The importance of clinical stage among patients with a complete pathologic response at radical cystectomy after neoadjuvant chemotherapy.

PURPOSE: Patients without evidence of disease at radical cystectomy (RC) following neoadjuvant chemotherapy (NAC) have the greatest potential for survival in muscle-invasive bladder cancer. Historically, 15 % of such patients will experience disease recurrence and cancer-specific mortality. We sought to evaluate the effect of pre-treatment clinical factors on the risk of recurrence in patients who were ypT0N0 at RC. METHODS: We performed a multi-institutional review of patients treated with NAC + RC for muscle-invasive bladder cancer (≥cT2) without pathologic evidence of disease at surgery (ypT0N0). The association of pre-treatment clinicopathologic features with recurrence was evaluated using Cox proportional hazards. RESULTS: A total of 78 patients were identified with ypT0 disease at RC after NAC. Median postoperative follow-up was 32.4 months (IQR 16.8, 60.0), during which time 17 patients recurred at a median of 6.4 months after RC. Estimated 3-year recurrence-free survival (RFS) of this cohort was 74.8 %. In univariate analysis, cT4 disease (HR 3.12; p = 0.04) and time to RC (HR 1.17 for each month increase; p < 0.01) were associated with inferior RFS. CONCLUSION: Patients without evidence of disease at the time of RC are still at risk of recurrence and death from bladder cancer. Higher clinical stage and increased time to RC were associated with an increased risk of recurrence and subsequent death. These data highlight the importance of timely RC and the continued risk of recurrence in higher clinically staged patients-underscoring the need for close monitoring and patient counseling.

Outcome of patients with clinically node-positive bladder cancer undergoing consolidative surgery after preoperative chemotherapy: The M.D. Anderson Cancer Center Experience.

PURPOSE: Patients with urothelial cancer with nodal metastasis have a poor prognosis, with many deemed incurable. We report outcomes of a prospective clinical protocol of patients with clinically node-positive disease treated via a multimodality treatment approach. PATIENTS AND METHODS: A total of 55 patients with bladder urothelial carcinoma with concurrent node-positive disease including pelvic nodal and retroperitoneal lymph node (RPLN) involvement underwent preoperative chemotherapy followed by consolidative surgery between 1995 and 2010. Associations between clinicopathologic factors and outcomes were analyzed using log-rank test and Cox regression analysis. RESULTS: Median cancer-specific survival (CSS) was 26 months (95% CI: 12.9-not applicable) for all patients. A total of 30 (55%) patients had pN0 category disease at the time of surgical extirpation. Despite radiologic complete response after chemotherapy, 6 of 21 patients (29%) had pN+category disease. The 5-year CSS rate was 66% for pN0 category disease vs. 12% for pN+category disease (P<0.001). Radiologic complete response to chemotherapy was associated with a 5-year CSS rate of 60% vs. 33% for a partial response (P = 0.038). Although no recurrences occurred within the lymphadenectomy template, 2 (14%) patients with cM1 RPLN disease who did not undergo RPLN dissection had recurrences in the RPLN basin and died within 6 months. CONCLUSION: Multimodality treatment approach with upfront chemotherapy followed by surgery can result in a 66% 5-year CSS rate for patients rendered as having pN0 category disease despite initially presenting with node-positive disease. However, as those with residual disease do so poorly, further efforts in refining selection of patients for surgical consolidation are needed.

In-vitro cytocidal effect of water on bladder cancer cells: The potential role for intraperitoneal lavage during radical cystectomy.

INTRODUCTION: We investigate the cytocidal effect of water on bladder cancer cells. Intraperitoneal lavage with sterile water is sometimes used during radical cystectomy to lyse cancer cells that might have escaped the surgical specimen. The efficacy of this approach at the cellular level is unknown. METHODS: Three bladder cancer cell lines of varying grade, RT4, TCCSUP and T24 were exposed to sterile water, and morphological changes were closely observed under microscopy. Changes of cell membrane integrity, cell viability, and cell number of re-incubated cells after water exposure were measured to determine water induced hypotonic shock. RESULTS: The low-grade RT4 cells started swelling immediately upon exposure to water followed by rupture within 3 minutes. The higher grade TCCSUP and T24 cells demonstrated limited hypotonic swelling with significantly less cell rupture after 10 minutes. The damage to cell membrane of RT4 cells was evident at 1 minute; only 10.0% of cells were intact at 10 minutes. On the other hand, 41.9% and 77.8% of TCCSUP and T24 cells were intact at 10 minutes, respectively. Percentage of viable cells at 10 minutes was 2.1 ± 2.3%, 2.3 ± 0.4%, and 16.1 ± 0.6% for RT4, TCCSUP, and T24, respectively. CONCLUSIONS: Cytocidal effect of hypotonic shock can be achieved, to varying degrees, by exposing bladder cancer cells to water for at least 10 minutes. This in vitro study may have bearing on the effects seen with intraperitoneal lavage using sterile water during radical cystectomy.

Immune therapies in non-muscle invasive bladder cancer.

OPINION STATEMENT: Non-muscle invasive bladder cancer (NMIBC) continues to be a challenging disease to manage. Treatment involves transurethral resection and, often, intravesical therapy. Appropriate patient selection, accurate staging, and morphological characterization are vital in risk-stratifying patients to those who would most benefit from receiving intravesical therapy. Bacillus of Calmette and Guérin (BCG) continues to be the first-line agent of choice for patients with intermediate- and high-risk NMIBC. Treatment should begin with the standard induction course of 6 weekly treatments. The inclusion of subsequent maintenance courses of BCG is imperative to optimal therapeutic response. While patients with intermediate-risk disease should receive 1 year of maintenance therapy, high-risk patients benefit from up to 3 years of maintenance therapy. BCG use should not be used in low-risk patients with de novo Ta, low-grade, solitary, <3-cm tumors. Conversely, patients with muscle-invasive disease should forgo intravesical immunotherapy and proceed directly to radical cystectomy. Cystectomy also should be considered in patients with multiple T1 tumors, T1 tumors located in difficult to resect locations, residual T1 on re-resection, and T1 with concomitant CIS. Although promising new immunotherapeutic agents, such as Urocidin, protein-based vaccines, and immune check point inhibitors are undergoing preclinical and clinical investigation, immunotherapy in bladder cancer remains largely reliant on intravesical BCG with surgical consolidation as the standard salvage treatment for patients with BCG failure.