ( OR 4.52; P < 0.001) were significantly associated with no response to NAC , after adjusting for age, gender, Charlson Comorbidity Index, and clinical stage. Similarly, current smoking status ( hazard ratio [HR] 2.14; P = 0.03) and extravesical pathological tumour stage ( HR 3.31; P < 0.001) were independently associated with an increased risk of recurrence after RC . Conclusion Cigarette smoking was significantly associated with adverse pathological response to cisplatin‐based NAC in patients with MIBC treated with RC . Current smokers were at significantly higher risk of disease recurrence as compared to former and never smokers.