Bladder Cancer - Volume 3, issue 2

Authors: Pan, Qi | Sathe, Anuja | Black, Peter C. | Goebell, Peter J. | Kamat, Ashish M. | Schmitz-Draeger, Bernd | Nawroth, Roman

Article Type: Review Article

Abstract: Patients with metastatic bladder cancer (mBC) treated with cisplatin-based chemotherapy have a limited median survival of only around 14 months [1 ]. Despite over 30 years of basic and clinical research, until recently no therapeutic options beyond cisplatin-based therapy had entered clinical routine and, at least in the US, none of the tested agents had been approved for second-line treatment. This has changed with the advent of immune checkpoint blockade, including especially PD-1/PD-L1 inhibitors. The high response rates of 24% over a 14.4 month follow up led to the first US Food and Drug Administration (FDA) approval for a second …line therapy for these patients, and it is likely that this marks the beginning of a new era in the systemic treatment of muscle-invasive bladder cancer [2–4 ]. The strong clinical need to improve the medical management of this disease for those patients, not responding to current therapy has led to an increased molecular understanding of bladder cancer and has forstered the development of many potential molecular manipulations and targeted strategies beyond the new immune-oncologic approaches. Among the molecular alterations indentified in bladder cancer, cell cycle deregulation appears to be a key driver of disease progression. Target-directed therapy against CDK4/6 is an emerging strategy to regain control of cell cycle deregulation. Here, we provide an overview of the current status of CDK4/6 inhibitors in cancer therapy, their potential use in mBC and the challenges for their clinical use. Show more

Keywords: Bladder cancer, targeted therapy, CDK4/6 inhibitor, cell cycle, retinoblastoma

DOI: 10.3233/BLC-170105

Citation: Bladder Cancer, vol. 3, no. 2, pp. 79-88, 2017

Authors: Tazeh, Ngii N. | Canter, Daniel J. | Damodaran, Shivashankar | Rushmer, Timothy | Richards, Kyle A. | Abel, E. Jason | Jarrard, David F. | Downs, Tracy M.

Article Type: Research Article

Abstract: Introduction: Neutrophil/lymphocyte ratio (NLR) is an indicator of systemic inflammation and has been proven to be associated with an increased risk of extravesical disease, decreased cancer specific survival and overall survival in bladder cancer patients. A large proportion of healthy African Americans have a WBC count that is persistently lower than the normal range defined for individuals of European ancestry, this condition has been called “benign ethnic neutropenia”. The purpose of our study was to determine if NLR was different in patients of African ancestry (AA) vs European ancestry (EA) across different tumor grades and stages at the time …of transurethral resection of bladder tumor(s) (TURBT). Materials and Methods: The records of consecutive patients who underwent TURBT were reviewed from the University of Wisconsin and the Atlanta Veterans’ Administration Medical Center (2000–2012). NLR was compared across tumor stage, tumor grade and ethnicity. Results: 297 consecutive patients met study criteria. 89% and 86%, were males and of European ancestry (EA) respectively. NLRs were different across T-stages (Ta-2.5, T1-3.9, T2-3.8; p  = 0.001). but not across tumor grades in Ta (LG-2.5 vs HG-3.9, p  = 0.57). EA had higher NLRs than AA (3.4 vs 1.9; p  < 0.001). Conclusions: Higher NLRs appear to be associated with more advanced tumor stage at the time of TURBT. Patients of African ancestry have lower NLRs across all tumor stages compared to patients of European ancestry. Ethnicity should be taken into account when interpreting the NLR in patients with bladder cancer. Show more

Keywords: Bladder cancer, transurethral resection, ethnicity, prognosis

DOI: 10.3233/BLC-160085

Citation: Bladder Cancer, vol. 3, no. 2, pp. 89-94, 2017

Authors: McIntosh, Andrew G. | Li, Tianyu | Ito, Timothy | Mannion, Jason | Dziemianowicz, Mark | Waingankar, Nikhil | Haseebuddin, Mohammed | Chen, David Y.T. | Greenberg, Richard E. | Viterbo, Rosalia | Kutikov, Alexander | Uzzo, Robert G. | Smaldone, Marc C. | Abbosh, Philip H.

Article Type: Research Article

Abstract: Background: Radical cystectomy is associated with perioperative complication rates exceeding 50% in some series. Readmission rates are increasingly used as a surgical quality metric. White blood cell count is a crude surrogate for physiologic processes which may reflect postoperative complications leading to readmission. Objective: We assessed the association between final white blood cell count at discharge and risk of readmission following radical cystectomy. Methods: Records on 477 patients undergoing radical cystectomy from 2006–2013 were reviewed. Final white blood cell count was defined as the last documented value during index admission. Univariate analysis was performed using …Fisher’s exact, Wilcoxon rank sum test, and Spearman’s coefficient tests where appropriate. Multivariable logistic regression models were used to test the associations between final white blood cell count and readmission. Results: 34% of patients were readmitted within 90 days of surgery. Amongst this cohort, a cutoff final white blood cell count of 9000/mm3 was identified, with a significantly higher proportion of patients with values >9000/mm3 experiencing readmission than those with values≤9000/mm3 (42% vs 28%, p  = 0.004). Other perioperative variables associated with an increased readmission rate included initial hospital length of stay≤10 days, and receipt of a continent diversion. Following adjustment, final white blood cell count >9000/mm3 was associated with increased risk of readmission (OR 2.09, 95% CI 1.23–3.53, p  = 0.006). Conclusions: Final white blood cell count is associated with hospital readmission following radical cystectomy. This metric may provide important guidance in discharge algorithms. Show more

Keywords: Urinary bladder neoplasms, cystectomy, patient readmission, leukocyte count

DOI: 10.3233/BLC-160088

Citation: Bladder Cancer, vol. 3, no. 2, pp. 95-103, 2017

Authors: Bachir, Bassel G. | Souhami, Luis | Mansure, Jose João | Cury, Fabio | Vanhuyse, Marie | Brimo, Fadi | Aprikian, Armen G. | Tanguay, Simon | Sturgeon, Jeremy | Kassouf, Wassim

Article Type: Research Article

Abstract: Background: Local control following trimodality therapy (TMT) for muscle-invasive bladder cancer (MIBC) requires further optimization. Objective: Evaluating the biologic endpoint, feasibility, and toxicity of integrating everolimus to TMT in patients with MIBC. Methods: This was a phase I trial in patients with MIBC who were not surgical candidates or who refused cystectomy. Following maximal transurethral tumor resection, patients were treated by radiotherapy (50 Gy/20 fractions), gemcitabine (100 mg/m2/weekly) and escalating doses of everolimus (2.5–5.0 mg/day). Everolimus was given daily for one month prior to radiation, during treatment, and one month post-radiation. Toxicity assessment followed the Radiation Therapy Oncology …Group Acute Radiation Morbidity Scoring Criteria. Biologic endpoint with downregulation of phospho-S6 (pS6) was assessed using immunohistochemistry. Local response was evaluated with imaging and bladder biopsy post-therapy. Results: 10 patients were recruited; 8 males, 2 females. Median age was 78 years (range: 63–85). Four patients entered everolimus 2.5 mg cohort. Six other patients entered everolimus 5.0 mg cohort. Toxicities were encountered in 2 patients (Grade I), 6 patients (Grade II), 9 patients (Grade III) and 1 patient (Grade IV), with some experiencing more than one toxicity. Most Grade III and IV toxicities were encountered from everolimus alone prior to combination testing. Trial was terminated early due to toxicity. Interestingly, 6/10 patients (60%) achieved a complete response with negative post-treatment biopsies. Significant decrease of pS6 was demonstrated post-therapy (p  = 0.03). Conclusions: Although combining everolimus with TMT achieved a biological endpoint and complete response in a significant number of patients with MIBC and negative prognostic factors, it was associated with unacceptable increased toxicity. Show more

Keywords: Everolimus, gemcitabine, intensity modulated radiotherapy, bladder cancer, dose hypofractionation

DOI: 10.3233/BLC-160090

Citation: Bladder Cancer, vol. 3, no. 2, pp. 105-112, 2017

Authors: Dalbagni, Guido | Benfante, Nicole | Sjoberg, Daniel D. | Bochner, Bernard H. | Machele Donat, S. | Herr, Harry W. | Mc Coy, Asia S. | Fahrner, Alicia J. | Retinger, Caitlyn | Rosenberg, Jonathan E. | Bajorin, Dean F.

Article Type: Research Article

Abstract: Background: Standard treatment for BCG-refractory urothelial cancer is radical cystectomy. Identification of active agents is clearly warranted. Objective: To determine a safe dose of oral everolimus in combination with standard intravesical gemcitabine and to evaluate the efficacy of this combination. Methods: Patients with carcinoma in situ refractory to intravesical bacillus Calmette-Guérin and refusing cystectomy were eligible. Patients in the phase I part of the trial received one of three dose levels of oral everolimus. Patients also received a fixed dose of intravesical gemcitabine. Maintenance everolimus was given for 12 months in patients achieving a …complete response confirmed by cystoscopy and cytology. Patients in phase II received continuous everolimus administered at 10 mg daily with intravesical gemcitabine followed by everolimus maintenance for 12 months of total therapy. The enrollment goal for the phase II was 33 patients. Results: 14 patients were enrolled in phase I of the trial. 23 patients were enrolled in phase II of the trial and 19 were evaluable for primary and secondary endpoints. Four patients withdrew consent prior to treatment initiation. Of the 19 patients evaluable for response, 3 (16%, 95% confidence interval [CI] 3% – 40%) were disease free at 1 yr. The probability of RFS was 20% (95% CI 5% – 42%) at 12 months. Ten patients out of 19 had grade 3 or greater toxicity events. Seven withdrew consent or were taken off study. Conclusions: Many patients withdrew, and enrollment was halted. Continuous oral everolimus plus intravesical gemcitabine was not well tolerated in this patient population where the threshold for tolerability is low. Show more

Keywords: Gemcitabine, urothelial cancer, bladder cancer, intravesical chemotherapy, phase II, everolimus, mTOR inhibitor, RAD001

DOI: 10.3233/BLC-170095

Citation: Bladder Cancer, vol. 3, no. 2, pp. 113-119, 2017

Authors: Patel, Vaibhav | Collazo Lorduy, Ana | Stern, Aaron | Fahmy, Omar | Pinotti, Rachel | Galsky, Matthew D. | Gakis, Georgios

Article Type: Research Article

Abstract: Background: Cisplatin-based combination chemotherapy is standard treatment for metastatic urothelial carcinoma; however, the vast majority of patients experience disease progression. As systemic therapy alone is rarely curative for the treatment of metastatic urothelial cancer, not only are new therapies needed but also refinement of general treatment principles. Herein, we conducted a systematic review and meta-analysis to explore the role of metastasectomy in metastatic urothelial carcinoma. Methods: We conducted a systematic review of the literature regarding local treatment for metastatic urothelial carcinoma. An online electronic search of the PubMed/MEDLINE and EMBASE databases was performed to identify peer-reviewed articles. …All procedures were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Information was then extracted including number of patients, gender, the site of the primary urothelial tumor, site of metastasis, chemotherapy before or after metastasectomy, overall survival (OS), and disease specific survival (DSS) after metastasectomy. A meta-analysis was performed with those studies with sufficient survival data to obtain pooled overall survival. The article quality was assessed using the Cochrane Handbook “risk of bias” tool. Results: Seventeen out of 3963 articles were eligible for review between 1990–2015, including a total of 412 patients. The mean time to recurrence after metastasectomy was 14.25 months. The overall survival from time of metastasectomy ranged from 2 to 60 months. Pooled analyses of studies reported survival data revealed an improved overall survival for patients treated with metastasectomy compared with non-surgical treatment of metastatic lesions (HR 0.63; 95% CI, 0.49–0.81). All, except for three studies, were retrospective and non-randomized, leading to a high risk of bias associated with patient selection, patient attrition, and reporting. Such high potential of selection bias may lead to higher OS than expected. Additionally, treatment and outcome details reported across studies was highly variable. Conclusions: Limited conclusions can be drawn from the available literature exploring the role of metastasectomy in the management of metastatic urothelial cancer due to lack of uniform reporting elements and multiple sources of bias particularly related to a lack of prospective randomized trials. As a subset of patients treated with metastasectomy achieve durable disease control, this approach may be considered for select patients. Show more

Keywords: Urothelial carcinoma, bladder cancer, metastasectomy, transitional cell carcinoma

DOI: 10.3233/BLC-170108

Citation: Bladder Cancer, vol. 3, no. 2, pp. 121-132, 2017

Authors: Luckenbaugh, Amy N. | Marks, Rory M. | Miller, David C. | Weizer, Alon Z. | Stoffel, John T. | Montgomery, Jeffrey S.

Article Type: Short Communication

Abstract: Background/Objective: A post-bladder tumor resection dose of MMC can reduce non-invasive papillary (pTa) bladder cancer recurrences by up to 40%; this treatment is recommended in both the AUA and EUA non-muscle-invasive bladder cancer guidelines. A common complication of this treatment is eosinophilic cystitis. Symptoms range from mild urinary frequency and urgency to debilitating pain and dysuria. Currently, there is no established treatment algorithm for MMC-induced cystitis. Methods: Members of the Urologic Surgery Quality Collaborative (USQC), a group composed of over 160 private and academic urologists, met to discuss the management of patients with cystitis following MMC therapy. …They devised a treatment algorithm based on experiences of urologic oncologists and neurourologists to aid in the diagnosis and management of MMC-induced cystitis. Results: The assessment begins with urinalysis and culture, followed by cystoscopy. For mild symptoms, behavioral therapy, including timed voids, fluid restriction and Kegel exercises are trialed. If symptoms have not resolved, treatment with an antihistamine, followed by a combination of anticholinergic and alpha-blocker medications. For persistent symptoms or severe symptoms at presentation, a course of prednisone plus antihistamine is prescribed. If symptoms are improving but have not resolved, this treatment is extended for a full 4 weeks prior to steroid taper. If symptoms do not improve, any visible bladder ulcerations are resected intraoperatively followed by an additional course of prednisone and antihistamine. Intravesical DMSO instillations and intra-ulcer steroid injection can be used as a final effort to treat this condition. Conclusion: We present the first formal management algorithm with escalating treatment intensity tailored to patient symptoms. Show more

Keywords: Urinary bladder neoplasms, mitomycin C

DOI: 10.3233/BLC-160089

Citation: Bladder Cancer, vol. 3, no. 2, pp. 133-138, 2017

Authors: Soloway, Mark S.

Article Type: Case Report

DOI: 10.3233/BLC-179015

Citation: Bladder Cancer, vol. 3, no. 2, pp. 139-140, 2017

Authors: Agarwal, Piyush K. | Sternberg, Cora N.

Article Type: Other

DOI: 10.3233/BLC-179016

Citation: Bladder Cancer, vol. 3, no. 2, pp. 141-142, 2017