Joshua Griffin

Multicenter Assessment of Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer

BACKGROUND The efficacy of neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (BCa) was established primarily with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), with complete response rates (pT0) as high as 38%. However, because of the comparable efficacy with better tolerability of gemcitabine and cisplatin (GC) in patients with metastatic disease, GC has become the most commonly used regimen in the neoadjuvant setting. OBJECTIVE We aimed to assess real-world pathologic response rates to NAC with different regimens in a large, multicenter cohort. DESIGN, SETTING, AND PARTICIPANTS Data were collected retrospectively at 19 centers on patients with clinical cT2-4aN0M0 urothelial carcinoma of the bladder who received at least three cycles of NAC, followed by radical cystectomy (RC), between 2000 and 2013. INTERVENTION NAC and RC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary outcome was pathologic stage at cystectomy. Univariable and multivariable analyses were used to determine factors predictive of pT0N0 and ≤pT1N0 stages. RESULTS AND LIMITATIONS Data were collected on 935 patients who met inclusion criteria. GC was used in the majority of the patients (n=602; 64.4%), followed by MVAC (n=183; 19.6%) and other regimens (n=144; 15.4%). The rates of pT0N0 and ≤pT1N0 pathologic response were 22.7% and 40.8%, respectively. The rate of pT0N0 disease for patients receiving GC was 23.9%, compared with 24.5% for MVAC (p=0.2). There was no difference between MVAC and GC in pT0N0 on multivariable analysis (odds ratio: 0.89 [95% confidence interval, 0.61-1.34]; p=0.6). CONCLUSIONS Response rates to NAC were lower than those reported in prospective randomized trials, and we did not discern a difference between MVAC and GC. Without any evidence from randomized prospective trials, the best NAC regimen for invasive BCa remains to be determined. PATIENT SUMMARY There was no apparent difference in the response rates to the two most common presurgical chemotherapy regimens for patients with bladder cancer.

Effects of Immunonutrition for Cystectomy on Immune Response and Infection Rates: A Pilot Randomized Controlled Clinical Trial

UNLABELLED After radical cystectomy (RC), patients are at risk for complications including infections. The expansion of myeloid-derived suppressor cells (MDSCs) after surgery may contribute to the lower resistance to infection. Immune response and postoperative complications were compared in men consuming either specialized immunonutrition (SIM; n=14) or an oral nutrition supplement (ONS; n=15) before and after RC. MDSC count (Lin- CD11b+ CD33+) was significantly different between the groups over time (p=0.005) and significantly lower in SIM 2 d after RC (p<0.001). MDSC count expansion from surgery to 2 d after RC showed a weak association with an increase in infection rate 90 d after surgery (p=0.061). Neutrophil:lymphocyte ratio was significantly lower in SIM compared with ONS 3h after the first incision (p=0.039). Participants receiving SIM had a 33% reduction in postoperative complication rate (95% confidence interval [CI], 1-64; p=0.060) and a 39% reduction in infection rate (95% CI, 8-70; p=0.027) during late-phase recovery. The small sample size limits the study findings. PATIENT SUMMARY Results show that the immune response to surgery and late infection rates differ between radical cystectomy patients receiving specialized immunonutrition versus oral nutrition supplement in the perioperative period. TRIAL REGISTRATION ClinicalTrials.gov NCT01868087.

Side Effects of Perioperative Intravesical Treatment and Treatment Strategies for These Side Effects

Perioperative intravesical chemotherapy has a well-established role in the treatment of non-muscle invasive bladder cancer. There are multiple agents that can be used in this fashion with varying properties. Although chemical cystitis is the most common side effect and is usually self-limiting, significant toxicity can occur with intravesical chemotherapy. It is imperative that the urologist is aware of the acute and delayed side effects of intravesical chemotherapy and how to manage potential complications. Both local and systemic toxicities are discussed, as well as strategies to minimize and manage them.

Neoadjuvant Dose Dense MVAC versus Gemcitabine and Cisplatin in Patients with cT3-4aN0M0 Bladder Cancer Treated with Radical Cystectomy

Purpose: Level I evidence supports the usefulness of neoadjuvant cisplatin based chemotherapy for muscle invasive bladder cancer. Since dose dense MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) has mostly replaced traditional MVAC, we compared pathological response and survival rates in patients with locally advanced bladder cancer who received neoadjuvant chemotherapy with dose dense MVAC vs gemcitabine and cisplatin. Materials and Methods: We retrospectively reviewed the records of patients with urothelial cancer who received neoadjuvant chemotherapy and underwent cystectomy at a total of 20 contributing institutions from 2000 to 2015. Patients with cT3‐4aN0M0 disease were selected for this analysis. The rates of ypT0N0 and ypT1N0 or less were compared between the gemcitabine and cisplatin, and dose dense MVAC regimens. Two multivariable Cox proportional hazards regression models of overall mortality were generated using preoperative and postoperative data. Results: Of the patients who underwent neoadjuvant chemotherapy and radical cystectomy during the study period 319 met our inclusion criteria. A significantly lower rate of ypT0N0 was observed in the gemcitabine and cisplatin arm than in the dose dense MVAC arm (14.6% vs 28.0%, p = 0.005). The rate of ypT1N0 or less was 30.1% for gemcitabine and cisplatin compared to 41.0% for dose dense MVAC (p = 0.07). The mean Kaplan‐Meier estimates of overall survival in the gemcitabine and cisplatin, and dose dense MVAC groups were 4.2 and 7.0 years, respectively (p = 0.001). On multivariable cox regression analysis based on preoperative data patients who received gemcitabine and cisplatin were at higher risk for death than patients who received dose dense MVAC (HR 2.07, 95% CI 1.25–3.42, p = 0.003). Lymph node invasion (HR 1.97, 95% CI 1.15–3.36, p = 0.01) and hydronephrosis (HR 2.18, 95% CI 1.43–3.30, p <0.001) were also associated with higher risk of death. Conclusions: In our retrospective cohort of patients with locally advanced bladder cancer dose dense MVAC was associated with higher complete pathological response and improved survival rates compared to gemcitabine and cisplatin. A clinical trial is warranted to validate these hypothesis generating results to test the superiority of neoadjuvant dose dense MVAC in patients with locally advanced bladder cancer.

Concomitant CIS on TURBT does not impact oncological outcomes in patients treated with neoadjuvant or induction chemotherapy followed by radical cystectomy

BackgroundCisplatin-based neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer improves all-cause and cancer specific survival. We aimed to evaluate whether the detection of carcinoma in situ (CIS) at the time of initial transurethral resection of bladder tumor (TURBT) has an oncological impact on the response to NAC prior to radical cystectomy.Patients and methodsPatients were identified retrospectively from 19 centers who received at least three cycles of NAC or induction chemotherapy for cT2-T4aN0-3M0 urothelial carcinoma of the bladder followed by radical cystectomy between 2000 and 2013. The primary and secondary outcomes were pathological response and overall survival, respectively. Multivariable analysis was performed to determine the independent predictive value of CIS on these outcomes.ResultsOf 1213 patients included in the analysis, 21.8% had concomitant CIS. Baseline clinical and pathologic characteristics of the ‘CIS’ versus ‘no-CIS’ groups were similar. The pathological response did not differ between the two arms when response was defined as pT0N0 (17.9% with CIS vs 21.9% without CIS; p = 0.16) which may indicate that patients with CIS may be less sensitive to NAC or ≤ pT1N0 (42.8% with CIS vs 37.8% without CIS; p = 0.15). On Cox regression model for overall survival for the cN0 cohort, the presence of CIS was not associated with survival (HR 0.86 (95% CI 0.63–1.18; p = 0.35). The presence of LVI (HR 1.41, 95% CI 1.01–1.96; p = 0.04), hydronephrosis (HR 1.63, 95% CI 1.23–2.16; p = 0.001) and use of chemotherapy other than ddMVAC (HR 0.57, 95% CI 0.34–0.94; p = 0.03) were associated with shorter overall survival. For the whole cohort, the presence of CIS was also not associated with survival (HR 1.05 (95% CI 0.82–1.35; p = 0.70).ConclusionIn this multicenter, real-world cohort, CIS status at TURBT did not affect pathologic response to neoadjuvant or induction chemotherapy. This study is limited by its retrospective nature as well as variability in chemotherapy regimens and surveillance regimens.

MP58-04 DENSE DOSE MVAC VERSUS GC IN PATIENTS WITH CT3-4A BLADDER CANCER TREATED WITH RADICAL CYSTECTOMY: A REAL WORLD EXPERIENCE

Homayoun Zargar*, Vancouver, Canada; Jay B Shah, Houston, TX; Elisabeth E Fransen van de Putte, Amsterdam, Netherlands; Kylea R. Potvin, London, Canada; Kamran Zargar-Shoshtari, Tampa, FL; Bas W van Rhijn, Amsterdam, Netherlands; Siamak Daneshmand, LA, CA; Jeff M Holzbeierlein, Kansas City, KS; Philippe E Spiess, Tampa, FL; Eric Winquist, London, Canada; Simon Horenblas, Amsterdam, Netherlands; Colin Dinney, Houston, TX; Peter C Black, Vancouver, Canada; Wassim Kassouf, Montreal, Canada; Homayoun Zargar, Vancouver, Canada

Imaging in Localized and Advanced Bladder Cancer

Bladder cancer is the most common neoplasm of the urinary tract and imaging has become vital in both the diagnosis and management of these patients. There are many different imaging modalities (e.g. ultrasound, computed tomography, magnetic resonance imaging, positron emission tomography, bone scans), each with their specific applications. It is important to understand the merits of each modality to use them in the proper clinical setting. As the use of neoadjuvant chemotherapy becomes more prevalent, accurate clinical staging of patients with advanced disease is paramount. This chapter discusses the role of multiple imaging modalities in the setting of both non-muscle invasive and muscle invasive bladder cancer, as well as in the setting of neoadjuvant chemotherapy and surveillance.

735 Nomogram predicting cancer specific mortality (CSM) after neoadjuvant chemotherapy and radical cystectomy for muscle-invasive bladder cancer (BC): Results of an international consortium

INTRODUCTION AND OBJECTIVES: Long non-coding RNAs (lncRNAs) are emerging as important drivers of disease progression, and have been shown to modulate gene expression at several levels. Unfortunately, the molecular functions of a majority of lncRNAs identified are still poorly understood. While recent studies have identified subtypes of muscle-invasive bladder cancer (MIBC) at the mRNA level, the overall goal of this study is to obtain a deeper understanding of the lncRNAs that contribute to the molecular mechanisms that underlie the intrinsic subtypes of MIBC. METHODS: In this study, we utilized TCGA’s RNA-sequencing data to extract whole genome lncRNA expression from 211 MIBCs. Unsupervised consensus clustering was utilized to identify subtypes based on lncRNA expression profiles, and differential expression analysis was performed in the R statistical programming environment. To further study the lncRNAs associated with the luminal subtype, cell lines were exposed to rosiglitazone, a PPARg agonist, and RNA-sequencing was performed. PPARg associated lncRNA candidates were validated in an independent cohort using quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: Consensus clustering of lncRNA expression identified two intrinsic subtypes of MIBCs, which were synonymous with the intrinsic basal and luminal subtypes recently discovered through mRNA expression profiling. Previous work has shown that PPARg is amplified in approximately 15% of luminal MIBCs, and luminal MIBCs are enriched with an activePPARgmRNAexpression signature. In this study, lncRNAs up-regulated after exposure to rosiglitazone were highly expressed in luminal MIBCs, as confirmed by gene set enrichment analysis (GSEA). Differential expression analysis revealed SNHG18 to be up-regulated after PPARg activation, and to be highly expressed in luminal MIBCs. RNA immunoprecipitation studies confirmed that SNHG18 is directly bound by PPARg, and subsequent knockdown of SNHG18 resulted in decreased expression of several luminal PPARg target genes including uroplakins and fibroblast growth factor receptor-3 (FGFR3). CONCLUSIONS: Currently, FGFR3 is an important therapeutic target in MIBCs with activating mutations occurring in approximately 17% of cases. Overall, we have identified a novel lncRNA, SNHG18, to be a co-activator of PPARg that controls downstream expression of FGFR3. The results suggest that SNHG18 could potentially serve as a predictive biomarker, or as a possible drug target to increase the efficiency of FGFR3 targeted therapies.

Penis, Testis, Urethra, and Other Genitourinary Malignancies

There are other urologic malignancies that can be seen in the geriatric population. Of those discussed in this chapter, penile cancers are likely the most common that will be encountered in this age group, and early diagnosis and treatment are essential in order to optimize outcomes. Testicular neoplasms, also discussed herein, are not as common but do occur and are usually associated with a good prognosis, although secondary malignancies at this site require different treatment algorithms compared to germ cell tumors. Urethral cancers of both the male and female are exceedingly rare and associated with a poor prognosis unless diagnosed at an early stage. Evaluation and management for these cancers is not different in other age groups; however, comorbid diseases may complicate treatment and outcomes. Lastly, within this group long-term complications of radiation therapy are increasingly seen affecting other organ systems as well as health-related quality of life.

Preoperative Preparation and Care

The feasibility of robotic radical cystectomy has been established. Given the advanced age of presentation, a thorough evaluation, involving cancer staging, review of medical history, and physical examination, is of utmost importance. Contraindications are similar to any laparoscopic surgery but special attention should be taken to underlying pulmonary disease. Mechanical bowel preparation is no longer considered necessary nor is the routine use of postoperative nasogastric tube use. Standardized postoperative pathways can possibly reduce hospital stay and morbidity.