Bladder Cancer - Volume 5, issue 1

Authors: Koshkin, Vadim S. | O’Donnell, Peter | Yu, Evan Y. | Grivas, Petros

Article Type: Review Article

Abstract: Background: HER2 (ErbB2) is a receptor of the Human Epidermal Growth Factor Receptor (HER) family whose role in oncogenesis of numerous malignancies is well described. Drugs targeting HER2 are currently approved in breast and gastroesophageal cancers while pan-HER targeting agents are being evaluated in multiple malignancies. HER2 genomic alterations are commonly described in urothelial cancer and multiple trials have assessed the efficacy of anti-HER2 agents in both muscle-invasive and metastatic urothelial carcinoma. Objective: To review prospective clinical trials of therapeutic agents with HER2– targeting activity in patients with bladder cancer. Methods: A systematic search of PubMed, …ASCO abstracts and Clinicaltrials.gov was performed to identify studies of HER2– targeting agents in bladder cancer. Reported results from prospective trials were reviewed and summarized. Results: Eleven prospective clinical trials with reported results were identified that investigated activity of trastuzumab, lapatinib, neratinib, afatinib, or autologous cellular immunotherapy (DN24–02) in various bladder cancer treatment settings. Another 11 prospective trials that include bladder cancer patients and are investigating agents with anti-HER2 activity are currently ongoing or have completed enrollment but do not have published results. The reported clinical trials had variable HER2– positivity inclusion criteria and most did not meet their pre-specified benchmarks of clinical efficacy. A recent afatinib trial in an unselected patient population had promising findings in patients with HER2 and HER3 alterations. Conclusion: Trials of HER2– targeting agents generally in unselected bladder cancer patients have not shown definitive clinical efficacy. Better patient selection, such as via utilization of next-generation sequencing assays that detect specific genomic alterations, and novel therapy combinations that include HER2– targeting agents (with immunotherapy or other modalities) may lead to improved outcomes in current, ongoing or future trials. Show more

Keywords: Bladder cancer, urothelial carcinoma, HER2, ERBB2, HER family, targeted therapy, trastuzumab, afatinib, lapatinib, neratinib

DOI: 10.3233/BLC-180196

Citation: Bladder Cancer, vol. 5, no. 1, pp. 1-12, 2019

Authors: Liu, Nick W. | Murray, Katie S. | Donat, S. Machele | Herr, Harry W. | Bochner, Bernard H. | Dalbagni, Guido

Article Type: Research Article

Abstract: Purpose: While a definitive cure can be achieved by radical cystectomy and pelvic lymph node dissection in select patients with regional lymphadenopathy, the benefit remains uncertain in patients who present with non-regional metastases. We analyzed the survival outcomes of post-chemotherapy retroperitoneal lymph node dissection. Materials and Methods: We reviewed our institutional database and identified 13 patients with radiographically evident or biopsy proven retroperitoneal nodal metastases with a significant response to chemotherapy. These patients underwent consolidative surgery with concomitant or delayed retroperitoneal lymph node dissection. The primary endpoints were progression-free survival and disease-specific survival from the time …of retroperitoneal lymph node dissection. Results: All patients had primary urothelial cell carcinoma. Twelve patients underwent concomitant radical cystectomy, pelvic and retroperitoneal lymph node dissection. Seven patients (54%) had residual disease in the retroperitoneum and the median number of retroperitoneal nodes containing metastases was 4 (IQR 2–6). Six (86%) developed disease recurrences within 2 years of surgery and 5 (71%) died of cancer. Of the 6 patients without residual disease in the retroperitoneum, 2 (33%) developed recurrences and died of disease progression. The 2-year disease-specific survival was worse for patients with residual disease in the retroperitoneum than those without residual retroperitoneal disease (34%, 95% CI 5–68 vs 50%, 95% CI 6–85). Conclusions: The presence of retroperitoneal nodal metastases at post-chemotherapy retroperitoneal lymph node dissection is a poor prognosticator. Consolidative surgery with retroperitoneal lymph node dissection provides important prognostic information and may be therapeutic in a very small subset of these patients. Show more

Keywords: Surgery

DOI: 10.3233/BLC-180186

Citation: Bladder Cancer, vol. 5, no. 1, pp. 13-19, 2019

Authors: Kleinmann, Nir | Wirth, Gregory | Lin, Jeffrey S. | Matin, Surena F. | Nativ, Ofer | Mayer, Gil | Witjes, J. Alfred | Shvero, Asaf | Chamie, Karim | Pantuck, Allan J. | Smith, Angela | Schoenberg, Mark | Malchi, Nadav | Hakim, Gil | Agmon-Gerstein, Yael | Jeshurun-Gutshtat, Michal | Klein, Ifat | Kopelen, Helen | Lerner, Seth P.

Article Type: Research Article

Abstract: Background: There is an unmet need for an effective local treatment of upper tract urothelial carcinoma (UTUC). Drug delivery to the pyelocaliceal system and pursuant efficacy of intracavitary therapy is limited by urine production that washes the drug away, shortening dwell time and direct contact with the urothelium. Successful endoscopic management is often dictated by lesion size, grade, and focality. A thermo-reversible hydrogel formulation of Mitomycin C (UGN-101, formerly MitoGel) was developed and has demonstrated the safety and feasibility of increased time of the drug in the pyelocaliceal system resulting in chemoablation of tumors. Objectives: To examine the …efficacy and safety of UGN-101 used for chemoablation of UTUC. Methods: There were 22 patients approved for compassionate use treatment at 14 institutions. Six-weekly instillations of UGN-101 were administered via ureteral catheter or percutaneous nephrostomy. Ureteroscopy was performed 2–6 weeks following treatment completion for response determination. Adverse events were recorded throughout treatment. Patients were followed up according to the standard of care of each center. Results: Median age of the cohort was 75 yrs., with 16 (73%) males. Eighteen patients had low-grade (LG) tumors, 2 high-grade (HG), and 2 had indeterminate grade. Median volume of UGN-101 instilled was 13.5cc with median Mitomycin dosage of 54 mg. Eight patients had complete response (36%) including 44% (8/18) of the patients with low grade tumors. Partial responses were observed in 23% and 28% of LG. Two patients had no response (9%) and 1 did not undergo ureteroscopy. Four patients could not complete 6 weeks due to adverse events (pyelonephritis, acute renal failure, pancytopenia, and unstable cardiac condition); 1 patient was diagnosed with a non-urothelial cancer during treatment; and 1 patient died prior to the third instillation due to suspected pulmonary embolus, determined to be unrelated to treatment with UGN-101. Out of the patients who had a complete response, 3 (37.5%) patients are recurrence free from 18–30 months. A total of 83 adverse events were recorded. Of these, 6 events related to UGN-101 were serious (requiring medical intervention), and 23 events related to UGN-101 were not serious. Conclusions: This compassionate use program of UGN-101 demonstrates proof of concept for chemoablation treatment of UTUC. A single arm Phase III multi-center registration trial to treat patients with low-grade low-volume renal pelvis tumors is open and enrolling patients (NCT02793128). Show more

Keywords: Mitomycin, urothelial carcinoma, urologic neoplasms, drug delivery systems, upper urinary tract

DOI: 10.3233/BLC-180182

Citation: Bladder Cancer, vol. 5, no. 1, pp. 21-29, 2019

Authors: Alberto, Matthew | Demkiw, Stephanie | Goad, Jeremy | Jenkins, Mark | Duggan, Genevieve | Mow, Tyler | Wong, Lih-Ming

Article Type: Research Article

Abstract: Background and Objectives: To validate the European Organization for Research and Treatment of Cancer (EORTC) model using an Australian cohort and to identify variables within our cohort that may predict non-muscle invasive bladder cancer (NMIBC) recurrence and progression. Methods: A retrospective chart review of patients undergoing transurethral resection of bladder tumour (TURBT) at a single academic institution between 1995 and 2015 was performed (n  = 366). Only patients with available TURBT pathology having initial Ta or T1 disease were included (n  = 255). EORTC risk groups were calculated for individual patients and compared to actual recurrence rates using a binomial …method comparing observed and expected proportions. Results: In our cohort of 255 patients, there were 209 men and 46 women, with a median age of 69 years (range 18–93). Intravesical therapy was given to 59% (n  = 152). In total, 142 patients (56%) experienced cancer recurrence, with median recurrence and progression free survival at 11 months and 25.5 months respectively. Comparison of EORTC estimates to actual recurrence proportions at 1, 3 and 5 years showed the EORTC calculator underestimated the actual recurrence that occurred. However, only EORTC group “score 1–4” estimate was statistically significant compared to the actual recurrence (at 1 year, predicted 24% vs actual 33%, p  < 0.001). Conclusion: In validating the EORTC risk calculator in our Australian cohort, we found the calculator underestimated NMIBC recurrence for most of our patients. Longer follow-up time and a larger sample size may assist with validation but true differences in population and treatment may exist. Our results suggest for now, care should be exercised when applying these risk tables to an Australian population. Show more

Keywords: Non-muscle invasive bladder cancer, EORTC risk tables, recurrence, Australia

DOI: 10.3233/BLC-180199

Citation: Bladder Cancer, vol. 5, no. 1, pp. 31-38, 2019

Authors: Steinberg, Ryan L. | Thomas, Lewis J. | Mott, Sarah L. | O’Donnell, Michael A.

Article Type: Research Article

Abstract: Background: Bacillus Calmette-Guerin (BCG) toxicities have been reported but with relative agranularity regarding severity and temporal changes during therapy. In its most severe form, BCG intolerance remains poorly understood and exploring ways to optimize toleration of the most effective treatment (BCG) is prudent. Objective: To report the results of both patient- and physician-centered metrics of BCG toxicity as part of the National Phase II BCG/Interferon (IFN) study, as well as the efficacy of low-dose BCG/IFN for previously deemed BCG intolerant patients. Methods: Patients were treated with 6 weekly treatments of BCG (various dosing based on prior …BCG exposure) with 50 million units of IFN. BCG intolerance was strictly defined. Maintenance BCG was instituted if disease free. Treatment tolerance during induction was measured using physician- and patient-completed evaluations. Linear mixed effects regression was used to evaluate differences. Results: 533 BCG naïve, 415 BCG failure, and 37 BCG intolerant patients were enrolled. There was no significant difference in quality of life scores between groups (p  = 0.70). A predictable temporal toxicity pattern was identified in all groups with symptom resolution by day 2-3. Despite BCG intolerant patients having significantly worse bladder pain/spasms and cystitis, treatment discontinuation was under 4%. Recurrence-free survival was similar between naïve and intolerant patients. Conclusions: BCG toxicity is common and follows a predictable pattern. While at slightly increased risk of toxicity, BCG intolerant patients may be managed successfully with 1/10th dose BCG with IFN. Show more

Keywords: Urinary bladder neoplasms, mycobacterium bovis, immunotherapy

DOI: 10.3233/BLC-180203

Citation: Bladder Cancer, vol. 5, no. 1, pp. 39-49, 2019

Authors: McMullen, Carmit K. | Kwan, Marilyn L. | Colwell, Janice C. | Munneke, Julie R. | Davis, James V. | Firemark, Alison | Brooks, Neon | Grant, Marcia | Gilbert, Scott M. | Altschuler, Andrea

Article Type: Research Article

Abstract: Background: Bladder cancer patients who undergo cystectomy and urinary diversion face functional and quality-of-life challenges. Little is known about these patients’ experiences during decision-making, surgery, and recovery, or how they vary by treatment setting. Objective: To learn about patients’ experiences with treatment choice, surgical care, and recovery across health settings. Understanding patient experiences is essential to closing care gaps and developing patient-reported measures. Methods: We conducted focus groups with cystectomy patients and family caregivers at a large comprehensive health care system (N = 32 patients) and an NCI-designated comprehensive cancer center (N = 25 patients and 5 caregivers). Using standard …qualitative methods, we identified themes that are not well-represented in existing research. Results: Across both systems, patients described variable experiences in decision-making about their cystectomy and urinary diversion. Some felt overwhelmed by information; others felt poorly informed. Many found self-care equipment challenging; many felt they knew little about what to expect regarding chemotherapy, recovery, and transitioning home. At times, health care personnel could not help manage patients’ ostomies or catheterization equipment. Our study also contributes a grounded theoretical framework for describing meaningful domains of patient experience with cystectomy and urinary diversion. We identified a common trajectory that includes decision-making, surgery and post-operative recovery, mastery of self-care, and reintegration. Conclusions: Patients with radical cystectomy and urinary diversion report a wide variety of experiences not captured by quantitative measures. These findings demonstrate that many cystectomy patients could benefit from additional post-operative support. We offer a framework to measure patient-centered domains in future research. Show more

Keywords: Patient-reported outcomes, bladder cancer, cystectomy, qualitative methods, focus groups

DOI: 10.3233/BLC-180202

Citation: Bladder Cancer, vol. 5, no. 1, pp. 51-61, 2019

Authors: Chand, Damini | Dhawan, Deepika | Sankin, Alexander | Ren, Xiaoxin | Lin, Juan | Schoenberg, Mark | Knapp, Deborah W. | Zang, Xingxing

Article Type: Research Article

Abstract: Background: B7x (B7-H4/B7S1/VTCN1), an inhibitory immune checkpoint molecule is a potential therapeutic target owing to its immunosuppressive effect and well-known expression in cancers. Immune checkpoints in canine bladder cancer are largely undefined. Here, we report the first evaluation on expression of B7x in spontaneous canine invasive bladder cancer, a novel model system for the study of invasive human urothelial carcinoma. Objective: This work aims to study expression of immune checkpoint B7x in spontaneous canine invasive bladder cancer. Methods: RNA-seq analysis was performed to determine B7x expression in tumor versus normal bladder. Gene ontology (GO) study was …used to explore the biological role of B7x. B7x protein expression was evaluated by immunohistochemistry (IHC). TCGA and GTEx were used to examine B7x expression in 599 human bladder urothelial carcinoma (BLCA). Results: RNA-seq analysis indicated 5.72 and 7.04 fold up regulation of B7x in tumors, using DESeq2 and edge R respectively (p  < 0.00008). B7x was closely associated with immune processes in GO analysis. IHC results revealed 60% of cases as B7x positive. B7x intensity was scored as negative in 40% (n  = 20/50), low in 24% (n  = 12/50), medium in 14% (n  = 7/50) and high in 22% (n  = 11/50) of cases. In human BLCA, B7x expression was significantly associated with worse overall survival (p  = 0.02). Conclusions: Our results suggest that B7x is over expressed in canine bladder cancer. Thus canine model can be vital in advancing the translational research on B7x, a new potential therapeutic target in human bladder cancer. Show more

Keywords: Canine bladder cancer, immune checkpoint, immunotherapy, human bladder urothelial carcinoma

DOI: 10.3233/BLC-180204

Citation: Bladder Cancer, vol. 5, no. 1, pp. 63-71, 2019

Authors: Grossman, H. Barton | Lamm, Donald | Sjödahl, Gottfrid | O’Donnell, Michael | Hahn, Noah | Kamat, Ashish

Article Type: Meeting Report

Abstract: Non-muscle invasive bladder cancer is marked by frequent recurrences and a risk for progression to life threatening disease. Intravesical Bacillus Calmette–Guérin (BCG), one of the earliest effective immunotherapies for cancer, remains the current standard for treating high-risk non-muscle invasive bladder cancer. Optimal treatment with BCG includes periodic 3 weekly maintenance instillations, often with dose reduction to minimize toxicity. However, despite its efficacy, treatment failure is common. Efforts to provide alternate and potentially more effective therapy for this disease include increased understanding of bladder cancer through molecular profiling, multi-agent intravesical chemotherapy, and novel forms of immunotherapy.

Keywords: Bladder cancer, BCG, immunotherapy, intravesical chemotherapy, molecular profiling

DOI: 10.3233/BLC-180198

Citation: Bladder Cancer, vol. 5, no. 1, pp. 73-80, 2019

Authors: Soloway, Mark S.

Article Type: Case Report

DOI: 10.3233/BLC-189041

Citation: Bladder Cancer, vol. 5, no. 1, pp. 81-82, 2019

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

Article Type: Other

DOI: 10.3233/BLC-189043

Citation: Bladder Cancer, vol. 5, no. 1, pp. 83-84, 2019