Bladder Cancer Journal Vol. 6 Issue 1

Chemotherapy Plus Immune Check-Point Inhibitors in Metastatic Bladder Cancer

BACKGROUND: Urothelial tumors are one of the most prevalent cancers worldwide. Cisplatin-based chemotherapy has been the standard first-line treatment for metastatic urothelial cancer (mUC). After nearly three decades of limited advances in the treatment, immune checkpoint inhibitors (ICI) are now available. Responses to immunotherapy (IO) may be long lasting and sustained but only occur in 20–30% of patients. Studies have shown that combining IO with different targeted therapies can lead to potentiating effects with promising results. The first result combining ICI plus chemotherapy shows positive outcomes over standard-of-care in first line mUC. The aim of this article is to review the results, the benefits and new challenges that the combination of chemotherapy and IO can bring to patients with metastatic urothelial carcinoma.

Lifestyle and Non-muscle Invasive Bladder Cancer Recurrence, Progression, and Mortality: Available Research and Future Directions

BACKGROUND:A broad, comprehensive review of studies exploring associations between lifestyle factors and non-muscle invasive bladder cancer (NMIBC) outcomes is warranted to consolidate recommendations and identify gaps in research. OBJECTIVE: To summarize the literature on associations between lifestyle factors and clinical outcomes among patients with NMIBC. METHODS: PubMed was systematically queried for articles published through March 2019 regarding lifestyle factors and recurrence, progression, cancer-specific mortality, and all-cause mortality among patients with NMIBC. RESULTS: Notwithstanding many ambiguities, there is good-quality evidence suggesting a benefit of smoking avoidance/cessation, healthy body mass index (BMI), and type II diabetes mellitus prevention and treatment. Lactobacillus casei probiotic supplementation may reduce recurrence. There have been individual studies suggesting a benefit for uncooked broccoli and supplemental vitamin E as well as avoidance of supplemental vitamin B9, areca nut chewing, and a “Western diet” pattern high in fried foods and red meat. Additional studies do not suggest associations between NMIBC outcomes and use of fibrin clot inhibitors; insulin and other oral hypoglycemics; statins; supplemental selenium, vitamin A, vitamin C, and vitamin B6; fluid intake and intake of specific beverages (e.g., alcohol, coffee, green tea, cola); various dietary patterns (e.g., Tex-Mex, high fruit and vegetable, low-fat); and occupational and chemical exposures. CONCLUSIONS:Despite a myriad of publications on lifestyle factors and NMIBC, a need remains for research on unexplored associations (e.g., physical activity) and further studies that can elucidate causal effects. This would inform future implementation strategies for healthy lifestyle change in NMIBC patients.

Salvage Hyperthermic Gemcitabine and Docetaxel Combination Chemotherapy After BCG Failure in Non-Muscle Invasive Bladder Cancer Patients

BACKGROUND: Bacillus Calmette-Guerin (BCG) is the recommended therapy for high and intermediate risk non-muscle invasive bladder cancer (NMIBC), but treatment failure is common. While a radical cystectomy is recommended after BCG failure, some patients desire bladder preservation and others are poor surgical candidates. Salvage chemotherapy treatments may be offered to this subgroup of patients. OBJECTIVE: To assess if combination, hyperthermic Gemcitabine and Docetaxel chemotherapy (GEM/DOCE) is a safe and effective salvage option for treating NMIBC. METHODS: Sixty patients who received our GEM/DOCE protocol between 2007–2017 were identified (51 BCG failures, 9 BCG naïve). This study measured overall treatment success, defined as no recurrence, progression, cystectomy, nor death due to bladder cancer. Kaplan-Meier curves were used to ascertain probability of treatment success. The log-rank test was used to identify factors associated with treatment success. RESULTS: Sixty patients received treatment with a median follow-up of 14.9 months. All patients completed the induction course with no significant adverse effects. Overall treatment success was 83% at first surveillance, 69% at 1 year, and 55% at 2 years in the entire cohort, and 90% at first surveillance, 74% at 1 year, and 56% at 2 years in the BCG-failure patients. All-cause and bladder-cancer-specific survival were both 97.9% at 1 year, 85.9% and 94.6% respectively at 2 years. Three patients underwent cystectomy at a median of 10.2 months, two of these were secondary to recurrences. Three patients had progression of their disease. CONCLUSIONS: Hyperthermic GEM/DOCE seems to be a well-tolerated salvage regimen that demonstrates a reasonable efficacy and warrants further investigation.

Implementation of a Reduced Opioid Utilization Protocol for Radical Cystectomy

BACKGROUND: Radical cystectomy (RC) often requires a prolonged course of opioid medications for postoperative pain management. We implemented a Reduced Opioid Utilization (ROU) protocol to decrease exposure to opioid medications. OBJECTIVE: To determine the impact of the ROU protocol on opioid exposure, pain control, inpatient recovery, and complication rates among patients who underwent RC. METHODS: The ROU protocol includes standardized recovery pathways, a multimodal opioid-sparing pain regimen, and improved patient and provider education regarding non-opioid medications. Opioid exposure was calculated as morphine equivalent dose (MED), and was compared between RC patients following the ROU protocol and patients who previously followed our traditional pathway. Opioid-related adverse drug events (ORADEs), pain scores, length of stay, and 90-day complications, readmission, and mortality were also compared between cohorts. RESULTS: 104 patients underwent RC, 54 (52%) of whom followed the ROU protocol. ROU patients experienced a statistically significant decrease in opioid exposure in the post-anesthesia care unit (p = 0.003) and during their postoperative recovery (85.7±21.0 MED vs 352.6±34.4 MED, p < 0.001). The ROU protocol was associated with a statistically significant decrease in ORADEs after surgery. There was no significant difference in average pain scores, length of stay, readmissions, or 90-day complication or mortality rates. CONCLUSIONS: The ROU protocol decreased opioid use by 77% without compromising pain control or increasing the rate of complications. This study demonstrates the efficacy of non-opioid medications in controlling postoperative pain, and highlights the role providers can play to decrease patient exposure to opioids after RC surgery.

BACKGROUND: The phase 3 RANGE trial found ramucirumab/docetaxel improved progression-free survival (PFS) versus placebo/docetaxel (median 4.1 vs 2.8 months; hazard ratio [HR] = 0.757, p = 0.0118) for treatment of platinum-refractory metastatic urothelial carcinoma (UC). Some patients received an immune checkpoint inhibitor (ICI) prior to RANGE. In other studies, unselected patients with platinum-refractory UC exhibited an overall response rate (ORR) of 15–31% to ICIs. OBJECTIVE: Efficacy and safety data from the subgroup of patients treated with prior ICI were examined using prespecified analyses to compare outcomes between RANGE treatment arms. METHODS: Randomized, double-blind RANGE study (n = 530) took place July 2015-April 2017 in 23 countries. Forty-five patients (8.5%) received prior ICI. PFS was evaluated using the Kaplan-Meier method and unstratified Cox proportional hazards model. RESULTS: 17 ramucirumab/docetaxel arm, 28 placebo/docetaxel arm patients were treated with an ICI. The prior-ICI ramucirumab subgroup had worse Bellmunt scores at baseline versus placebo (score of 2-3 : 70.6% vs 25%, respectively). Most patients (84.4%) received the ICI immediately following platinum and immediately prior to RANGE. ORR to prior ICI was 6.7% Responses were achieved by 5/17 (29.4%) on ramucirumab/docetaxel, compared to 2/28 (7.1%) on placebo/docetaxel. Median PFS was 3.15 months on ramucirumab/docetaxel versus 2.73 months on placebo/docetaxel (HR = 0.786, 95% CI = 0.404–1.528, p = 0.4877). The frequency of grade≥3 adverse events was similar between arms. Limitations include sample size and treatment setting of the analyzed population. CONCLUSIONS: Ramucirumab/docetaxel may provide a clinical benefit with acceptable safety in the third-line setting for metastatic UC patients whose disease has progressed on both prior platinum chemotherapy and ICI therapy.

Statins are Associated with Reduced Overall and Cancer-Specific Mortality in Patients Undergoing Radical Cystectomy for Bladder Cancer

BACKGROUND: Existing literature provides contrasting data on statin use and bladder cancer (BC) outcome. OBJECTIVE: We evaluated whether (chronic) statin use was associated with clinical outcomes in patients with BC undergoing radical cystectomy (RC). METHODS: Using provincial health administrative databases, we retrospectively identified BC patients undergoing RC in Quebec province in 2000-2015, and collected data from two years before RC until December 2016 or death. We compared patients who chronically used statins before RC to never statin users. Survival analyses were conducted using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. Covariates in multivariable analyses were age, sex, Charlson’s comorbidity index, year of RC, distance to hospital, hospital type, hospital’s and surgeon’s annual RC volume, and neoadjuvant chemotherapy. RESULTS: Our cohort contained 1406 chronic and 1754 never statin users. Five-year overall, BC-specific and recurrence-free survival rates were 40.5% (95% confidence interval (95% CI) 37.8–43.2%), 52.8% (95% CI 49.8–55.7%), and 50.1% (95% CI 47.2–53.0%) for chronic statin users, versus 34.9% (95% CI 32.5–37.2%), 45.5% (95% CI 42.9–48.1%), and 43.4% (95% CI 40.9–45.9%) for never statin users (p≤0.001). In multivariable analyses, hazard ratios (HR) for death, BC-specific deaths and recurrences were 0.83 (95% CI 0.75–0.91), 0.81 (95% CI 0.72–0.91), and 0.83 (95% CI 0.74–0.93) for chronic statin users, respectively. Similar observations were made in patients with diabetes and/or cardiovascular comorbidities (p≤0.001). Clinical outcome was not improved in patients who started statins in the year following surgery compared to never statin users (p > 0.4). CONCLUSIONS: Chronic statin use is associated with improved clinical outcome in BC patients undergoing RC in Quebec.

Does 5-alpha Reductase Inhibitor Use Improve The Efficacy of Intravesical Bacille Calmette-Guérin (BCG) for Non-muscle Invasive Bladder Cancer?

BACKGROUND: Prior research implicates the androgen receptor pathway as important in bladder cancer progression and recurrence. In particular, use of 5-alpha reductase inhibitors (5-ARIs) appears to improve bladder cancer outcomes. This study aims to determine if concomitant use of 5-ARIs with intravesical Bacille Calmette-Guérin (BCG) decreases recurrences in patients with non-muscle invasive bladder cancer (NMIBC). MATERIALS & METHODS: This retrospective analysis included male patients diagnosed with NMIBC who were treated with induction intravesical BCG at our institution from 2013 to 2018. Patients were excluded who received prior induction BCG. Recurrence and progression-free survival were estimated using the Kaplan-Meier method. Univariate and multivariate analyses were performed using Cox proportional hazards and Poisson events models. RESULTS: We identified 206 male patients, of whom 39 received 5-ARIs and 167 did not. Most patients (72.8%) received >6 instillations of BCG, with 20.4% completing all induction and maintenance treatments during a median follow up of 3.31 years. There were no significant differences in recurrence or progression-free survival between 5-ARI users or non-users (59% vs 55.7%; p = 0.72 and 97.4% vs 98.2%; p = 1.00, respectively). Similarly, no differences in the number of recurrences between groups was observed (p = 0.78). However, the proportion of patients who completed all prescribed BCG installations was higher among 5-ARI users (39.7% vs 17.9 %, p = 0.07). CONCLUSIONS: In contrast to prior reports, our study does not suggest that 5-ARI use decreases the recurrence rate in men receiving induction BCG for NMIBC. However, our results suggest 5-ARI use may improve patient tolerance to BCG.

Plasmacytoid Urothelial Carcinoma: Response to Chemotherapy and Oncologic Outcomes

BACKGROUND: Plasmacytoid urothelial carcinoma is a rare bladder cancer variant with scarce data on outcomes and prognostic factors. OBJECTIVE: We report our institutional experience with this histology to determine response to neoadjuvant chemotherapy, definitive surgery and survival. METHODS: We conducted a retrospective chart review of consecutive patients with plasmacytoid, as well as conventional urothelial carcinoma (for comparison) seen in our institution (2007– 2018). Baseline characteristics, clinicopathologic and treatment data were captured. T-test, chi-squared and log-rank test was used for group comparison. Kaplan Meier method was used for estimation of overall survival and Cox regression for identification of prognostic factors. RESULTS: 64 patients with plasmacytoid and 418 with conventional urothelial histology were identified; 53% of those with plasmacytoid presented with cT3/4 stage and 67% underwent extirpative surgery. Patients with plasmacytoid histology had higher rates of pT3/4 (65% vs. 28%), nodal disease (37% vs. 16%) and positive surgical margins (23% vs. 5%) compared to urothelial group (p < 0.01), as well as higher incidence of post-operative recurrence (47% vs. 29%, p = 0.05) and lower ypT0N0 rates after neoadjuvant chemotherapy (10% vs. 33%, p = 0.03). Plasmacytoid histology was associated with lower median overall survival compared to conventional urothelial (24 vs. 154 months, p < 0.01). CONCLUSIONS: Plasmacytoid urothelial carcinoma frequently presented with advanced stage at diagnosis and extirpative surgery, poor pathologic response to neoadjuvant chemotherapy, and inferior outcomes, when compared to conventional urothelial. Prospective trials evaluating upfront cystectomy versus preoperative chemotherapy and/or novel treatments should be considered.

Limited Stage Small Cell Bladder Cancer: Outcomes of a Contemporary Cohort

BACKGROUND: Limited stage small cell bladder cancer is curable with multi-modality therapy using external beam radiotherapy or radical cystectomy. The optimal management strategy for this rare disease is still debated, yet few case series have described patients treated after 2010. OBJECTIVE: To analyze outcomes from a contemporary cohort of patients undergoing definitive treatment. METHODS: Patients diagnosed with small cell bladder cancer after January 1, 2010 were identified from an institutional database. Clinical histories were collected by chart review. Survival outcomes were analyzed in patients who received curative-intent therapy consisting of bladder radiotherapy or cystectomy. RESULTS: Thirty patients with limited stage disease that received definitive therapy were identified. Seventeen patients received primary radiotherapy, and thirteen underwent cystectomy. Median age was 70 years. Median follow up was 39.6 months (range 7.2–95.8). The median overall survival of patients undergoing radiotherapy or cystectomy were 36.8 and 30.6 months, respectively (hazard ratio 0.99, 95% confidence interval 0.35–2.85). The median metastasis free survival for patients receiving radiotherapy was not reached, and 18.9 months in the cystectomy group (hazard ratio 0.94, 95% confidence interval 0.34–2.61). The most common sites of relapse were lymph node (n = 6) and bone (n = 5). Brain metastases were less common (n = 3). CONCLUSIONS: Patients receiving cystectomy or radiotherapy had similar outcomes in this contemporary series, but definitive comparisons are limited by the cohort size and high censoring rate (53%). Survival in our cohort is improved compared with older reports, though outcomes remain poor, reiterating the need for better therapeutic options.