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Bladder Cancer COE

  • FDA ALERT: RE: Label Updates in Clinical Trials for Some Patients Taking Pembrolizumab or Atezolizumab as Monotherapy to Treat Urothelial Cancer with Low Expression of PD-L1

    San Francisco, CA USA (UroToday.com) FDA Update: The FDA is restricting the use of Keytruda and Tecentriq for patients with locally advanced or metastatic urothelial cancer who are not eligible for cisplatin-containing therapy.

    This results from decreased survival associated with the use of Keytruda (pembrolizumab) or Tecentriq (atezolizumab) as single therapy (monotherapy) compared to platinum-based chemotherapy in clinical trials to treat patients with metastatic urothelial cancer who have not received prior therapy and who have low expression of the protein programmed death ligand 1 (PD-L1).
    Published June 22, 2018
  • FDA Breakthrough Therapy Designation for Erdafitinib in the Treatment of Metastatic Urothelial Cancer

    TRUCKEE, CA (UroToday.com) The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation for erdafitinib in the treatment of urothelial cancer. Urothelial cancer, most frequently in the bladder, is the sixth most common type of cancer in the U.S. A Breakthrough Therapy Designation is granted to expedite the development and regulatory review of an investigational medicine that is intended to treat a serious or life-threatening condition.  The criteria for Breakthrough Therapy Designation require preliminary clinical evidence that demonstrates the drug may have substantial improvement on at least one clinically significant endpoint over available therapy.
    Published March 16, 2018
  • TURBT More Important Than Ever

    Non-muscle invasive bladder cancer (NMIBC) will account for 75% of the 79,000 new cases of bladder cancer expected to be diagnosed in 2017. Fortunately, most cases can be successfully treated and carry a relatively good prognosis. However, depending on the grade and stage at initial diagnosis, as many as 60% of patients with NMIBC can experience orthotopic tumor recurrence within the first year after initial resection and up to 78% can recur within five years. 
    Published April 20, 2017
  • [Concurrent renal cell carcinoma and urothelial carcinoma: long-term follow-up study of 24 cases].

    Objective: To investigate the clinical manifestation, diagnosis, treatment and outcome of simultaneous occurrence of renal cell carcinoma and urothelial carcinoma. Methods: Twenty-four consecutive patients with synchronous renal cell carcinoma and urothelial carcinoma treated in our center from March 2005 to December 2015 were retrospectively reviewed.

    Published April 4, 2017
  • A Care Bundle to Improve Perioperative Mitomycin Use in Non-Muscle-Invasive Bladder Cancer – Beyond the Abstract

    There is good quality evidence that instillation of a chemotherapeutic agent such as mitomycin into the bladder within twenty-four hours of an initial transurethral bladder tumour resection reduces the rate of recurrences and prolongs recurrence-free intervals in patients with non-muscle invasive bladder cancer. Most guideline panels recommend this practice. However, despite this evidence and recommendations, there is considerable disparity in the actual use of intravesical chemotherapy amongst urologists. The reasons are manifold and include lack of awareness of the benefits, non-availability of the drug, delay in procurement from pharmacies, fear of side effects and complications, reimbursement issues and wariness of deep resections leading to extravasation.
    Published April 16, 2018
  • ASCO GU 2018: Lessons Learned From New Guidelines and How They Have Changed Management of Muscle-Invasive Bladder Cancer

    San Francisco, CA (UroToday.com)  Dr. Holzbeierlein began his discussion on the new muscle-invasive bladder cancer (MIBC) guidelines,1 a collaborative multi-disciplinary effort led by Dr. Sam Chang that involved input from all the major organizations, including AUA, ASCO, ASTRO, and patient advocates. The final analysis was built on prior work by Dr. Chou’s AHRQ systematic reviews (through 2015).
    Published February 10, 2018
  • ASCO GU 2019: Genomic Insights and Biomarkers for Treatment Selection in Muscle-Invasive and Non-Muscle-Invasive Bladder Cancer

    San Francisco, CA (UroToday.com) Dr. Yair Lotan presented on Genomic Insights and Biomarkers for Treatment Selection in Muscle-Invasive and Non-Muscle-Invasive Bladder Cancer. He discussed the role of markers in bladder cancer and how they add independent information that can impact patient care. The markers can either be prognostic which provide information about patient’s overall cancer outcome, regardless of therapy, or predictive markers that provide information about the effect of the therapeutic intervention and can be a target for therapy.
    Published February 15, 2019
  • ASCO GU 2019: Multimodality Treatment in Challenging Cases of Urothelial Carcinoma: Case Panel Discussion

    San Francisco, CA (UroToday.com) In this case panel discussion, 3 patient cases were reviewed highlighting important points in the management of bladder cancer. The text below includes a summary of each case presented and key points made by the panelists.

    Case 1: Small Cell Bladder Cancer: 65-year-old man who presents feeling lethargic, 10 lb weight loss, poor appetite. He has microscopic hematuria. Cystoscopy and subsequent TURBT demonstrates small cell bladder cancer.
    Published February 16, 2019
  • ASCO GU 2019: PIVOT-02 Study of NKTR-214 with Nivolumab in Metastatic Urothelial Carcinoma

    San Francisco, CA (UroToday.com) Immune checkpoint inhibitors are approved both in the first line and second line for patients with metastatic urothelial carcinoma. In the first line, KEYNOTE 052 showed that pembrolizumab has significant anti-tumor activity for cisplatin ineligible patients with UC1, for a 38% objective response rate for patients with a combined positive score of 10% or more (PD-L1 positive). Further analysis last year found that the benefit to checkpoint inhibition in the first line was restricted to patients with a high PD-L1 expression, as defined by CPS≥10 or PD-L1 IC ≥5%. In the second line, KEYNOTE 045 improved median overall survival compared with chemo (10.3 v 7.4 months; HR, 0.70; P < 0.001)2.
    Published February 20, 2019
  • ASCO GU 2019: Sacituzumab Govitecan (IMMU-132) in Patients with Previously Treated Metastatic Urothelial Cancer

    San Francisco, CA (UroToday.com) Sacituzumab govitecan (SG) is a humanized antibody-drug conjugate, made from anti-Trop-2 monoclonal antibody linked with SN-38, the active metabolite of irinotecan.1  Trop-2 is transmembrane glycoprotein encoded by the Tacstd2 gene, and is differentially expressed in a wide range of tumor types, including gastric, pancreatic, triple-negative breast, colonic, prostate, and lung cancer2. In hormone-receptor positive (HR+)/HER2- metastatic breast cancer (mBC), the overall response rate was 31% by local assessment, and the clinical benefit rate (PR+SD > 6 months) was 48%3. In an early phase study with metastatic non-small cell lung cancer, 47 patients were treated and the objective response rate was 19% with a median response duration of 6.0 months4.
    Published February 16, 2019
  • Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial

    Background: First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed
    atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatinineligible patients.

    Methods: For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible. Patients were given 1200 mg intravenous atezolizumab every 21 days until progression. The primary endpoint was independently confi rmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 (central review), assessed in prespecifi ed subgroups based on PD-L1 expression and in all patients. All participants who received one or more doses of atezolizumab were included in the primary and safety analyses. This study was registered with ClinicalTrials.gov, number NCT02108652.

    Findings: Between June 9, 2014, and March 30, 2015, we enrolled 123 patients, of whom 119 received one or more doses of atezolizumab. At 17·2 months’ median follow-up, the objective response rate was 23% (95% CI 16 to 31), the complete response rate was 9% (n=11), and 19 of 27 responses were ongoing. Median response duration was not reached. Responses occurred across all PD-L1 and poor prognostic factor subgroups. Median progression-free survival was 2·7 months (2·1 to 4·2). Median overall survival was 15·9 months (10·4 to not estimable). Tumour mutation load was associated with response. Treatment-related adverse events that occurred in 10% or more of patients were fatigue (36 [30%] patients), diarrhoea (14 [12%] patients), and pruritus (13 [11%] patients). One treatment-related death (sepsis) occurred. Nine (8%) patients had an adverse event leading to treatment discontinuation. Immune-mediated events occurred in 14 (12%) patients.

    Interpretation: Atezolizumab showed encouraging durable response rates, survival, and tolerability, supporting its therapeutic use in untreated metastatic urothelial cancer.

    Funding: F Hoff mann-La Roche, Genentech.

    Authors: Arjun V Balar, Matthew D Galsky, Jonathan E Rosenberg, Thomas Powles, Daniel P Petrylak, Joaquim Bellmunt, Yohann Loriot, Andrea Necchi, Jean Hoffman-Censits, Jose Luis Perez-Gracia, Nancy A Dawson, Michiel S van der Heijden, Robert Dreicer, Sandy Srinivas, Margitta M Retz, Richard W Joseph, Alexandra Drakaki, Ulka N Vaishampayan, Srikala S Sridhar, David I Quinn, Ignacio Durán, David R Shaff er, Bernhard J Eigl, Petros D Grivas, Evan Y Yu, Shi Li, Edward E Kadel III, Zachary Boyd, Richard Bourgon, Priti S Hegde, Sanjeev Mariathasan, AnnChristine Thåström, Oyewale O Abidoye, Gregg D Fine, Dean F Bajorin, for the IMvigor210 Study Group*

    Go "Beyond the Abstract" - Read an article written by the authors for UroToday.com

    Author Affiliations: Genitourinary Cancers Program, Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA (A V Balar MD); The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA (M D Galsky MD); Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA (J E Rosenberg MD, D F Bajorin MD); Barts Cancer Institute ECMC, Barts Health and the Royal Free NHS Trust, Queen Mary University of London, London, UK (T Powles MD); Smilow Cancer Center, Yale University, New Haven, CT, USA (D P Petrylak MD); Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA (J Bellmunt MD); Département de médecine oncologique, Université Paris-Saclay and Gustave Roussy, Villejuif, France (Y Loriot MD); Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy (A Necchi MD); Sidney Kimmel Cancer Center at Jefferson, Philadelphia, PA, USA (J Hoffman-Censits MD); Department of Oncology, Clínica Universidad de Navarra, University of Navarra, Pamplona, Navarre, Spain (J L Perez-Gracia MD); MedstarGeorgetown University Hospital, Lombardi Comprehensive Cancer Center, Washington, DC, USA (N A Dawson MD); Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands (M S van der Heijden MD); Division of Hematology/ Oncology, University of Virginia School of Medicine, Charlottesville, VA, USA (R Dreicer MD); Division of Oncology/Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA (S Srinivas MD); Department of Urology, Klinikum rechts der Isar, Technical University Munich, Munich, Germany (M M Retz MD); Department of Hematology/Oncology, Mayo Clinic, Jacksonville, FL, USA (R W Joseph MD); Department of Medicine, Division of Hematology and Oncology and Institute of Urologic Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA, USA (A Drakaki MD); Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA (U N Vaishampayan MD); Department of Medical Oncology and Hematology, Princess Margaret Cancer Center, Toronto, ON, Canada (S S Sridhar MD); University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA (D I Quinn MD); Department of Medical Oncology, Hospital Universitario Virgen del Rocío and Institute of Biomedicine of Seville, Seville, Spain (I Durán MD); New York Oncology Hematology, Albany, NY, USA (D R Shaffer MD); British Columbia Cancer Agency, British Columbia, Vancouver, Canada (B J Eigl MD); Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA (P D Grivas MD); Division of Oncology, Department of Medicine, University of Washington and Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA (E Y Yu MD); and Genentech, South San Francisco, CA, USA (S Li PhD, E E Kadel III BS,Z Boyd MSc, R Bourgon PhD, P S Hegde PhD, S Mariathasan PhD, AC Thåström PhD, O O Abidoye MD, G D Fine MD)

    Published Online December 7, 2016 http://dx.doi.org/10.1016/ S0140-6736(16)32455-2
    Published March 7, 2017
  • Atezolizumab as First-line Treatment in Cisplatin-ineligible Patients with Locally Advanced and Metastatic Urothelial Carcinoma: A Single-arm, Multicentre, Phase 2 Trial

    BACKGROUND: First-line chemotherapy for patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma is associated with short response duration, poor survival, and high toxicity. This study assessed atezolizumab (anti-programmed death-ligand 1 [PD-L1]) as treatment for metastatic urothelial cancer in cisplatin-ineligible patients.

    METHODS: For this single-arm, multicentre, phase 2 study, in 47 academic medical centres and community oncology practices in seven countries in North America and Europe, we recruited previously untreated patients with locally advanced or metastatic urothelial cancer who were cisplatin ineligible.
    Published December 12, 2018
  • BCG-Unresponsive Nonmuscle Invasive Bladder Cancer: Developing Drugs and Biologics for Treatment Guidance for Industry

    Introduction 
    The purpose of this guidance is to assist sponsors in the development of drugs, including biologics, for the treatment of patients who have bacillus Calmette-Guérin (BCG)-unresponsive nonmuscle invasive bladder cancer (NMIBC). This guidance is intended for pharmaceutical sponsors, the academic community, and the public and provides a framework, based on current Food and Drug Administration (FDA) thinking, to facilitate the development of drugs to treat this patient population. This guidance discusses pathological diagnosis and staging, risk stratification, and trial design, including assessment of appropriate clinical endpoints. These issues were discussed at the FDA/American Urological Association Bladder Cancer Workshop held on May 6, 2013, and in published literature. 2,3 
    Published September 27, 2018
  • Bladder Cancer BioMarkers: Optimal Utilization for Diagnosis and Recurrence: EVERYDAY UROLOGY- Full text article

    Published in Everyday Urology - Oncology Insights: Volume 1, Issue 3
    Everyday Urology-Oncology Insights: Volume 1, Issue 3

    Voided urine cytology has been the gold standard for detecting bladder cancer since 1945. Its specificity nears 90%, meaning that a positive result is highly reliable. But cytology is unreliable for detection of low grade tumors such that only about 20% to 30% of low grade bladder tumors are identified using cytology.  Furthermore, up to one-third of cytology specimens are considered atypical because of confounding factors such as instrumented sampling or recent therapy with bacillus Calmette-Guérin.13
    Published January 6, 2017
  • Bladder Cancer Immunotherapy: Establishing a Clinic of Excellence

    Published in Everyday Urology - Oncology Insights: Volume 3, Issue 1
    Until recently, decades had elapsed with little progress in treating metastatic urothelial cancer (mUC). Cisplatin-based chemotherapy, the best available treatment option, had a median overall survival (OS) of 12-15 months, an overall response rate (ORR) of 50-60%, and was curative in about 10% of cases, but also was associated with potentially serious toxicities.12, 13, 2, 7, 3 
    Published August 14, 2018
  • Bladder Cancer: New Insights Into its Molecular Pathology - Beyond the Abstract

    Bladder cancer is one of the most prevalent cancers worldwide. The majority of patients present with non-invasive bladder cancer, comprising non-invasive papillary carcinoma (Ta) and carcinoma in situ (CIS; Tis). Bladder cancer develops either via the FGFR3/RAS pathway (for Ta) or the TP53/RB1 pathway (for Tis). Non-invasive papillary carcinoma (Ta) develops from hyperplasia post FGFR3/HRAS mutation; then, it potentially progresses to invasive carcinoma after the inactivation of CDKN2A/TP53/RB1. Carcinoma that develops via this FGFR3/RAS pathway has been considered as the luminal type. CIS develops from dysplasia after the inactivation of TP53/RB1, followed by aggressive invasive carcinoma. Carcinoma that develops via the TP53/RB1 pathway has been considered as the basal type.
    Published April 13, 2018
  • Blue Light Cystoscopy: Insights on Recurrence, Progression, and Clinical Management

    Published in Everyday Urology - Oncology Insights: Volume 3, Issue 3

    More than 81,000 individuals are diagnosed with bladder cancer in the United States every year, of whom 75% have non-muscle invasive disease.1,2 Unfortunately, half these cases recur despite transurethral resection of bladder tumor (TURBT), and from 5% to 25% of repeated recurrences progress to muscle-invasive disease.3,4,5

    Published December 4, 2018
  • Brief Q&A for Patients by the International Bladder Cancer Group on the BCG Shortage

    BCG: What to do when there is a Shortage 

    Introduction 
    Intravesical therapy may be an important component of the management of bladder cancer (BC). The delivery of anticancer medication directly into the bladder with a catheter placed into the bladder through the urethra has been a part of bladder cancer management for many decades. All patients with BC have an initial transurethral resection (TUR BT) which is designed to remove all of the tumor, when possible. The tumor tissue is then submitted to a pathologist for diagnosis. The pathology report states the tumor grade as well as the presence or absence of invasion into the muscular layer of the bladder. The urologist will review this information, and along with his/her understanding of the appearance of the bladder cancer as well as their impression of whether or not all of the tumor has been removed, decide about the treatment strategy. 
    Published February 14, 2019
  • Clinical impact of postoperative loss in psoas major muscle and nutrition index after radical cystectomy for patients with urothelial carcinoma of the bladder.

    Although the significance of preoperative nutritional status has been investigated, there is no report regarding the relationship of their postoperative changes on outcomes in patients who underwent radical cystectomy for bladder cancer.

    Published April 3, 2017
  • Clinical Outcomes in Patients with Panurothelial Carcinoma Treated with Radical Nephroureterectomy Following Cystectomy for Metachronous Recurrence.

    We report pathologic, functional, and oncologic outcomes in patients treated with radical nephroureterectomy following radical cystectomy.

    We identified patients who underwent radical cystectomy then radical nephroureterectomy for metachronous urothelial recurrence at our institution between January 1995 and December 2014.

    Published April 3, 2017
  • Comparing the Outcomes of ddMVAC vs. GC before Cystectomy in Patients with Muscle Invasive Bladder Cancer - Expert Commentary

    Patients with muscle-invasive bladder cancer  (MIBC) who are treated with neoadjuvant chemotherapy (NAC) before cystectomy have a survival advantage. Few studies comparing cancer control and survival outcomes for different NAC regimens exist.
    Published October 26, 2018
  • Contemporary treatment patterns and outcomes of sarcomatoid bladder cancer: Beyond the Abstract

    In 2016, 750,000 bladder cancer survivors are estimated to live in the United States alone and over 75,000 new cases will be diagnosed.1,2 The vast majority are urothelial tumors however a small proportion of these will be variant histologies. Sarcomatoid carcinoma (SaC) is such a subtype and is estimated to represent 0.3% of all urothelial cancers.3 Much of our knowledge about this disease is derived from case studies or single-institution reports of which have totaled fewer than 100 cases in the last several decades.4-7
    Published April 7, 2017
  • CUOS 2019: Bladder Preservation for Invasive Bladder Cancer: Lessons Learned and Future Perspectives

    Toronto, Ontario (UroToday.com) In this discussion, the topic of bladder preservation was presented by Dr. Huddart from the Royal Marsden NHS Foundation Trust in the United Kingdom.

    Muscle invasive bladder cancer, after diagnosis using TURBT, is usually treated with radical cystectomy with the option of neoadjuvant chemotherapy before surgery. However, another option is treatment with Radiotherapy with or without chemotherapy (radiosensitizer). These patients are then followed with cystoscopy, which can then lead to either salvage radical cystectomy for residual/recurrent invasive disease, or another TURBT with local treatment for the superficial disease recurrence.
    Published January 13, 2019
  • CUOS 2019: Five-Year Outlook in the Management of Metastatic Urothelial Carcinoma

    Toronto, Ontario (UroToday.com) In this discussion, Dr. Bellmunt presented the standard of care in second-line management of advanced bladder cancer and gave an update on targeted therapies. He also discussed some of the phase 2 and phase 3 trials with PD-1/PD-L1 inhibitors, and associated biomarkers.
    Published January 12, 2019
  • Diagnosing Bladder Cancer using Urinary Cell-Free microRNA - Expert Commentary

    Although hematuria is the most common symptoms of bladder cancer (BC), it can be caused by many non-malignant conditions. The low sensitivity of voided urine cytology (VUC) and the invasiveness the cystoscopy, create an unmet need for a noninvasive test with high accuracy to detect BC in patients with hematuria. 
    Published October 24, 2018
  • Diagnosis and Pathology of Bladder Cancer

    Diagnosis:

    Clinical Presentation

    There are no reliable screening tests available for detecting bladder cancer; hence the diagnosis is usually made based on clinical signs and symptoms. Painless hematuria – microscopic or gross – is the most common presentation and a hematuria investigation in an otherwise asymptomatic patient detects bladder neoplasm in roughly 20% of gross and 5% of microscopic cases.1,2 Irritative voiding (frequency, urgency, and/or dysuria) is usually ascribed to benign urinary tract disorders but has been associated with carcinoma in situ. Other symptoms are often a signal of more advanced disease, such as flank pain caused by ureteral obstruction or pelvic pain from extravesical invasion of surrounding structures.  

    Cystoscopy

    Cystoscopy is a mainstay for the diagnosis and treatment of bladder cancer, allowing for direct access to a tumor for biopsy, fulguration, and/or resection. Low grade (LG), papillary (Ta) tumors can be reliably eradicated with one treatment but more advanced disease (high grade and/or T1) often requires repeat resection for complete eradication. Following an initial diagnosis of HG Ta or T1, between 40% and 78% of re-TUR specimens may contain residual disease, with muscle invasion present in 2% and 14%, respectively.3-6 Hence the AUA and EAU guidelines recommend repeat TURBT within 6 weeks from the index procedure to confirm tumor stage, ensure complete visual tumor clearance, and optimize response to subsequent intravesical therapy.7,8 

    Recent technological advances promise improved detection over white light cystoscopy (WLC) alone, theoretically allowing for a more complete endoscopic tumor removal. Blue light cystoscopy (BLC) has been approved for over a decade in Europe and the US based on numerous studies showing improvement in detection of bladder tumors as well as lengthening the time to recurrence by as much as 7 months (9.4 months vs 16.4 months). The improvement in tumor detection estimated to be 20% greater with BLC compared to WLC, and up to 40% specifically for CIS, however, the beneficial effect on disease recurrence and/or progression has not been universally reported in all studies.9-12 Narrow band imaging (NBI) also offers better detection than WLC but does not require a pre-operative medication instillation like BLC. Specialized optical equipment emits light in two specific wavelengths (415 nm and 540 nm) that are more readily absorbed by hemoglobin, thereby enhancing submucosal vascularity associated with malignancy.13 In a recent systematic review of five RCTs comparing WLC to NBI, the authors found statistically significant reduction in NMIBC recurrence at 3 months (RR 0.39), 1 year (RR 0.52), and 2 years (RR 0.60).14 No matter the technique, enhanced cystoscopy improves detection but whether the added time and expense translate into improved patient outcomes is still not entirely clear. 

    Urinary Markers

    The urothelium is particularly well suited anatomically for assessment of potential biomarkers that can be obtained with little to no need for invasive procedures. Cells and cellular molecules (proteins, RNA, etc.) shed into the urine as it passes through the upper and lower urinary tract; they can be collected and purified from voided or catheterized specimens. The information gathered can then be used for screening, diagnosis, treatment response, and/or surveillance. The most well-known and widely used technique is urinary cytology, by which the cellular component of a urine specimen is microscopically assessed for features typically associated with high-grade malignancy (mitotic figures, condensed chromatin, enlarged nucleoli, etc.). Interpretation and reporting by cytopathologists has contributed to confusion surrounding urinary cytology with the use of terms like “suspicious, atypical, or indeterminate. The Paris Reporting System for Urinary Cytology has standardized the cytopathologic nomenclature while providing an estimated risk of malignancy based on associated literature (Table 1).15 While specificity has historically been very high (>99%), the poor sensitivity of urinary cytology, especially for papillary tumors (4-31%), make it far from ideal for either screening or surveillance.16-19 More contemporary data has been less robust, placing specificity at a more modest 82-88% and highlighting the need for more advanced markers.20
    table-1-diagnosis-pathology-bladder-cancer@2x.jpg
    There are now five FDA-approved tests available (Table 2) in addition to many more potential biomarkers (i.e. DNA methylation, cell free DNA, histone modification) in various stages of development.21,22 The UroVysion test uses fluorescence in situhybridization (FISH) to detect common chromosomal aberrations associated with bladder cancer and outperforms urinary cytology in terms of sensitivity, though this is almost entirely attributable to better detection of Ta tumors.23 The ImmunoCyt (uCyt+) assay was designed to complement cytology and increases the sensitivity to 59% for grade 1 tumors and up to 90% for grade 3 by using monoclonal antibodies directed against common urothelial surface markers.24 Nuclear matrix protein-22 (NMP-22) is involved in normal chromatin maintenance during mitosis but is greatly overexpressed in bladder carcinoma cells. Despite a reported sensitivity of 73% and specificity of 80%, the test has not gained widespread acceptance due to variability in accuracy between institutions and a high rate of false positive tests.25,26 The newest test to gain FDA-approval is the RNA based CxBladder test which measures the relative levels of 5 different mRNA transcripts within the urine (4 associated with malignancy and 1 with benign conditions) to produce an impressive combination of sensitivity and specificity at 82% and 85%, respectively.27,28 
    table-2-diagnosis-pathology-bladder-cancer@2x.jpg
    To date, none of the available data supports the use of urinary biomarkers as the sole method of bladder cancer detection, diagnosis, or follow-up, as stated by both the EAU and AUA in their respective NMIBC guidelines, however, they may offer useful information when assessing treatment response and during long-term surveillance as an adjunct to cystoscopy.7,8 Initial enthusiasm for these tests in the early to mid-2000s has waned, whereas use of urinary cytology has remained constant despite its shortcomings.29 The use of markers in prognostication and prediction of response to therapy is discussed in the next section on management of NMIBC.

    Imaging

    A complete diagnostic evaluation includes imaging of the entire urinary tract to assess for abnormalities of the urothelium normally out of view from cystoscopy. Upper tract urothelial tumors are uncommon, present in only 1.5% of patients with NMIBC, but certain features (multifocality, trigonal lesions, and/or CIS) raise this risk to more than 7%.30,31 The best combination of sensitivity (67-100%) and specificity (93-99%) is offered by computed tomographic urography (CTU) because of high soft tissue special resolution and contrast enhanced assessment of the urothelial surfaces and this has replaced intravenous urography in most centers in North America.32-35 Magnetic resonance imaging can be used as a substitute for CTU if the patient has an allergy to iodinated contrast or low GFR.36 In an effort to standardize MRI reporting and improve diagnostic accuracy, the multiparametric MRI based Vesical Imaging-Reporting and Data System (VI-RADS) was introduced in early 2018 with a 5 tiered system designed to predict likelihood of finding muscle invasion on TURBT, though it has not been validated in the clinical setting as of yet.37 Ultrasonography with retrograde pyelography is reserved for circumstances where both CT and MRI cannot be performed.

    Pathology:

    Urothelial carcinoma is the most common bladder cancer histology (~90%) diagnosed in the US, followed by squamous (2-5%), adenocarcinoma (2%), neuroendocrine (1%), and other rare tumors (<1%).38 The urothelium is the epithelial lining of the urinary tract and has a thickness in the bladder of approximately 5 to 7 cell layers overlying the lamina propria. Tumors that are confined to the bladder and do not invade the muscularis propria are considered non-muscle invasive bladder cancer (NMIBC) comprised of stages Ta, T1, and carcinoma in situ (CIS). Invasion of the muscularis propria – so called muscle invasive bladder cancer (MIBC,T2)“ represents an advanced stage with life threatening consequences requiring surgical management (i.e. radical cystectomy). 

    Tumor Grading

    Tumor grade is an important prognostic feature of bladder cancer but there is a lack of consensus internationally regarding the classification system. The extreme ends of the spectrum (highly aggressive and low malignant potential) are easy to identify but the middle ground has proved more elusive. In the World Health Organization 1973 grading system, there are 3 tiers of tumor grade (1, 2, and 3), though a majority of tumors end up as the intermediate grade 2 as a diagnosis of exclusion. The International Society of Urologic Pathologists (ISUP)/WHO 2004 grading system includes only high or low grade and exhibits better prognostic ability over the WHO 1973 system, at the expense of upward stage migration.39,40 Enrichment of the grade 3 group via inclusion of borderline grade 2 cases only leaves more indolent disease in the LG category and exposes those patients to overtreatment. The final version released as the ISUP/WHO 2004 grading system (now updated with minor revisions as the 2016 system) has been adopted throughout North America but the 1973 version is still in widespread use across Europe (Figure 1).41 
    diagram-bladder-cancer@2x.jpg
    Divergent Differentiation and Histologic Variants

    The ability of the urothelium to exhibit divergent differentiation is well known and may occur in a pure or mixed form (Table 3).42,43 When certain subtypes are present without elements of usual urothelial carcinoma, the tumor is referred to in terms of its pure histology (i.e. squamous cell carcinoma [SCC] of the bladder, adenocarcinoma of the bladder), in contrast to variant histology discussed below.41 Adenocarcinoma has a typical glandular (intestinal) appearance and tends to be more aggressive than UC.44 As such, complete early resection with radical cystectomy is advocated, even for T1 tumors, to achieve the best clinical outcomes.45 Pure SCC is more common in regions with endemic Bilhazrial infections and has been associated with a favorable clinical course, however, the non-infectious form is a distinct entity with a worse prognosis warranting similar management as adenocarcinoma.46 Small cell carcinoma is a neuroendocrine tumor with a very high propensity for distant spread at presentation and should be treated with upfront chemotherapy followed by surgery if free of detectable metastasis.47
    table-3-diagnosis-pathology-bladder-cancer@2x.jpg
    The impact of mixed histologic variants is less clear owing to multiple factors including low recognition historically among pathologists and tumor under-sampling during resection.48,49 In one study, repeat pathologic review of more than 1,200 bladder cancers diagnosed as pure UC between 1980 and 2005 found that 1/3rd actually contained a variant component.50 The sarcomatoid subtype is characterized by a mesenchymal and spindle-cell like appearance and exhibits a propensity for aggressive growth.51 These tumors present with extravesical invasion (T3-4) in about 1/3rd of cases.52 Micropapillary histologic architecture has been described in other malignancies and is typically associated with poor prognosis.53 Higher stage on presentation and increased likelihood for bladder invasion have been noted when even small regions of micropapillary differentiation are present (~10%), but the optimal treatment approach (neoadjuvant chemotherapy versus immediate RC) is still a topic for debate.54,55 Plasmacytoid variant is locally aggressive and frequently under-staged as evidenced by an 80% upstaging rate of clinical T1 to pathologic after cystectomy.56,57 The pattern of spread of plasmacytoid is particularly unusual for bladder cancer given its predilection for peritoneal implantation.58 The histologic appearance of nested subtype is similar to von Brunn nests, but unlike the benign nature of the latter, nested variant carries significant probability of muscle invasion (70%) and/or lymph node positivity (67%).59 Squamous and glandular differentiation are associated with a higher stage at initial diagnosis, however, clinical outcomes are no different than conventional urothelial carcinoma and standard treatment pathways should be sufficient.60,61 The AUA NMIBC guidelines direct the clinician to consider upfront radical cystectomy in T1 patients with any variant histology, citing the association of variant histology with a high rate of under-staging, however, the EAU guidelines limit their recommendation to only micropapillary histology.7,8,55,62

    Molecular Classification

    The accumulation of DNA damage necessary to produce bladder cancer requires several decades to occur, and as a result, MIBC exhibits a very high mutational burden and chromosomal instability. Concurrent genomic studies from several international research groups produced a range of intrinsic MIBC molecular subtypes with similar expressional profiles but different nomenclature. It is generally accepted that there are 2 major subtypes, luminal and basal, with better prognosis among the former. These tumors tend to be enriched for FGFR3 mutations associated with hyperproliferation and found at high frequency in non-invasive tumor. Despite the poor prognosis of the basal subtype, characterized by p53 mutations and alterations of DNA-damage repair pathways, these tumors are more responsive to platinum-based neoadjuvant chemotherapy than any other group.63 Low-grade tumors are genetically far more stable than MIBC, with highly conserved alterations in FGFR3 (79%), KDM6A (53%), and PIK3CA (52%).64,65 NMIBC has also been classified according to a molecular profiling schema, though it is less robust than what is available for MIBC. The major take-home point from this work thus far is the similarity between HG NMIBC and MIBC, pointing to a common pathway for progression.64,66,67


    Written by: Justin T. Matulay, MD and Ashish Kamat, MD, MBBS
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    18. Xylinas E, Kluth LA, Rieken M, et al. Urine markers for detection and surveillance of bladder cancer. Urol Oncol. 2014;32(3):222-229.
    19. Zuiverloon TCM, de Jong FC, Theodorescu D. Clinical Decision Making in Surveillance of Non-Muscle-Invasive Bladder Cancer: The Evolving Roles of Urinary Cytology and Molecular Markers. Oncology (Williston Park). 2017;31(12):855-862.
    20. Yafi FA, Brimo F, Auger M, et al. Is the performance of urinary cytology as high as reported historically? A contemporary analysis in the detection and surveillance of bladder cancer. Urol Oncol. 2014;32(1):27 e21-26.
    21. Chou R, Gore JL, Buckley D, et al. Urinary Biomarkers for Diagnosis of Bladder Cancer: A Systematic Review and Meta-analysis. Ann Intern Med. 2015;163(12):922-931.
    22. Santoni G, Morelli MB, Amantini C, et al. Urinary Markers in Bladder Cancer: An Update. Front Oncol. 2018;8:362.
    23. Hajdinjak T. UroVysion FISH test for detecting urothelial cancers: meta-analysis of diagnostic accuracy and comparison with urinary cytology testing. Urol Oncol. 2008;26(6):646-651.
    24. Comploj E, Mian C, Ambrosini-Spaltro A, et al. uCyt+/ImmunoCyt and cytology in the detection of urothelial carcinoma: an update on 7422 analyses. Cancer Cytopathol. 2013;121(7):392-397.
    25. Shariat SF, Marberger MJ, Lotan Y, et al. Variability in the performance of nuclear matrix protein 22 for the detection of bladder cancer. J Urol. 2006;176(3):919-926; discussion 926.
    26. Poulakis V, Witzsch U, De Vries R, et al. A comparison of urinary nuclear matrix protein-22 and bladder tumour antigen tests with voided urinary cytology in detecting and following bladder cancer: the prognostic value of false-positive results. BJU Int. 2001;88(7):692-701.
    27. Kavalieris L, O'Sullivan PJ, Suttie JM, et al. A segregation index combining phenotypic (clinical characteristics) and genotypic (gene expression) biomarkers from a urine sample to triage out patients presenting with hematuria who have a low probability of urothelial carcinoma. BMC urology. 2015;15:23.
    28. O'Sullivan P, Sharples K, Dalphin M, et al. A multigene urine test for the detection and stratification of bladder cancer in patients presenting with hematuria. J Urol. 2012;188(3):741-747.
    29. Narayan VM, Adejoro O, Schwartz I, et al. The Prevalence and Impact of Urinary Marker Testing in Patients with Bladder Cancer. J Urol. 2018;199(1):74-80.
    30. Palou J, Rodriguez-Rubio F, Huguet J, et al. Multivariate analysis of clinical parameters of synchronous primary superficial bladder cancer and upper urinary tract tumor. J Urol. 2005;174(3):859-861; discussion 861.
    31. Millan-Rodriguez F, Chechile-Toniolo G, Salvador-Bayarri J, et al. Upper urinary tract tumors after primary superficial bladder tumors: prognostic factors and risk groups. J Urol. 2000;164(4):1183-1187.
    32. Chlapoutakis K, Theocharopoulos N, Yarmenitis S, et al. Performance of computed tomographic urography in diagnosis of upper urinary tract urothelial carcinoma, in patients presenting with hematuria: Systematic review and meta-analysis. Eur J Radiol. 2010;73(2):334-338.
    33. Cowan NC, Turney BW, Taylor NJ, et al. Multidetector computed tomography urography for diagnosing upper urinary tract urothelial tumour. BJU Int. 2007;99(6):1363-1370.
    34. Froemming A, Potretzke T, Takahashi N, et al. Upper tract urothelial cancer. Eur J Radiol. 2018;98:50-60.
    35. Roupret M, Babjuk M, Comperat E, et al. European Association of Urology Guidelines on Upper Urinary Tract Urothelial Carcinoma: 2017 Update. Eur Urol. 2018;73(1):111-122.
    36. Takahashi N, Glockner JF, Hartman RP, et al. Gadolinium enhanced magnetic resonance urography for upper urinary tract malignancy. J Urol. 2010;183(4):1330-1365.
    37. Panebianco V, Narumi Y, Altun E, et al. Multiparametric Magnetic Resonance Imaging for Bladder Cancer: Development of VI-RADS (Vesical Imaging-Reporting And Data System). Eur Urol. 2018;74(3):294-306.
    38. Hansel DE, Amin MB, Comperat E, et al. A contemporary update on pathology standards for bladder cancer: transurethral resection and radical cystectomy specimens. Eur Urol. 2013;63(2):321-332.
    39. Cao D, Vollmer RT, Luly J, et al. Comparison of 2004 and 1973 World Health Organization Grading Systems and Their Relationship to Pathologic Staging for Predicting Long-term Prognosis in Patients With Urothelial Carcinoma. Urology. 2010;76(3):593-599.
    40. Lokeshwar SD, Ruiz-Cordero R, Hupe MC, et al. Impact of 2004 ISUP/WHO classification on bladder cancer grading. World Journal of Urology. 2015;33(12):1929-1936.
    41. Humphrey PA, Moch H, Cubilla AL, et al. The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part B: Prostate and Bladder Tumours. Eur Urol. 2016;70(1):106-119.
    42. Lopez-Beltran A, Cheng L. Histologic variants of urothelial carcinoma: differential diagnosis and clinical implications. Hum Pathol. 2006;37(11):1371-1388.
    43. Shanks JH, Iczkowski KA. Divergent differentiation in urothelial carcinoma and other bladder cancer subtypes with selected mimics. Histopathology. 2009;54(7):885-900.
    44. Wright JL, Porter MP, Li CI, et al. Differences in survival among patients with urachal and nonurachal adenocarcinomas of the bladder. Cancer. 2006;107(4):721-728.
    45. Zaghloul MS, Nouh A, Nazmy M, et al. Long-term results of primary adenocarcinoma of the urinary bladder: a report on 192 patients. Urol Oncol. 2006;24(1):13-20.
    46. Ehdaie B, Maschino A, Shariat SF, et al. Comparative outcomes of pure squamous cell carcinoma and urothelial carcinoma with squamous differentiation in patients treated with radical cystectomy. J Urol. 2012;187(1):74-79.
    47. Lynch SP, Shen Y, Kamat A, et al. Neoadjuvant chemotherapy in small cell urothelial cancer improves pathologic downstaging and long-term outcomes: results from a retrospective study at the MD Anderson Cancer Center. Eur Urol. 2013;64(2):307-313.
    48. Willis D, Kamat AM. Nonurothelial bladder cancer and rare variant histologies. Hematol Oncol Clin North Am. 2015;29(2):237-252, viii.
    49. Shah RB, Montgomery JS, Montie JE, et al. Variant (divergent) histologic differentiation in urothelial carcinoma is under-recognized in community practice: Impact of mandatory central pathology review at a large referral hospital. Urol Oncol. 2013;31(8):1650-1655.
    50. Linder BJ, Boorjian SA, Cheville JC, et al. The impact of histological reclassification during pathology re-review--evidence of a Will Rogers effect in bladder cancer? J Urol. 2013;190(5):1692-1696.
    51. Moch H, Humphrey PA, Ulbright TM, et al. WHO Classification of Tumours of the Urinary System and Male Genital Organs. 4th ed. Lyon, France: International Agency for Research on Cancer; 2016.
    52. Sui W, Matulay JT, Onyeji IC, et al. Contemporary treatment patterns and outcomes of sarcomatoid bladder cancer. World J Urol. 2017;35(7):1055-1061.
    53. Sui W, Matulay JT, James MB, et al. Micropapillary Bladder Cancer: Insights from the National Cancer Database. Bladder Cancer. 2016;2(4):415-423.
    54. Kamat AM, Dinney CP, Gee JR, et al. Micropapillary bladder cancer: a review of the University of Texas M. D. Anderson Cancer Center experience with 100 consecutive patients. Cancer. 2007;110(1):62-67.
    55. Meeks JJ, Taylor JM, Matsushita K, et al. Pathological response to neoadjuvant chemotherapy for muscle-invasive micropapillary bladder cancer. BJU Int. 2013;111(8):E325-330.
    56. Kaimakliotis HZ, Monn MF, Cary KC, et al. Plasmacytoid variant urothelial bladder cancer: is it time to update the treatment paradigm? Urol Oncol. 2014;32(6):833-838.
    57. Keck B, Wach S, Stoehr R, et al. Plasmacytoid variant of bladder cancer defines patients with poor prognosis if treated with cystectomy and adjuvant cisplatin-based chemotherapy. BMC Cancer. 2013;13:71.
    58. Ricardo-Gonzalez RR, Nguyen M, Gokden N, et al. Plasmacytoid carcinoma of the bladder: a urothelial carcinoma variant with a predilection for intraperitoneal spread. J Urol. 2012;187(3):852-855.
    59. Wasco MJ, Daignault S, Bradley D, et al. Nested variant of urothelial carcinoma: a clinicopathologic and immunohistochemical study of 30 pure and mixed cases. Hum Pathol. 2010;41(2):163-171.
    60. Amin MB. Histological variants of urothelial carcinoma: diagnostic, therapeutic and prognostic implications. Mod Pathol. 2009;22 Suppl 2:S96-S118.
    61. Mitra AP, Bartsch CC, Bartsch G, Jr., et al. Does presence of squamous and glandular differentiation in urothelial carcinoma of the bladder at cystectomy portend poor prognosis? An intensive case-control analysis. Urol Oncol. 2014;32(2):117-127.
    62. Vetterlein MW, Wankowicz SAM, Seisen T, et al. Neoadjuvant chemotherapy prior to radical cystectomy for muscle-invasive bladder cancer with variant histology. Cancer. 2017;123(22):4346-4355.
    63. Seiler R, Ashab HA, Erho N, et al. Impact of Molecular Subtypes in Muscle-invasive Bladder Cancer on Predicting Response and Survival after Neoadjuvant Chemotherapy. Eur Urol. 2017.
    64. Hurst CD, Alder O, Platt FM, et al. Genomic Subtypes of Non-invasive Bladder Cancer with Distinct Metabolic Profile and Female Gender Bias in KDM6A Mutation Frequency. Cancer Cell. 2017;32(5):701-715 e707
    65. Robertson AG, Kim J, Al-Ahmadie H, et al. Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer. Cell. 2017;171(3):540-556 e525.
    66. Hedegaard J, Lamy P, Nordentoft I, et al. Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma. Cancer Cell. 2016;30(1):27-42.
    67. Pietzak EJ, Bagrodia A, Cha EK, et al. Next-generation Sequencing of Nonmuscle Invasive Bladder Cancer Reveals Potential Biomarkers and Rational Therapeutic Targets. Eur Urol. 2017;72(6):952-959.
    68. Soloway MS, Briggman V, Carpinito GA, et al. Use of a new tumor marker, urinary NMP22, in the detection of occult or rapidly recurring transitional cell carcinoma of the urinary tract following surgical treatment. J Urol. 1996;156(2 Pt 1):363-367.
    69. Irani J, Desgrandchamps F, Millet C, et al. BTA stat and BTA TRAK: A comparative evaluation of urine testing for the diagnosis of transitional cell carcinoma of the bladder. Eur Urol. 1999;35(2):89-92.
    70. Fradet Y, Lockhard C. Performance characteristics of a new monoclonal antibody test for bladder cancer: ImmunoCyt trade mark. Can J Urol. 1997;4(3):400-405.
    71. Mostofi FK, Sobin LH, Torloni H. Histological typing of urinary bladder tumours. Geneva, Switerland: World Health Organization; 1973.
    72. Eble JN, Sauter G, Epstein JI, et al. Pathology and Genetics of Tumors of the Urinary System and Male Genital Organs. Lyon: IARC Press; 2004.
    Published April 16, 2019
  • EAU 2019: Blue Light Flexible Cystoscopy – Improving the Patient Experience

    Barcelona, Spain (UroToday.com) At the urogenital cancer treatment session, Dr. Yair Lotan discussed the impact of blue light flexible cystoscopy and utilization in the clinic setting. Dr. Lotan notes that there are several unmet medical needs with regards to non-muscle invasive bladder cancer (NMIBC). First, it is associated with a high risk of recurrence, with up to 61% of patients recurring in the first year, and up to 78% within 5 years. Second, NMIBC may progress to muscle invasion, including 17% at 1 year and up to 45% at 5 years. Third, there is a high rate of residual tumor after TURBT in that 34-76% of patients have evidence of tumor on repeat TURBT at 2-6 weeks. Fourth, patients with incomplete initial resection are at high risk of recurrence. This may be secondary to the continued growth of microscopic lesions which were not observed at initial TURBT, or new growth of small residual traces of tumor, often at the surgical margins.
    Published March 18, 2019
  • EAU 2019: Primary Results from SAUL: A Prospective, Multinational Single-Arm Study of Atezolizumab for Locally Advanced or Metastatic Urothelial Carcinoma of the Urinary Tract

    Barcelona, Spain (UroToday.com) Dr. Axel Merseburger presented the preliminary results of the Safety of Atezolizumab in locally advanced or metastatic UrotheliaL and non-urothelial carcinoma of the urinary tract (SAUL) study at the EAU 2019 Breaking News session. Atezolizumab is a humanized monoclonal antibody that targets PD-L1 and inhibits the interaction with PD-L1 receptors. This treatment was approved as monotherapy for patients with locally advanced or metastatic urothelial carcinoma1-3:
    Published March 22, 2019
  • EAU 2019: TERT Promoter and FGFR3 Mutations – A Highly Sensitive and Non-invasive Tool for Bladder Cancer Recurrence Detection

    Barcelona, Spain (UroToday.com) Up to 3/4 of non-muscle invasive bladder cancer (NMIBC) patients will endure recurrence during their lifetime. Disease follow up is invasive, costly and long and consists of cystoscopy, cytology, and imaging. The most prevalent non-invasive approach for the diagnosis of recurrence remains urinary cytology, although far from ideal with reduced sensitivity and specificity.  
    Published March 21, 2019
  • Enhanced Recovery After Surgery, Radical Cystectomy and Urinary Diversion

    Published in Everyday Urology - Oncology Insights: Volume 2, Issue 1
    Everyday Urology-Oncology Insights: Volume 2, Issue 1

    Bladder cancer presents an ever increasing health care burden across the globe. The large majority of patients diagnosed with bladder cancer are over the age of 55, with an average age at the time of diagnosis of 73 and an increasing percentage 80 years and older.1 Men are about three to four times more likely to get bladder cancer during their lifetime than women.1
    Published June 9, 2017
  • Enhanced Recovery after Urological Surgery: A Contemporary Systematic Review of Outcomes, Key Elements, and Research Needs.

    Enhanced Recovery after Surgery (ERAS) programs are multimodal care pathways that aim to decrease intra-operative blood loss, decrease postoperative complications, and reduce recovery times.
    Published August 31, 2017
  • Epidemiology and Etiology of Bladder Cancer

    Epidemiology


    Bladder cancer is the most common malignancy of the urinary tract and second only to the prostate in the entire genitourinary system. The most updated available global estimate, based on registry data collected through the year 2012, found approximately 430,000 new diagnoses worldwide, making it the 9th most common malignancy overall (6th in men and 17th in women) while being the 13th leading cause of cancer mortality (Figure 1).1 A more recent estimate available for the United States population based on Surveillance, Epidemiology, and End Results (SEER) data estimates the annual incidence will be 81,000 for the year 2018 corresponding to the 4th and 11th most common cancer among men and women, respectively.2 In the decade between 2006 and 2015 the annual incidence of bladder cancer per 100,000 persons has declined by 1.3% annually, however, the mortality rate has remained nearly unchanged.3 By comparison, the mortality rates of the other top malignancies, lung, colon, and prostate, have declined by 2.6%, 2.4%, and 2.9% over the same period of time, respectively.

    figure-1a-epidemiology-bladder-cancer@2x.jpgfigure-1b-epidemiology-bladder-cancer@2x.jpg
    Figure 1.  Age-standardized rates (ASR) of incidence (gold) and mortality (blue) from the World Health Organization International Agency for Research on Cancer GLOBOCAN 2012 dataset. (A) Worldwide ASR for the top 20 cancers, divided by sex. Bladder cancer incidence is the 6th most common among men and 17th among women. (B) Bladder cancer ASR incidence and mortality by WHO reporting region. More developed regions have 2-3 times higher incidence than less developed regions.


    The gender disparity in bladder cancer risk is readily evident considering men represent slightly more than 75% of new diagnoses each year.2 Perhaps the most obvious explanation for this difference is the inequality in exposure to bladder carcinogens, namely tobacco smoke. This topic has undergone close examination but higher rates of smoking and tobacco use among males fails to entirely account for the increased bladder cancer risk.4,5 Sex hormones may play a key role in the development and progression of bladder cancer, with increased androgen receptor expression noted in lower stage/grade tumors while higher stage disease is associated with increased expression of the estrogen receptor β isoform (Figure 2).6-9 This may point to an explanation for the poorer stage-adjusted cancer-specific mortality in women compared to men (HR 1.17-4.47) in spite of a male to female incidence ratio of 4 to 1.10-14


    figure-2-epidemiology-bladder-cancer@2x.jpg
     
    Internationally, gender differences in bladder cancer mirrors the trends seen in the US population but incidences vary widely from region to region. For instance, the lowest age-standardized rates (ASR) in men are seen in Africa (Uganda ASR = 2.6 per 100,000) while the highest are found in North America (ASR = 19.5 per 100,000) and Europe (ASR = 17.7 per 100,000), including Spain with its ASR of 36.7 per 100,000 men.1 In an analysis of the WHO cancer databases, Antoni et al. made several notable observations regarding worldwide bladder cancer incidence and mortality.15 The ASR of more developed regions is approximately 3-times higher than the developing world and is likely explained by the high prevalence of cigarette smoking among the former population during the preceding three to four decades. Case-in-point, nearly 2 in 3 Spanish adult males actively smoked in the late 1970s, and while smoking rates have certainly declined among the developed world, it will take many more years to see the attendant decline in the disease burden of bladder cancer.15-17 Egypt – and the Northern African region as a whole – are worth highlighting given the abnormally high incidence when compared to the continent overall (ASR = 19.0, 15.1, and 6.3 per 100,000, respectively).15 Endemic parasitic infection with Schistoma haematobiumhas traditionally been associated with the increased prevalence of disease among the Egyptian population, especially squamous cell carcinoma (SCC) which accounted for up to 81% of all bladder cancers diagnosed before the turn of the century.18 More recently, bilharzial infection rates have fallen and SCC now accounts for less than 30% of bladder cancer pathology, but the overall incidence is holding steady due to smoking rates among the male population that has increased to over 50%.18,19

    Racial disparity among the US population is skewed towards a 2-fold higher incidence of bladder cancer among Caucasian men, however, tumor stage and grade are higher at the presentation in African American men.20 Several researchers have noted worse disease-specific outcomes for African Americans and hypothesize that this is probably due to socioeconomic factors and poor access to healthcare, but a recent evaluation of a Florida cancer registry actually found significantly better overall survival among blacks (HR=0.35, p=0.045) when controlling for patient and disease factors.21-25

    Etiology



    Risk Factors

    The urothelium is exposed to the outside environment, not unlike the skin or the lung epithelium, making it susceptible to damage from environmental toxins. Once filtered by the kidney and concentrated in the urine, these toxins remain in continuous contact with the urothelium of the bladder until expelled during urination. The result is DNA damage caused by several carcinogenic compounds (aromatic amines, polycyclic aromatic hydrocarbons, etc.) which leads to accumulation of oncogenic mutations over the course of decades and explains why bladder cancer carries one of the highest mutational burdens of all cancers.26,27

    The most strongly attributable risk factor for bladder cancer is cigarette smoking, which causes approximate 50% of cases annually across both sexes.28 Since the overall rate of smoking in the US has dropped in the past several decades, one would expect to see a commensurate decline in the incidence of bladder cancer, but this has not been the case. Instead, it appears that the strength of association between bladder cancer and smoking has increased, likely due to the enrichment of carcinogenic agents found in cigarette tobacco over time – specifically nitrates, which become metabolized into carcinogenic N-nitrosamines.28,29

    E-cigarettes are a popular “safe” alternative to cigarette smoking, but the vaporized liquid, comprised of nicotine and flavoring, contains several carcinogenic compounds found in tobacco smoke, such as polycyclic aromatic hydrocarbons, phenols, nitrosamines, and aldehydes, among others.30 It is too early to make a causal link between e-cigarettes and bladder cancer, however, studies have discovered, while less than cigarette smokers, levels of carcinogenic metabolites in the urine of e-cigarette smokers are significantly higher than non-smoking controls.31,32 Furthermore, pre-clinical work with mouse models demonstrated DNA damage induced by nitrosamines from e-cigarettes in the murine lungs, heart, and bladder.33

    Other environmental toxins, aside from tobacco smoke, that are known to cause bladder cancer are often found in industrial settings where workers are subjected to repeated daily exposure. In a contemporary analysis of bladder cancer risk from occupational exposures, workers in tobacco, dye, rubber, printing, leather, and hairdressing industries as well as chimney sweeps, firefighters, aluminum workers, and oil workers were at highest risk for bladder cancer secondary to environmental presence of aromatic amines and polycyclic aromatic hydrocarbons (Table).26,34-37 The inorganic form of arsenic found both naturally and as a contaminant in the environment, has been strongly linked to urothelial malignancy, especially when the concentration in drinking water is over 150-300 µg/L.38,39

    table-1-epidemiology-bladder-cancer@2x.jpg

    Innumerable dietary risk factors have been associated with cancer risk in general and even a few with particular emphasis on bladder cancer.40 Meat consumption at the population level appears to be positively correlated with bladder cancer risk for both red meat and processed meats, but the quality of evidence is generally poor.41,42 Likewise, artificial sweeteners are a frequent suspect for dietary carcinogenesis while lacking any clear link to cancer of the urinary tract, only conflicting results from case-control studies.43-45

    The most commonly cited hereditary links to bladder cancer are not tumor suppressor or proto-oncogene mutations, but rather related to the manner in which an individual metabolizes the carcinogens from the environment, especially in the form of cigarette smoke. Two isoforms of the N-acetyltransferase enzyme (NAT1 and NAT2) that are responsible for inactivating the carcinogenic aromatic and heterocyclic amine compounds can be associated with an increased risk of developing bladder cancer when certain germline polymorphisms are present that correlate with “slow” enzyme activity.46,47 Enzymes in the glutathione S-transferase (GST) family also carry a detoxifying function, and bladder cancer risk is increased in the GSTM1-null genotype, however, the effect in this population is more pronounced among never smokers over former or current smokers through an as of yet unknown mechanism.48,49

    Chronic inflammation contributes to bladder cancer formation through a process by which immune cells (neutrophils, monocytes, and macrophages) generate reactive oxygen species that induce DNA damage as well as stimulate cellular proliferation through cell-signaling pathways. 50 Urinary tract infections and urothelial irritants, such as calculi and indwelling catheters, are associated with increased risk of bladder cancer overall, as well as an increased proportion of squamous cell carcinoma.51,52 This is particularly evident among spinal cord injury patients and populations with endemic Schistosomiasis, and though the exact mechanism is unknown, urothelial to squamous metaplasia appears to precede the development of invasive carcinoma in these patients.50,53

    Iatrogenic causes of bladder cancer include systemic agents (i.e. chemotherapy) and pelvic irradiation for other malignancies. The popular class of anti-diabetic medications known as thiazolidinediones (TZD), which includes the specific drugs pioglitazone and rosiglitazone, have been implicated in urothelial carcinoma carcinogenesis via activation of the peroxisome proliferator-activated receptors gamma (PPARγ). Large cohort studies have reported conflicting results regarding an increased incidence of bladder cancer that increases with duration of TZD therapy, especially pioglitazone, prompting the FDA to include a warning label regarding the increased risk and recommend ongoing re-evaluation of the data.54-58 Bladder cancer risk is also associated with systemic cyclophosphamide chemotherapy, due to either direct effect of toxic metabolites in the urine (acrolein and phosphoramide) or severe urothelial inflammation.59,60 Radiotherapy of the pelvis may lead to at least 30% increased risk, though this effect is seen only with the external beam but not brachytherapy.61

    Prevention

    Given the role of inflammation in carcinogenesis, it makes sense that inhibiting enzymes within the pro-inflammatory pathways (i.e. cyclooxygenase-2 [COX-2] or 3-hydroxy-3-mehylglutaryl-coenzyme A [HMGCoA] reductase) might be useful for disease prevention. Laboratory models of nonsteroidal anti-inflammatories (NSAIDs) have demonstrated promising results related to bladder cancer prevention, however, a randomized controlled trial of the COX-2 inhibitor celecoxib failed significantly reduce NMIBC recurrences in humans.62-64 Likewise, results from case-control studies suggest that HMGCoA reductase inhibitors do not offer a significant benefit.65,66

    Smoking cessation, on the other hand, can help to erase some of the tobacco-associated bladder cancer risks, especially when the user quits prior to disease onset. The risk of developing bladder cancer in former smokers decreases with time since quitting but they still maintain a higher risk when compared to never smokers, though, this is approximately 50% less than that of current smokers.37,67-69 Smoking status remains important even after bladder cancer has developed, as former smokers who quit at least 1 year prior to bladder cancer diagnosis appear to have a lower recurrence risk when compared to more recent former smokers and current smokers, but some studies have only found a difference for patients who quit more than 10 years before.70,71

    Cannabis may possess antineoplastic properties based on inhibition of tumor growth and pro-apoptotic effects seen in the laboratory, but supporting clinical data is currently lacking.72-74  A slightly higher incidence of bladder cancer was noted in non-smokers (neither tobacco nor cannabis) when compared to cannabis users (0.4% v. 0.3%, respectively) in one large cohort study, translating into a relative risk of 0.55 (p=0.048) on multivariate analysis, though only age, race, and BMI were used as co-variables.75 Conversely, a much smaller case-control study of Vietnam-era veterans found increased rates of habitual marijuana use among bladder cancer patients (88.5%) when compared to matched controls (69.2%), though tobacco use was equal among both groups.76

    Proposed dietary factors offering a protective effect include increased fluid intake, fruits, vegetables, vitamin supplements (A, C, & D), selenium, and other antioxidants.67 Randomized controlled trials are lacking in this arena and systematic reviews of retrospective, case-control studies have yielded mixed results, so no definitive conclusions can be drawn at this time.40,77,78

    Summary/Conclusions:

    • Bladder cancer is a leading malignancy worldwide but incidence is disproportionately higher among more developed nations, including the US.
    • The most important recognized risk factor is cigarette smoking, but despite declining rates of smoking, bladder cancer incidence has declined only slightly, owing to the long lead time and potentially increased carcinogenicity of modern tobacco products.
    • Men continue to have a 3-4 fold higher lifetime risk even though the gender gap for smoking has narrowed significantly, raising the possibility of a hormonal influence
    • Other environmental risks are largely related to occupational exposures to carcinogenic compounds (i.e. aromatic amines).
    • Lifestyle factors and chemoprevention may be able to reduce bladder cancer risk but currently available literature is inconclusive
    • Smoking cessation substantially lowers lifetime risk, though not reaching the same level as a never smoker.
    Written by: Justin T. Matulay, MD, and Ashish Kamat, MD, MBBS
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    38. Meliker JR, Nriagu JO. Arsenic in drinking water and bladder cancer: review of epidemiological evidence. Trace Metals Other. 2007;9:551-584.
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    40. Al-Zalabani AH, Stewart KF, Wesselius A, Schols AM, Zeegers MP. Modifiable risk factors for the prevention of bladder cancer: a systematic review of meta-analyses. Eur J Epidemiol. 2016;31(9):811-851.
    41. Crippa A, Larsson SC, Discacciati A, Wolk A, Orsini N. Red and processed meat consumption and risk of bladder cancer: a dose-response meta-analysis of epidemiological studies. Eur J Nutr. 2018;57(2):689-701.
    42. Li F, An S, Hou L, Chen P, Lei C, Tan W. Red and processed meat intake and risk of bladder cancer: a meta-analysis. Int J Clin Exp Med. 2014;7(8):2100-2110.
    43. Andreatta MM, Munoz SE, Lantieri MJ, Eynard AR, Navarro A. Artificial sweetener consumption and urinary tract tumors in Cordoba, Argentina. Prev Med. 2008;47(1):136-139.
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    45. Morrison AS, Buring JE. Artificial sweeteners and cancer of the lower urinary tract. N Engl J Med. 1980;302(10):537-541.
    46. Garcia-Closas M, Malats N, Silverman D, et al. NAT2 slow acetylation, GSTM1 null genotype, and risk of bladder cancer: results from the Spanish Bladder Cancer Study and meta-analyses. Lancet. 2005;366(9486):649-659.
    47. Moore LE, Baris DR, Figueroa JD, et al. GSTM1 null and NAT2 slow acetylation genotypes, smoking intensity and bladder cancer risk: results from the New England bladder cancer study and NAT2 meta-analysis. Carcinogenesis. 2011;32(2):182-189.
    48. Gu J, Wu X. Genetic susceptibility to bladder cancer risk and outcome. Per Med. 2011;8(3):365-374.
    49. Rothman N, Garcia-Closas M, Chatterjee N, et al. A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci. Nat Genet. 2010;42(11):978-984.
    50. Michaud DS. Chronic inflammation and bladder cancer. Urol Oncol. 2007;25(3):260-268.
    51. Vermeulen SH, Hanum N, Grotenhuis AJ, et al. Recurrent urinary tract infection and risk of bladder cancer in the Nijmegen bladder cancer study. Br J Cancer. 2015;112(3):594-600.
    52. Clouston D, Lawrentschuk N. Metaplastic conditions of the bladder. BJU Int. 2013;112 Suppl 2:27-31.
    53. Mostafa MH, Sheweita SA, O'Connor PJ. Relationship between schistosomiasis and bladder cancer. Clin Microbiol Rev. 1999;12(1):97-111.
    54. Lewis JD, Habel LA, Quesenberry CP, et al. Pioglitazone Use and Risk of Bladder Cancer and Other Common Cancers in Persons With Diabetes. JAMA. 2015;314(3):265-277.
    55. Tuccori M, Filion KB, Yin H, Yu OH, Platt RW, Azoulay L. Pioglitazone use and risk of bladder cancer: population based cohort study. BMJ. 2016;352:i1541.
    56. Tang H, Shi W, Fu S, et al. Pioglitazone and bladder cancer risk: a systematic review and meta-analysis. Cancer Med. 2018;7(4):1070-1080.
    57. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366(9493):1279-1289.
    58. Erdmann E, Harding S, Lam H, Perez A. Ten-year observational follow-up of PROactive: a randomized cardiovascular outcomes trial evaluating pioglitazone in type 2 diabetes. Diabetes Obes Metab. 2016;18(3):266-273.
    59. Talar-Williams C, Hijazi YM, Walther MM, et al. Cyclophosphamide-induced cystitis and bladder cancer in patients with Wegener granulomatosis. Ann Intern Med. 1996;124(5):477-484.
    60. Travis LB, Curtis RE, Glimelius B, et al. Bladder and kidney cancer following cyclophosphamide therapy for non-Hodgkin's lymphoma. J Natl Cancer Inst. 1995;87(7):524-530.
    61. Wallis CJ, Mahar AL, Choo R, et al. Second malignancies after radiotherapy for prostate cancer: systematic review and meta-analysis. BMJ. 2016;352:i851.
    62. Elwood PC, Gallagher AM, Duthie GG, Mur LA, Morgan G. Aspirin, salicylates, and cancer. Lancet. 2009;373(9671):1301-1309.
    63. Nicastro HL, Grubbs CJ, Margaret Juliana M, et al. Preventive effects of NSAIDs, NO-NSAIDs, and NSAIDs plus difluoromethylornithine in a chemically induced urinary bladder cancer model. Cancer Prev Res (Phila). 2014;7(2):246-254.
    64. Sabichi AL, Lee JJ, Grossman HB, et al. A randomized controlled trial of celecoxib to prevent recurrence of nonmuscle-invasive bladder cancer. Cancer Prev Res (Phila). 2011;4(10):1580-1589.
    65. Cholesterol Treatment Trialists C, Emberson JR, Kearney PM, et al. Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy. PLoS One. 2012;7(1):e29849.
    66. Crivelli JJ, Xylinas E, Kluth LA, et al. Effect of statin use on outcomes of non-muscle-invasive bladder cancer. BJU Int. 2013;112(2):E4-12.
    67. Kwan ML, Garren B, Nielsen ME, Tang L. Lifestyle and nutritional modifiable factors in the prevention and treatment of bladder cancer. Urol Oncol. 2018.
    68. van Osch FH, Jochems SH, van Schooten FJ, Bryan RT, Zeegers MP. Quantified relations between exposure to tobacco smoking and bladder cancer risk: a meta-analysis of 89 observational studies. Int J Epidemiol. 2016;45(3):857-870.
    69. Baris D, Karagas MR, Verrill C, et al. A case-control study of smoking and bladder cancer risk: emergent patterns over time. J Natl Cancer Inst. 2009;101(22):1553-1561.
    70. Rink M, Furberg H, Zabor EC, et al. Impact of smoking and smoking cessation on oncologic outcomes in primary non-muscle-invasive bladder cancer. Eur Urol. 2013;63(4):724-732.
    71. Simonis K, Shariat SF, Rink M, Urothelial Cancer Working Group of the Young Academic Urologists Working Party of the European Association of U. Smoking and smoking cessation effects on oncological outcomes in nonmuscle invasive bladder cancer. Curr Opin Urol. 2014;24(5):492-499.
    72. Orellana-Serradell O, Poblete CE, Sanchez C, et al. Proapoptotic effect of endocannabinoids in prostate cancer cells. Oncol Rep. 2015;33(4):1599-1608.
    73. Sreevalsan S, Joseph S, Jutooru I, Chadalapaka G, Safe SH. Induction of apoptosis by cannabinoids in prostate and colon cancer cells is phosphatase dependent. Anticancer Res. 2011;31(11):3799-3807.
    74. Gasperi V, Evangelista D, Oddi S, et al. Regulation of inflammation and proliferation of human bladder carcinoma cells by type-1 and type-2 cannabinoid receptors. Life Sci. 2015;138:41-51.
    75. Thomas AA, Wallner LP, Quinn VP, et al. Association between cannabis use and the risk of bladder cancer: results from the California Men's Health Study. Urology. 2015;85(2):388-392.
    76. Chacko JA, Heiner JG, Siu W, Macy M, Terris MK. Association between marijuana use and transitional cell carcinoma. Urology. 2006;67(1):100-104.
    77. Liu H, Wang XC, Hu GH, et al. Fruit and vegetable consumption and risk of bladder cancer: an updated meta-analysis of observational studies. Eur J Cancer Prev. 2015;24(6):508-516.
    78. 78. Xu C, Zeng XT, Liu TZ, et al. Fruits and vegetables intake and risk of bladder cancer: a PRISMA-compliant systematic review and dose-response meta-analysis of prospective cohort studies. Medicine (Baltimore). 2015;94(17):e759.
    Published April 16, 2019
  • Expert Commentary: Avelumab, an Anti–Programmed Death-Ligand 1 Antibody, In Patients With Refractory Metastatic Urothelial Carcinoma: Results From a Multicenter, Phase Ib Study.

    Platinum-resistant urothelial carcinoma is a lethal disease. After a long period of therapeutic stagnation, the last two years have witnessed an explosion in the development of new second-line therapies.
    Published August 10, 2017
  • Expert Commentary: Neoadjuvant chemotherapy prior to radical cystectomy for muscle-invasive bladder cancer with variant histology.

    Neoadjuvant chemotherapy is a standard of care for patients with urothelial muscle-invasive bladder cancer. Histologic variants of bladder cancer are less common but often clinically aggressive. Understanding whether neoadjuvant chemotherapy results in the same benefit in histological variants as in urothelial bladder cancer is crucial.
    Published August 8, 2017
  • Expert Commentary:Contemporary use trends and survival outcomes in patients undergoing radical cystectomy or bladder-preservation therapy for muscle-invasive bladder cancer.

    Bladder preservation therapy is a definitive treatment option for clinically localized bladder cancer.  Previous studies demonstrated improved 10-year locoregional control when comparing chemo-radiotherapy with radiation therapy alone. However, evidence from prospective or randomized controlled trials comparing survival outcomes of patients treated with bladder preservation with those of patients receiving radical cystectomy is generally lacking.
    Published August 8, 2017
  • Factors Associated with Recurrence in Primary Carcinoma in situ of the Bladder Treated with Bacillus Calmette-Guérin - Expert Commentary

    Primary carcinoma in situ (P-CIS) of the bladder is rare. Adjuvant intravesical Bacillus Calmette-Guérin (BCG) immunotherapy has been reported to be effective in reducing recurrence rates in CIS and P-CIS patients but the clinical factors associated with the recurrence of P-CIS are not well-defined. 
    Published November 5, 2018
  • First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study

    Background

    More than half of all patients with advanced urothelial cancer cannot receive standard, first-line cisplatin based chemotherapy because of renal dysfunction, poor performance status, or other comorbidities. We assessed the activity and safety of first-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer.
    Published September 27, 2017
  • Gene Methylation and Urine Cytology to Monitor Bladder Cancer - Expert Commentary

    Currently, intermediate or high-risk non-muscle-invasive bladder cancer patients (NMIBC) require intensive follow-up. This usually consists of urethrocystoscopy (gold standard) and urine cytology to monitor the recurrence of NMIBC. The current methods are expensive and invasive and have low sensitivity. 
    Published July 23, 2018
  • Identification of key pathways and genes influencing prognosis in bladder urothelial carcinoma.

    Genomic profiling can be used to identify the predictive effect of genomic subsets for determining prognosis in bladder urothelial carcinoma (BUC) after radical cystectomy. This study aimed to investigate potential gene and pathway markers associated with prognosis in BUC.

    Published April 4, 2017
  • Immune Phenotype of Peripheral Blood Mononuclear Cells in Patients with High-risk Non-muscle Invasive Bladder Cancer - Expert Commentary

    Non-muscle-invasive bladder cancer (NMIBC) has a high recurrence rate. Although the BCG therapy is recommended as an immune targeting treatment in high-risk NMIBC tumors, the BCG’s role in the eliciting a response by the innate and adaptive immunity is unclear. A recent study by Audenet et al. published recently in the World Journal of Urology, investigated the immune phenotype of peripheral blood mononuclear cells (PBMC) in patients with NMIBC treated with intravesical BCG. 
    Published July 31, 2018
  • Immunohistochemical and molecular characterizations in urothelial carcinoma of bladder in patients less than 45 years.

    Bladder tumours in early-onset patients are rare and seem to exhibit unique clinicopathological features. Only few studies have investigated somatic alterations in this specific age of onset group and evidence is accumulating of a distinct molecular behaviour of early-onset bladder tumours.

    Published March 22, 2017
  • Impact of divergent differentiation in urothelial carcinoma on oncological outcome in patients with T1 high-grade bladder cancer.

    T1 high-grade bladder cancer has a poor prognosis compared with other non-muscle-invasive bladder cancers. We investigated the clinical outcomes among patients with T1 high-grade bladder cancer to identify factors related to cancer recurrence and disease progression.

    Published March 27, 2017
  • Implications of Micropapillary Urothelial Carcinoma Variant on Prognosis Following Radical Cystectomy: A Multi-Institutional Investigation – Beyond the Abstract

    The presence of micropapillary urothelial carcinoma is being increasingly recognized in recent years during the histopathologic examination of bladder cancers and is typically considered an aggressive variant with poor prognosis. This is based on prior single-institution or population-based series with limited clinical events or pathologic data.
    Published December 9, 2018
  • Intravesical rAd-IFNα/Syn3 for Patients With High-Grade, Bacillus Calmette-Guerin-Refractory or Relapsed Non-Muscle-Invasive Bladder Cancer: A Phase II Randomized Study.

    Purpose Many patients with high-risk non-muscle-invasive bladder cancer (NMIBC) are either refractory to bacillus Calmette-Guerin (BCG) treatment or may experience disease relapse. We assessed the efficacy and safety of recombinant adenovirus interferon alfa with Syn3 (rAd-IFNα/Syn3), a replication-deficient recombinant adenovirus gene transfer vector, for patients with high-grade (HG) BCG-refractory or relapsed NMIBC.

    Published August 29, 2017
  • Inverted Papilloma: A Rare and Benign Cause for Upper Urinary Tract Neoplasia

    Abstract: Inverted papilloma (IP) of the ureter is a very rare benign neoplasm with around 50 cases reported in the literature 1.  Radiologically and endoscopically these lesions are indistinguishable from urothelial cancers. It is therefore essential to obtain a tissue diagnosis prior to treatment.
    Published November 28, 2018
  • Management of Non-Muscle Invasive Bladder Cancer

    In the previous sections, we have covered Epidemiology, Diagnosis, and Pathology of Bladder Cancers. As noted, most patients present at a potentially curative stage non-muscle invasive bladder cancer (NMIBC). Although NMIBC can generally be managed with endoscopic resections followed by some form of intravesical therapy, some have the potential to progress to muscle-invasive bladder cancer (MIBC) or develop metastases. Key to the management of NMIBC is making the distinction between tumors likely to progress vs. those that will not, and for the appropriate personalized therapy for each patient.


    stages_of_bladder_cancer.jpg

    Endoscopic Surgical Management

    Cystoscopic Resection

    NMIBC is usually diagnosed with cystoscopic evaluation. Upon diagnosis, the location, number, and morphology of the tumors are recorded. Urinary cytology is sent and upper tract imaging performed to assess for extravesical urothelial tumors and staging purposes. 

    Transurethral resection of bladder tumor (TURBT) is the initial treatment. Bimanual exam under anesthesia should be performed to complete clinical staging. It is imperative that deeper resections are obtained to ensure adequate muscle sampling and en bloc resection or at least sending the base separately can help pathologists make the best diagnosis. Resecting tumors within a bladder diverticulum may be easily complicated by bladder perforation. Invasion beyond the lamina propria in diverticula should be categorized as cT3a disease. When resecting near the ureteral orifice caution is advised and using pure cutting current is important to minimize scarring which may lead to ureteral obstruction. Alternatively, small tumors may be resected using the cold-cup biopsy forceps. 

    To improve the quality of TUR and reporting, a 10-item checklist designed to encompass both the description of tumor characteristics associated with oncologic outcomes (e.g. tumor number, size, and characteristics) and steps ensuring adequate tumor evaluation and treatment (e.g. bimanual exam, visually complete resection) has been proposed. The implementation of this checklist enhanced surgeon attention to the critical aspects of the procedure, improving surgical quality.1

    Expected side effects of TURBT include minor bleeding and irritative symptoms. Excessive bleeding and bladder perforation are uncommon (<5% of cases). Fortunately, in cases of perforation, the risk of tumor seeding appears to be low.2 Extraperitoneal perforations can usually be managed with prolonged catheterization, while intraperitoneal rupture often requires surgical repair. TUR syndrome may occur due to the absorption of hypotonic fluid if due diligence is not observed.3 As long as minimal energy is applied to the ureteral orifice, the incidence of scarring is low.4

    Additional Strategies

    Concurrent with resection of the tumor, any suspicious area within the lower urinary tract should be sampled, either with formal resection or with cold cup biopsy. Prostatic urethral biopsies are recommended in patients with a multifocal tumor or visible abnormalities. Repeat TUR within 2-4 weeks is recommended when primary resection is incomplete or in the presence of high-grade T1 tumors.5

    Laser therapy is sometimes used, not only for tumor coagulation but also for en bloc resection. In a recent meta-analysis of en bloc resection series, 96% of the cases demonstrated the presence of detrusor muscle within the specimen and residual disease was present on re-TUR in only 1/119 cases.6 Treatment should be under direct visualization and discontinued as soon as a coagulative effect is observed around the tumor base.7

    Narrowband imaging (NBI) and blue light cystoscopy (BLC) has been used to enhance visualization of bladder tumors. BLC is a technique that identifies cancer through the selective accumulation of photosensitizing drugs (5-aminolevulinic acid and hexyl-aminolevulinate) in the malignant cells. When used in conjunction with white light cystoscopy, BLC provides enhanced detection rates of non-muscle invasive lesions.8-10 In a meta-analysis consisting of 12 randomized controlled trials with a total 2258 patients, a lower recurrence rate (OR 0.5; p<0.0001) with a delayed time to the first occurrence (by 7.39 weeks, p<0.0001) was seen with BLC.11 As a result, recommendations for its use have been incorporated into the NCCN guidelines. Recently, flexible blue light cystoscopy was also demonstrated to detect additional malignant lesions in 63% of the patients with recurrence after primary therapy and in 21% of the patients with lesions not otherwise seen on white light cystoscopy.12

    In NMIBC, the most important prognostic factor for progression is grade.13 While high-grade tumors often appear sessile and broad-based, low-grade tumors typically exhibit papillary architecture on a thin stalk. In conjunction, LG tumors’ low likelihood of progression and favorable morphology lend themselves to biopsy and fulgurations that can be accomplished in the outpatient setting.14 Adopting this strategy can significantly reduce the therapeutic burden associated with bladder cancer treatment. 

    Perioperative Intravesical Chemotherapy

    The most widely studied agent has been Mitomycin C (MMC), used as a single dose immediately after TURBT. Although MMC was shown to reduce the risk of recurrence by 35% (HR: 0.65; 95% CI, 0.58-0.74; p<0.001), it was not efficacious in patients with a prior recurrence rate of more than one per year or in patients with EORTC recurrence score 5.15 A recent prospective randomized trial using perioperative infusion of gemcitabine demonstrated a reduction of recurrence from 47% to 35% (p<0.001). Corroborating the findings in a previous meta-analysis of perioperative instillation of Mitomycin C, among the target population with low-grade, non-muscle invasive cancer, the reduction was even more dramatic (from 54% to 34%, p-0.001). There were also minimal complications (2.4% ≥Grade 3).16 

    Adjuvant Intravesical Therapy

    Immunotherapy

    Bacillus Calmette-Guerin is an attenuated mycobacterium with proven efficacy in reducing recurrences, progression and death from  NMIBC.17 Therapy is usually started 2-4 weeks after tumor resection.18 Therapeutic protocol includes induction with 6 weeks followed by maintenance therapy (3 weekly maintenances at 3mo, 6mo, 12mo, 18mo, 24mo, 30mo, and 36mo). This is now accepted as standard of care in patients with high-risk disease, with one year maintenance as an alternative for intermediate risk patients (Figure 2).19 If tumor recurrence is found after induction therapy, an additional induction course may be attempted. 


    figure-2-non-muscle-invasive-bladder-cancer@2x.jpg


    Although side-effects are usually temporary and self-limited, significant morbidity can occur with fevers, lung infections, and sepsis. While most can be treated with symptomatic therapy, in the case of severe infections or BCG-osis, addition of steroids should be considered in addition to anti-tuberculosis therapy. In a randomized study by the EORTC, reduced dose was compared to full dose BCG, and 1 compared to 3 years. While full dose for 3 years was associated with the best reduction in recurrences, there was no significant difference with regards to progression.20 Interestingly, there was no difference in local or systemic side effects between low dose or full dose BCG.20  Nonetheless in clinical practice, reduction of dose for cause - i.e. when side effects are reported -  has been noted to allow patients to continue on therapy and finish the duration of maintenance.

    A number of other immunogenic agents have been tested for the treatment of NMIBC, some in the setting of BCG failure. These include keyhole limpet hemocyanin (KLH), mycobacterial cell wall DNA extract (MCNA), IL-2, and IFN-α. None of these, however, proved to be as effective as treatment with BCG. 

    Chemotherapy

    In general, intravesical chemotherapy may improve recurrence-free rates, but these are not as effective as BCG in preventing progression (Table 1). They are, however, better tolerated. MMC, the most extensively studied intravesical chemotherapy agent, was associated with 9. 4% progression rate, compared to 7.7% after BCG.21 Strategies such as electromotive therapy have been seeking to enhance the efficacy of MMC, although results have been mixed thus far. In studies limited to high-risk NMIBC, recurrence-free rates following chemohyperthermia ranged from 29-71%.22 Gemcitabine and the taxanes paclitaxel and docetaxel may be used in combination, even in the treatment of BCG-Unresponsive disease (Figure 2). 


    table-1-non-muscle-invasive-bladder-cancer@2x.jpg

    BCG Unresponsive Disease

    Recurrent tumors after intravesical BCG treatment confer a high risk of progression and salvage radical cystectomy is recommended.23 In practice, many patients may need to resort to less radical treatment options due to their physical frailty or rejection of complete bladder removal. Alternate options for these patients remain scarce. Valrubicin, the only approved agent for recurrent CIS after intravesical BCG treatment, has only an 8% complete response rate at 30-month follow-up.24 Alternative options include other intravesical chemotherapies including gemcitabine, docetaxel and sequential or combination therapy (Table 2). Gene therapies options include the use of Instiladrin®, an IFN-α expressing recombinant adenoviral vector, which has recently achieved 35% 12-month relapse-free survival in a cohort of high risk, BCG-Unresponsive NMIBC patients (Figure 2).25 Ongoing trials in this space are listed in Table 3.


    table-2-non-muscle-invasive-bladder-cancer@2x.jpg


    table-3-non-muscle-invasive-bladder-cancer@2x.jpg


    Strategies for Surveillance 

    Due to its high recurrence rate and the need for vigilant cystoscopic surveillance, the management of bladder cancer is the most costly amongst all cancers in the US; $2.2 billion was spent in 2003.26 Surveillance relies on cystoscopy and urine cytology, with most recommending this every 3 months up to 24 months after initial diagnosis, followed by every 6 months up to 5 years.19 

    Although generally regarded as the urinary test of choice, urine cytology has very low sensitivity (48%), especially in detecting a low-grade tumor (16%).27 Recent studies have also demonstrated the decreased performance of cytology for high-grade tumors – for example in a recent multicenter study, as many as 40% of CIS were not detected by cytology. Thus, caution must be exercised when relying on cytology alone.28 Other urinary markers available today include BTA stat and BTA TRAK (detect human complement factor H-related protein), ImmunoCyt (fluorescent-labeled monoclonal antibodies), NMP22 (detection of nuclear matrix protein 22), UroVysion (FISH of DNA probes specific for bladder cancer aneuploidy) and Cxbladder (measures the expression of 5 biomarkers). However, none are recommended for use in the management guidelines other than potential use of Urovysion FISH in clarifying atypical cytology or in predicting response to BCG. A positive FISH result after BCG induction confers an increased risk of recurrence (3-5 fold) and progression (5-13 fold), depending on the timing of FISH positivity.  For example in one study; at the 3-month time point, patients with a positive FISH result had a 58% risk of recurrence compared to 15% with a negative result (p < 0.001). For disease progression, the incidence was 25% with a positive FISH compared to 7% with a negative result (p < 0.013).29 Since many patients who have a positive FISH test have no visible tumor at the time of assessment but subsequently develop recurrence in 6-24 months, this phenomenon has been categorized as a molecular failure and such patients can be considered for clinical trials for salvage therapies.30

    In addition, cytokines and biomarkers have been assessed to predict response to BCG. However, due to the complexity of the immune response to BCG, no single marker is likely to definitively predict a positive or negative response. We have prospectively tested the hypothesis that a panel of urinary cytokines can accurately assess the multifaceted immune response generated by intravesical BCG.31 A nomogram (CyPRIT, Cytokine Panel for Response to Intravesical Therapy) using a panel of 9 cytokines (IL-2, IL-6, IL-8, IL-18, IL-1ra, TRAIL, IFN-g, IL-12[p70], and TNF-a) was found to have an accuracy of 85.5% in predicting response to BCG (95% CI 77.9–93.1%). Efforts to validate the use of CyPRIT are currently underway.
    Written by: Roger Li, MD and Ashish Kamat, MD, MBBS
    References:
    1. Anderson C, Weber R, Patel D, Lowrance W, Mellis A, Cookson M, et al. A 10-Item Checklist Improves Reporting of Critical Procedural Elements during Transurethral Resection of Bladder Tumor. J Urol. 2016;196(4):1014-20.
    2. Balbay MD, Çimentepe E, ÜNsal A, Bayrak Ö, KoÇ A, Akbulut Z. The actual incidence of bladder perforation following transurethral bladder surgery. The Journal of urology. 2005;174(6):2260-3.
    3. Bolat D, Gunlusoy B, Aydogdu O, Aydin ME, Dincel C. Comparing the short - term outcomes and complications of monopolar and bipolar transurethral resection of bladder tumors in patients with coronary artery disease: a prospective, randomized, controlled study. Int Braz J Urol. 2018;44(4):717-25.
    4. Mano R, Shoshany O, Baniel J, Yossepowitch O. Resection of ureteral orifice during transurethral resection of bladder tumor: functional and oncologic implications. J Urol. 2012;188(6):2129-33.
    5. Cumberbatch MGK, Foerster B, Catto JWF, Kamat AM, Kassouf W, Jubber I, et al. Repeat Transurethral Resection in Non-muscle-invasive Bladder Cancer: A Systematic Review. Eur Urol. 2018;73(6):925-33.
    6. Naselli A, Puppo P. En bloc transurethral resection of bladder tumors: a new standard? J Endourol. 2017;31(S1):S-20-S-4.
    7. Liem EI, de Reijke TM. Can we improve transurethral resection of the bladder tumour for nonmuscle invasive bladder cancer? Current opinion in urology. 2017;27(2):149-55.
    8. Fradet Y, Grossman HB, Gomella L, Lerner S, Cookson M, Albala D, et al. A comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of carcinoma in situ in patients with bladder cancer: a phase III, multicenter study. The Journal of urology. 2007;178(1):68-73.
    9. Grossman HB, Gomella L, Fradet Y, Morales A, Presti J, Ritenour C, et al. A phase III, multicenter comparison of hexaminolevulinate fluorescence cystoscopy and white light cystoscopy for the detection of superficial papillary lesions in patients with bladder cancer. The Journal of urology. 2007;178(1):62-7.
    10. Hermann GG, Mogensen K, Carlsson S, Marcussen N, Duun S. Fluorescence-guided transurethral resection of bladder tumours reduces bladder tumour recurrence due to less residual tumour tissue in T a/T1 patients: a randomized two‐centre study. BJU Int. 2011;108(8b):E297-E303.
    11. Yuan H, Qiu J, Liu L, Zheng S, Yang L, Liu Z, et al. Therapeutic outcome of fluorescence cystoscopy guided transurethral resection in patients with non-muscle invasive bladder cancer: a meta-analysis of randomized controlled trials. PLoS One. 2013;8(9):e74142.
    12. Daneshmand S, Patel S, Lotan Y, Pohar K, Trabulsi E, Woods M, et al. Efficacy and Safety of Blue Light Flexible Cystoscopy with Hexaminolevulinate in the Surveillance of Bladder Cancer: A Phase III, Comparative, Multicenter Study. J Urol. 2018;199(5):1158-65.
    13. Fernandez-Gomez J, Solsona E, Unda M, Martinez-Pineiro L, Gonzalez M, Hernandez R, et al. Prognostic factors in patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guerin: multivariate analysis of data from four randomized CUETO trials. Eur Urol. 2008;53(5):992-1001.
    14. Sabir EF, Holmäng S. TaG1 Bladder Cancer: A Third of All Primary Tumors and 80% of All Recurrences Can Be Treated in the Office Using Local Anesthesia. Urology Practice. 2014;1(4):184-8.
    15. Sylvester RJ, Oosterlinck W, Holmang S, Sydes MR, Birtle A, Gudjonsson S, et al. Systematic review and individual patient data meta-analysis of randomized trials comparing a single immediate instillation of chemotherapy after transurethral resection with transurethral resection alone in patients with stage pTa–pT1 urothelial carcinoma of the bladder: which patients benefit from the instillation? Eur Urol. 2016;69(2):231-44.
    16. Messing EM, Tangen CM, Lerner SP, Sahasrabudhe DM, Koppie TM, Wood DP, Jr., et al. Effect of Intravesical Instillation of Gemcitabine vs Saline Immediately Following Resection of Suspected Low-Grade Non-Muscle-Invasive Bladder Cancer on Tumor Recurrence: SWOG S0337 Randomized Clinical Trial. JAMA. 2018;319(18):1880-8.
    17. Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol. 1976;116(2):180-3.
    18. Lamm DL, Van Der Meijden AP, Morales A, Brosman SA, Catalona WJ, Herr HW, et al. Incidence and treatment of complications of bacillus Calmette-Guerin intravesical therapy in superficial bladder cancer. The Journal of urology. 1992;147(3):596-600.
    19. Babjuk M, Bohle A, Burger M, Capoun O, Cohen D, Comperat EM, et al. EAU Guidelines on Non-Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2016. Eur Urol. 2016.
    20. Oddens J, Brausi M, Sylvester R, Bono A, van de Beek C, van Andel G, et al. Final results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette-Guerin in intermediate- and high-risk Ta, T1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. Eur Urol. 2013;63(3):462-72.
    21. Böhle A, Jocham D, Bock P. Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity. The Journal of urology. 2003;169(1):90-5.
    22. Liem EI, Crezee H, de la Rosette JJ, de Reijke TM. Chemohyperthermia in non-muscle-invasive bladder cancer: An overview of the literature and recommendations. Int J Hyperthermia. 2016;32(4):363-73.
    23. Babjuk M, Böhle A, Burger M, Capoun O, Cohen D, Compérat EM, et al. EAU Guidelines on Non-Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2016. Eur Urol. 2017;71(3):447-61.
    24. Steinberg G, Bahnson R, Brosman S, Middleton R, Wajsman Z, Wehle M. Efficacy and safety of valrubicin for the treatment of Bacillus Calmette-Guerin refractory carcinoma in situ of the bladder. The Valrubicin Study Group. J Urol. 2000;163(3):761-7.
    25. Shore ND, Boorjian SA, Canter DJ, Ogan K, Karsh LI, Downs TM, et al. Intravesical rAd-IFNalpha/Syn3 for Patients With High-Grade, Bacillus Calmette-Guerin-Refractory or Relapsed Non-Muscle-Invasive Bladder Cancer: A Phase II Randomized Study. J Clin Oncol. 2017;35(30):3410-6.
    26. Donat SM. Evaluation and follow-up strategies for superficial bladder cancer. The Urologic clinics of North America. 2003;30(4):765-76.
    27. Yafi FA, Brimo F, Steinberg J, Aprikian AG, Tanguay S, Kassouf W. Prospective analysis of sensitivity and specificity of urinary cytology and other urinary biomarkers for bladder cancer. Urologic Oncology: Seminars and Original Investigations. 2015;33(2):66.e25-66.e31.
    28. Tan WS, Sarpong R, Khetrapal P, Rodney S, Mostafid H, Cresswell J, et al. Does urinary cytology have a role in haematuria investigations? BJU Int. 2018.
    29. Kamat AM, Dickstein RJ, Messetti F, Anderson R, Pretzsch SM, Gonzalez GN, et al. Use of fluorescence in situ hybridization to predict response to bacillus Calmette-Guerin therapy for bladder cancer: results of a prospective trial. The Journal of urology. 2012;187(3):862-7.
    30. Kamat AM, Willis DL, Dickstein RJ, Anderson R, Nogueras-Gonzalez G, Katz RL, et al. Novel fluorescence in situ hybridization-based definition of bacille Calmette-Guerin (BCG) failure for use in enhancing recruitment into clinical trials of intravesical therapies. BJU international. 2016;117(5):754-60.
    31. Kamat AM, Briggman J, Urbauer DL, Svatek R, Nogueras Gonzalez GM, Anderson R, et al. Cytokine Panel for Response to Intravesical Therapy (CyPRIT): Nomogram of Changes in Urinary Cytokine Levels Predicts Patient Response to Bacillus Calmette-Guerin. Eur Urol. 2016;69(2):197-200.
    Published April 16, 2019
  • MDACC 2018: Optimizing the Management of cT2N0 Disease

    Houston, TX (UroToday.com) When Surgery Alone is Enough Dr. Neema Navai discussed the rationale for using systemic therapy in managing cT2N0 bladder cancer, noting that goals include downstaging of disease and eliminating the micrometastatic disease. Ideally, we would like to be able to select out which patients may be able to benefit from surgery alone without compromising oncologic outcomes, while potentially sparing them the toxicities associated with chemotherapy.
    Published November 11, 2018
  • MDACC 2018: Options for Patients Failing BCG Therapy

    Houston, TX (UroToday.com) Dr. Ashish Kamat reviewed the emerging options that are currently under investigation for use in patients with non-muscle invasive bladder cancer who have failed BCG. Among these include novel formulations of mitomycin C (MMC), including MMC that is combined in a thermoreversible hydrogel, which is liquid when chilled and solidifies at body temperature.
    Published November 11, 2018
  • MDACC 2018: Update in Robotic vs Open Radical Cystectomy – Where Do We Stand in 2018?

    Houston, TX (UroToday.com) Dr. Neema Navai reviewed the current state of the literature comparing open versus robot-assisted radical cystectomy, highlighting five key papers on the subject. Nix et al. published in 2010 the first prospective randomized controlled trial comparing the two modalities from the University of North Carolina.1 A small trial with 41 randomized patients, the study found that lymph node yield was not inferior in the robotic approach when compared to patients who underwent open surgery.
    Published November 11, 2018
  • Microfluidic Analysis of Captured Urinary Exfoliated Tumor Cells - Expert Commentary

    Due to the very high risk of recurrence, bladder cancer patients require periodic screening and monitoring. Due to the invasiveness and cost of the currently used tools like cystoscopy, the low sensitivity of urine cytology and the lack of sensitivity and specificity of the recent molecular techniques (BTA and NMP22), there is an unmet clinical need for less invasive and more sensitive and specific methods to detect UBC. 
    Published August 6, 2018

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