The Value of Multiparametric Magnetic Resonance Imaging Sequences to Assist in the Decision Making of Muscle-Invasive Bladder Cancer - Beyond the Abstract

Over the last few years, the landscape of bladder cancer (BC) management has profoundly changed, thanks to increased knowledge of disease biology and the identification of novel therapeutic approaches and biomarkers.1 No more than 5 years ago, the treatment-decision process for non muscle-invasive BC (NMIBC) or muscle-invasive BC (MIBC) was represented by radical surgery in most cases, with an opportunity for perioperative systemic therapy in a few cases. To date, the diagnostic and therapeutic armamentarium has been exceedingly enlarged for these patients.
Written by: Marco Bandini, and Andrea Necchi
References:
  1. Vetterlein MW, Witjes JA, Loriot Y, et al. Cutting-edge Management of Muscle-invasive Bladder Cancer in 2020 and a Glimpse into the Future. Eur Urol Oncol. Published online June 15, 2020. doi:10.1016/j.euo.2020.06.001
  2. Merck Sharp & Dohme Corp. A Phase II Clinical Trial to Study the Efficacy and Safety of Pembrolizumab (MK-3475) in Subjects With High Risk Non-Muscle Invasive Bladder Cancer (NMIBC) Unresponsive to Bacillus Calmette-Guerin (BCG) Therapy. clinicaltrials.gov; 2020. Accessed July 16, 2020. https://clinicaltrials.gov/ct2/show/NCT02625961
  3. Safety and efficacy of intravesical nadofaragene firadenovec for patients with high-grade, BCG unresponsive nonmuscle invasive bladder cancer (NMIBC): Results from a phase III trial. | Journal of Clinical Oncology. Accessed July 18, 2020. https://ascopubs.org/doi/abs/10.1200/jco.2020.38.6_suppl.442
  4. Powles T, Kockx M, Rodriguez-Vida A, et al. Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial. Nat Med. Published online November 4, 2019. doi:10.1038/s41591-019-0628-7
  5. Necchi A, Raggi D, Gallina A, et al. Updated Results of PURE-01 with Preliminary Activity of Neoadjuvant Pembrolizumab in Patients with Muscle-invasive Bladder Carcinoma with Variant Histologies. Eur Urol. 2020;77(4):439-446. doi:10.1016/j.eururo.2019.10.026
  6. ASCO GU 2020: Results from BLASST-1 - Nivolumab, Gemcitabine, and Cisplatin in Muscle Invasive Bladder Cancer (MIBC) Undergoing Cystectomy. Accessed July 18, 2020. https://www.urotoday.com/conference-highlights/asco-gu-2020/asco-gu-2020-bladder-cancer/119384-asco-gu-2020-results-from-blasst-1-bladder-cancer-signal-seeking-trial-of-nivolumab-gemcitabine-and-cisplatin-in-muscle-invasive-bladder-cancer-mibc-undergoing-cystectomy.html
  7. Tan TZ, Rouanne M, Tan KT, Huang RY-J, Thiery J-P. Molecular Subtypes of Urothelial Bladder Cancer: Results from a Meta-cohort Analysis of 2411 Tumors. Eur Urol. 2019;75(3):423-432. doi:10.1016/j.eururo.2018.08.027
  8. Necchi A, Raggi D, Gallina A, et al. Impact of Molecular Subtyping and Immune Infiltration on Pathological Response and Outcome Following Neoadjuvant Pembrolizumab in Muscle-invasive Bladder Cancer. Eur Urol. Published online March 9, 2020. doi:10.1016/j.eururo.2020.02.028
  9. Necchi A, Raggi D, Giannatempo P, et al. Can Patients with Muscle-invasive Bladder Cancer and Fibroblast Growth Factor Receptor-3 Alterations Still Be Considered for Neoadjuvant Pembrolizumab? A Comprehensive Assessment from the Updated Results of the PURE-01 Study. Eur Urol Oncol. Published online May 14, 2020. doi:10.1016/j.euo.2020.04.005
  10. Bandini M, Ross JS, Raggi D, et al. Predicting the pathologic complete response after neoadjuvant pembrolizumab in muscle-invasive bladder cancer. J Natl Cancer Inst. Published online June 9, 2020. doi:10.1093/jnci/djaa076
  11. Necchi A, Gallina A, Dyrskjøt L, et al. Converging Roads to Early Bladder Cancer. Eur Urol. Published online March 17, 2020. doi:10.1016/j.eururo.2020.02.031
  12. 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. doi:10.1016/j.eururo.2018.04.029
  13. Necchi A, Bandini M, Calareso G, et al. Multiparametric Magnetic Resonance Imaging as a Noninvasive Assessment of Tumor Response to Neoadjuvant Pembrolizumab in Muscle-invasive Bladder Cancer: Preliminary Findings from the PURE-01 Study. Eur Urol. 2020;77(5):636-643. doi:10.1016/j.eururo.2019.12.016
  14. Bandini M, Calareso G, Raggi D, et al. The Value of Multiparametric Magnetic Resonance Imaging Sequences to Assist in the Decision Making of Muscle-invasive Bladder Cancer. Eur Urol Oncol. Published online June 27, 2020. doi:10.1016/j.euo.2020.06.004

A Golden Age of Bladder Cancer Drug Development

Recent years have seen an explosive rate of transformative advances in both pre-clinical and clinical urothelial carcinoma research.  With the public dissemination of comprehensive molecular data from The Cancer Genome Atlas (TCGA) urothelial carcinoma cohort, the global urothelial carcinoma research community now has the initial road map of the key biological themes that drive carcinogenesis, growth, invasion, and metastasis.1 
Written by: Noah M. Hahn, MD
References:
  1. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507:315-22, 2014
  2. Bellmunt J, de Wit R, Vaughn DJ, et al: Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. N Engl J Med 376:1015-1026, 2017
  3. Patel MR, Ellerton J, Infante JR, et al: Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol 19:51-64, 2018
  4. Powles T, O'Donnell PH, Massard C, et al: Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: Updated results from a phase 1/2 open-label study. JAMA Oncology 3:e172411, 2017
  5. Rosenberg JE, Hoffman-Censits J, Powles T, et al: Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. The Lancet 387:1909-1920, 2016
  6. Sharma P, Retz M, Siefker-Radtke A, et al: Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. The Lancet Oncology 18:312-322, 2017
  7. Rosenberg JE, Sridhar SS, Zhang J, et al: Updated results from the enfortumab vedotin phase 1 (EV-101) study in patients with metastatic urothelial cancer (mUC). Journal of Clinical Oncology 36:4504-4504, 2018
  8. Siefker-Radtke AO, Necchi A, Park SH, et al: First results from the primary analysis population of the phase 2 study of erdafitinib (ERDA; JNJ-42756493) in patients (pts) with metastatic or unresectable urothelial carcinoma (mUC) and FGFR alterations (FGFRalt). J Clin Oncol 36, 2018

Risks of Delaying Bladder Cancer Diagnosis- Surveillance and Surgery During COVID-19

The rapid spread of Coronavirus Disease 2019 (COVID-19), caused by the betacoronavirus SARS-CoV-2, throughout the world has had dramatic effects on healthcare systems with impacts far beyond the patients actually infected with COVID-19.

Patients who manifest severe forms of COVID-19 requiring respiratory support typically require this for prolonged durations, with a mean of 13 days of respiratory support reported by the China Medical Treatment Expert Group for COVID-19.1 This lengthy requirement for ventilator support and ICU resources, exacerbated by relatively little excess health system capacity to accommodate epidemics, means that healthcare systems can (and have in the case of many hospitals in Italy) become overwhelmed relatively quickly. In an effort to conserve hospital resources, the American College of Surgeons on March 13th recommended that health systems, hospitals, and surgeons should attempt to minimize, postpone, or outright cancel electively scheduled operations.2 This was done with the primary goal to immediately decrease the use of items essential for the care of patients with COVID-19 including ICU beds, ventilators, personal protective equipment, and terminal cleaning supplies. On March 17th, the American College of Surgeon then provided further guidance on the triage of non-emergent surgeries, including an aggregate assessment of the risk incurred from surgical delays of six to eight weeks or more as compared to the risk (both to the patient and the healthcare system) of proceeding with the operation.3 In the UK, all non-urgent elective surgical procedures have been put on hold for three months to use all of those clinical resources to care for patients with COVID-19.

Most bodies, including the American College of Surgeons, have recommended proceeding with most cancer surgeries. Thus, clinicians and patients must carefully weigh the benefit of proceeding with cancer treatment as scheduled, the risks of COVID-19 to the individual patient, to health care workers caring for patients potentially infected with COVID-19, and the need to conserve health care resources. A severe SARS-CoV-2 phenotype is seen more commonly in men and older, more comorbid patients.4 These characteristics are common in many patients with urologic malignancies, particularly those with bladder cancer. Baseline characteristics among 1,591 patients admitted to the ICU in the Lombardy Region, Italy showed that the median age was 63 years (IQR 56-70), 82% were male, 68% had ≥1 comorbidity, 88% required ventilator support, and the mortality rate was 26%, with a large proportion requiring ongoing ICU level care at the time of data cut-off.5 Work from China demonstrated that patients with cancer had a higher incidence of COVID-19 infection than expected in the general population and had a more severe manifestation of the disease with a significantly higher proportion requiring invasive ventilation in the ICU or death.6 Thus, considering differences in the natural history of different cancers may meaningfully change this balance of risks and benefits.

In the urologic literature, the effect of delays in surgical intervention has been most thoroughly explored in muscle-invasive bladder cancer and prostate cancer. In bladder cancer, these studies have predominately assessed the association between time from transurethral resection of bladder tumor (TURBT) to radical cystectomy. At least nineteen studies have been published assessing this research question. Published October 23, 2019, in European Urology Oncology, Dr. Russell and colleagues provide a contemporary systematic review and meta-analysis of these data.7 The authors undertook a systematic review of Medline®, Embase®, and Ovid® for randomized trials and observational studies assessing the association between delay in treatment and survival (overall or bladder cancer-specific) for patients with bladder cancer. Among 399 identified articles, the authors included 19 studies in systematic review and 10 in meta-analysis. Utilizing the Risk of Bias in Non-randomised studies – of Interventions (ROBINS-I) and the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria, the authors assessed that most studies were of good quality with low or moderate risk of bias. To account for this, the authors performed “leave out one” sensitivity analyses.

Perhaps the most striking conclusion of this systematic review is the considerable heterogeneity in the source literature, including in methodology. There was considerable variation in the nature of the delay investigated: from the diagnosis of bladder cancer to radical cystectomy (10 studies), from TURBT to radical cystectomy (seven studies), from first clinic visit to radical cystectomy (or radiotherapy; one study), from referral to first treatment (one study), and from neoadjuvant chemotherapy to radical cystectomy (four studies). Additionally, the delay interval was operationalized inconsistently across studies with some using time as a continuous variable, some utilizing splines to model a non-linear relationship, and many utilizing a categorical approach with a variety of thresholds.

Among these studies, a number assessed reasons for delay. Identified reasons for delay included scheduling, seeking multiple medical opinions, social issues, misdiagnosis, and patient comorbidity.

Assessing the delay between bladder cancer and survival, four of nine studies found a significant association between delay from diagnosis to radical cystectomy and survival, with a number concluding that tumor stage was a potential confounder in this relationship. Russell and colleagues meta-analyzed three studies with suitable data and found an increased risk of death for patients with significant delays between diagnosis and radical cystectomy (hazard ratio [HR] 1.34, 95% confidence interval [CI] 1.18-1.53; I2=0%).7

Operationalizing delay as the interval between TURBT and radical cystectomy, four of six studies found an association between this time and survival; a meta-analysis of five studies with suitable data for pooling found a borderline non-significant increased risk of overall mortality (odds ratio 1.18, 95% confident interval 0.99-1.41), with significant between study heterogeneity (I2=73%).7 Utilizing a cubic spline to model the non-linear relationship, Kulkarni and colleagues found that the risk of death began to rise beginning at 40 days between TURBT and radical cystectomy.8

An additional five studies assess the association between the time duration between the completion of neoadjuvant chemotherapy and radical cystectomy and survival. Two demonstrated that prolonged durations between neoadjuvant chemotherapy and radical cystectomy was associated with adverse survival outcomes and an additional one demonstrated upstaging was associated with delays. Boeri et al. found that patients who had greater than 10 weeks between the last cycle of neoadjuvant chemotherapy and radical cystectomy had significantly lower cancer-specific and overall survival.9 Chu et al. found similar results10 while three other analyses failed to support these results. A meta-analysis of three studies with data suitable for pooling failed to demonstrate a significant association between delays from the end of neoadjuvant chemotherapy to radical cystectomy with survival (HR 1.04, 95% CI 0.93-1.16; I2=82%).7

Particularly relevant in the context of the COVID-19 pandemic, Audenet and colleagues found that delays to neoadjuvant chemotherapy of greater than eight weeks were associated with an increased risk of upstaging, while they found no harm in delays up to six months from diagnosis to radical cystectomy, assuming that neoadjuvant chemotherapy was administered in the meantime.11

While the meta-analysis of Russell and colleagues focused on patients with urothelial histology, recently Lin-Brande examined outcomes for patients with variant histology undergoing radical cystectomy.12 In this analysis, patients with variant histology had a similar time from diagnosis to radical cystectomy as those with urothelial histology. In this cohort, delays from diagnosis to radical cystectomy were associated with worse overall survival (HR 1.36, 95% CI 1.11-1.65 per month of delay) after adjusting for relevant clinicopathologic features. The authors then subsequently dichotomized surgical delays using thresholds of four-, eight-, and 12-weeks. On multivariable analysis, no difference in overall survival was apparent when “early” versus “late” was dichotomized at four weeks (hazard ratio 0.92, 95% CI 0.32-2.59) or eight weeks (HR 1.50, 95% CI 0.68-3.29) but significant differences were apparent when delayed surgery was defined as that beyond 12 weeks following diagnosis (HR 3.45, 95% CI 1.51-7.86).

There is somewhat less evidence in patients with non-muscle invasive disease, with significant differences between patients with low-grade and high-grade disease. Low-grade non-muscle invasive bladder cancer has low cancer-specific mortality13 and there is no evidence of harm from delays in management.14-16

In contrast, for patients with high-grade non-muscle invasive disease, progression to muscle invasion/metastases occurs in 15-40% and 10-20% of patients may die from bladder cancer.17,18 In patients who underwent radical cystectomy for recurrent non-muscle invasive bladder cancer following Bacillus Calmette-Guerin (BCG) with or without further intravesical therapy, the delay caused by an additional (unsuccessful) course of intravesical therapy did not result in differences in five-year overall or cancer-specific survival despite a median delay of 1.7 years.19 In contrast, among patients with non-muscle invasive (cT1) micropapillary bladder cancer treated with upfront radical cystectomy or intravesical BCG, Willis et al. demonstrated significantly poorer survival outcomes for patients who underwent initial intravesical therapy.20

In the absence of data, guidance on the care of patients with high-grade non-muscle invasive bladder cancer has relied upon expert guidance. A collaborative review pre-published in European Urology suggested that these patients should receive induction BCG and at least one course of maintenance therapy as the first-line treatment. The authors recommended that re-resection should be continued for patients with pT1 disease while this may be omitted for those with pTa and muscle in the initial resection.

The data regarding delays to radical cystectomy demonstrate considerable heterogeneity with mixed results. This is in large part due to varying definitions of a delay, despite the threshold of 12 weeks advocated in EAU guidelines.21 However, in aggregate, these data suggest that prolonged delays (likely 90 days although potentially as short as 40 days) between bladder cancer diagnosis or TURBT and radical cystectomy are associated with worse survival. However, the data are mixed and pooled results demonstrate considerable heterogeneity. Further, when neoadjuvant chemotherapy is employed, delays to radical cystectomy no longer appear to be significant. Finally, an analysis of funnel plots indicates that there is a publication bias towards studies which demonstrate worse survival associated with delays suggesting that this finding may be exaggerated in the literature.7

A recent multi-institutional analysis from Campi and colleagues assessed the proportion of patients undergoing urologic oncology surgery who had “nondeferrable” indications for treatment.22 The authors identified 2387 patients undergoing radical cystectomy, radical nephroureterectomy, nephrectomy, and radical prostatectomy in the past 12 months at San Luigi Hospital in Turin, San Raffaele Hospital in Milan, and Careggi Hospital in Florence. Assessing patients undergoing radical cystectomy, the authors considered all cases “nondeferrable”. Radical cystectomy comprised 36.2% of all so-called high-priority or nondeferrable cases. They also noted that a large proportion of these patients (50%) are at elevated perioperative risk (defined at American Society of Anesthesiologists score ≥ 3).

In the context of non-muscle invasive disease, delays appear to be significantly more likely to cause harm in patients with high-grade than low-grade disease. However, the evidence base in non-muscle invasive disease is much weaker than for muscle-invasive bladder cancer.

However, when considering delays in performing TURBT, it is not always apparent whether the patient has non-muscle invasive or muscle-invasive disease. Wallace and colleagues examined delays throughout the trajectory of patients with a new diagnosis of urothelial carcinoma, including a preponderance of non-muscle invasive disease (pTa = 51% and pT1 = 22%).23 The authors divided delays in the evaluation of these patients into three: from initial symptom onset to general practitioner presentation (patient-derived delay), from general practitioner presentation to hospital referral (general practitioner-derived delay), and from hospital referral to TURBT (hospital-derived delay). Shorter delays from initial symptom onset to general practitioner presentation were associated with lower tumor stage and improved five-year survival. In this analysis, the authors dichotomized this patient-derived delay at 14 days. Notably, patients with shorter general practitioner-derived delay had worse survival, likely reflecting a selection bias in which patients with particularly worrisome presentations received expedited care. Finally, hospital-derived delays were not significantly associated with survival, whether adjusted for tumor stage or not. When considered in aggregate, total delays from initial symptom onset to TURBT were not significantly associated with survival.

During the COVID-19 pandemic, there will be regional variations in the risk of infection and availability of resources, both with regards to medical treatment and operating room availability. Expert recommendations from the pre-published paper in European Urology suggest it is reasonable that patients with high-grade NMIBC should undergo induction BCG and maintenance therapy if possible. For high-risk NMIBC, radical cystectomy should still be offered if the resources are feasible and the patient’s comorbidity profile does not place them at higher post-operative COVID-19 risk. Based on the available literature, delays in radical cystectomy of up to three months may be safe for muscle-invasive bladder cancer. However, clinicians should prioritize high-grade bladder cancer (NMIBC and muscle-invasive) over other urologic oncology procedures during COVID-19 restrictions.

Written by: Christopher J.D. Wallis, MD, PhD, Instructor in Urology, Vanderbilt University Medical Center, Nashville, Tennessee; Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Atlanta, Georgia

Published Date: April 20th, 2020

Written by: Christopher J.D. Wallis, MD, PhD and Zachary Klaassen, MD, MSc
References: 1. Guan, Wei-jie, Zheng-yi Ni, Yu Hu, Wen-hua Liang, Chun-quan Ou, Jian-xing He, Lei Liu et al. "Clinical characteristics of coronavirus disease 2019 in China." New England Journal of Medicine (2020).

2. March 13, Online, and 2020. “COVID-19: Recommendations for Management of Elective Surgical Procedures.” American College of Surgeons. Accessed April 10, 2020. https://www.facs.org/covid-19/clinical-guidance/elective-surgery.

3.  March 17, Online, and 2020. “COVID-19: Guidance for Triage of Non-Emergent Surgical Procedures.” American College of Surgeons. Accessed April 17, 2020. https://www.facs.org/covid-19/clinical-guidance/triage.

4. COVID, CDC, and Response Team. "Severe outcomes among patients with coronavirus disease 2019 (COVID-19)—United States, February 12–March 16, 2020." MMWR Morb Mortal Wkly Rep 69, no. 12 (2020): 343-346.

5. Grasselli, Giacomo, Alberto Zangrillo, Alberto Zanella, Massimo Antonelli, Luca Cabrini, Antonio Castelli, Danilo Cereda et al. "Baseline Characteristics and Outcomes of 1591 Patients Infected With SARS-CoV-2 Admitted to ICUs of the Lombardy Region, Italy." JAMA (2020).

6. Liang, Wenhua, Weijie Guan, Ruchong Chen, Wei Wang, Jianfu Li, Ke Xu, Caichen Li et al. "Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China." The Lancet Oncology 21, no. 3 (2020): 335-337.

7. Russell, Beth, Fredrik Liedberg, Muhammad Shamim Khan, Rajesh Nair, Ramesh Thurairaja, Sachin Malde, Pardeep Kumar, Richard T. Bryan, and Mieke Van Hemelrijck. "A Systematic Review and Meta-analysis of Delay in Radical Cystectomy and the Effect on Survival in Bladder Cancer Patients." European urology oncology (2019).

8. Kulkarni, Girish S., David R. Urbach, Peter C. Austin, Neil E. Fleshner, and Andreas Laupacis. "Longer wait times increase overall mortality in patients with bladder cancer." The Journal of urology 182, no. 4 (2009): 1318-1324.

9. Boeri, Luca, Matteo Soligo, Igor Frank, Stephen A. Boorjian, R. Houston Thompson, Matthew Tollefson, Fernando J. Quevedo, John C. Cheville, and R. Jeffrey Karnes. "Delaying radical cystectomy after neoadjuvant chemotherapy for muscle-invasive bladder cancer is associated with adverse survival outcomes." European urology oncology 2, no. 4 (2019): 390-396.

10. Chu, Alice T., Sarah K. Holt, Jonathan L. Wright, Jorge D. Ramos, Petros Grivas, Evan Y. Yu, and John L. Gore. "Delays in radical cystectomy for muscle‐invasive bladder cancer." Cancer 125, no. 12 (2019): 2011-2017.

11. Audenet, François, John P. Sfakianos, Nikhil Waingankar, Nora H. Ruel, Matthew D. Galsky, Bertram E. Yuh, and Greg E. Gin. "A delay≥ 8 weeks to neoadjuvant chemotherapy before radical cystectomy increases the risk of upstaging." In Urologic Oncology: Seminars and Original Investigations, vol. 37, no. 2, pp. 116-122. Elsevier, 2019.

12. Lin-Brande, Michael, Shane M. Pearce, Akbar N. Ashrafi, Azadeh Nazemi, Madeleine L. Burg, Saum Ghodoussipour, Gus Miranda, Hooman Djaladat, Anne Schuckman, and Siamak Daneshmand. "Assessing the Impact of Time to Cystectomy for Variant Histology of Urothelial Bladder Cancer." Urology 133 (2019): 157-163.

13. Lopez-Beltran, Antonio, and Rodolfo Montironi. "Non-invasive urothelial neoplasms: according to the most recent WHO classification." European urology 46, no. 2 (2004): 170-176.

14. Soloway, Mark S., Darren S. Bruck, and Sandy S. Kim. "Expectant management of small, recurrent, noninvasive papillary bladder tumors." The Journal of urology 170, no. 2 (2003): 438-441.

15. Guidance, N. I. C. E. "Bladder cancer: diagnosis and management of bladder cancer." BJU Int 120, no. 6 (2017): 755-765.

16. Matulay, Justin T., Mark Soloway, J. Alfred Witjes, Roger Buckley, Raj Persad, Donald L. Lamm, Andreas Boehle et al. "Risk‐adapted management of low‐grade bladder tumours: recommendations from the International Bladder Cancer Group (IBCG)." BJU international 125, no. 4 (2020): 497-505.

17. Klaassen, Zachary, Ashish M. Kamat, Wassim Kassouf, Paolo Gontero, Humberto Villavicencio, Joaquim Bellmunt, Bas WG van Rhijn, Arndt Hartmann, James WF Catto, and Girish S. Kulkarni. "Treatment strategy for newly diagnosed T1 high-grade bladder urothelial carcinoma: new insights and updated recommendations." European urology 74, no. 5 (2018): 597-608.

18. Thomas, Francis, Aidan P. Noon, Naomi Rubin, John R. Goepel, and James WF Catto. "Comparative outcomes of primary, recurrent, and progressive high-risk non–muscle-invasive bladder cancer." European urology 63, no. 1 (2013): 145-154.

19. Haas, Christopher R., LaMont J. Barlow, Gina M. Badalato, G. Joel DeCastro, Mitchell C. Benson, and James M. McKiernan. "The timing of radical cystectomy for bacillus Calmette-Guerin failure: comparison of outcomes and risk factors for prognosis." The Journal of urology 195, no. 6 (2016): 1704-1709.

20. Willis, Daniel L., Mario I. Fernandez, Rian J. Dickstein, Sahil Parikh, Jay B. Shah, Louis L. Pisters, Charles C. Guo et al. "Clinical outcomes of cT1 micropapillary bladder cancer." The Journal of urology 193, no. 4 (2015): 1129-1134.

21. Witjes, J. Alfred, Thierry Lebret, Eva M. Compérat, Nigel C. Cowan, Maria De Santis, Harman Maxim Bruins, Virginia Hernandez et al. "Updated 2016 EAU guidelines on muscle-invasive and metastatic bladder cancer." European urology 71, no. 3 (2017): 462-475.

22. Campi, Riccardo, Daniele Amparore, Umberto Capitanio, Enrico Checcucci, Andrea Salonia, Cristian Fiori, Andrea Minervini et al. "Assessing the Burden of Nondeferrable Major Uro-oncologic Surgery to Guide Prioritisation Strategies During the COVID-19 Pandemic: Insights from Three Italian High-volume Referral Centres." European Urology (2020).

23. Wallace, D. M. A., R. T. Bryan, J. A. Dunn, G. Begum, S. Bathers, and West Midlands Urological Research Group. "Delay and survival in bladder cancer." BJU international 89, no. 9 (2002): 868-878.

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.

Published Date: April 16th, 2019

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.

Beyond Bladder Cancer: Bacillus Calmette-Guérin (BCG) Vaccination Revisited as a Strategy to Reduce COVID-19 Related Adverse Events in High Risk Health Care Workers and the Elderly

First Published April 2, 2020

The ongoing pandemic involving severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and its resulting coronavirus disease 2019 (COVID-19) has caused widespread infection worldwide, with over 660,000 confirmed cases as of March 28, 2020 and nearly 31,000 deaths.1 Data from the Italian National Institute of Health (Istituto Superiore di Sanità [ISS]) where fatalities are thus far the highest suggest a fatality rate of 7.2%, significantly higher than that which has been observed in other countries.2 Elderly patients are at greatest risk of mortality from COVID-19, and approximately 23% of the Italian populace is aged 65 years or older, making the country particularly vulnerable.2

Written by: Vikram M. Narayan, Paul Hegarty, Gianluca Giannarini, Rick Bangs, Stephanie Chisolm, and Ashish M. Kamat
References:

1. University JH. Johns Hopkins Center for Systems Science and Engineering Coronavirus Resource Center n.d.

2. Onder G, Rezza G, Brusaferro S. Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy. JAMA 2020. doi:10.1001/jama.2020.4683.

3. Liang W, Guan W, Chen R, Wang W, Li J, Xu K, et al. Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. Lancet Oncol 2020;21:335–7. doi:10.1016/S1470-2045(20)30096-6.

4. Moulton LH, Rahmathullah L, Halsey NA, Thulasiraj RD, Katz J, Tielsch JM. Evaluation of non-specific effects of infant immunizations on early infant mortality in a southern Indian population. Trop Med Int Heal 2005;10:947–55. doi:10.1111/j.1365-3156.2005.01434.x.

5. Aaby P, Roth A, Ravn H, Napirna BM, Rodrigues A, Lisse IM, et al. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J Infect Dis 2011;204:245–52. doi:10.1093/infdis/jir240.

6. Leentjens J, Kox M, Stokman R, Gerretsen J, Diavatopoulos DA, van Crevel R, et al. BCG Vaccination Enhances the Immunogenicity of Subsequent Influenza Vaccination in Healthy Volunteers: A Randomized, Placebo-Controlled Pilot Study. J Infect Dis 2015;212:1930–8. doi:10.1093/infdis/jiv332.

7. Arts RJW, Moorlag SJCFM, Novakovic B, Li Y, Wang S-Y, Oosting M, et al. BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity. Cell Host Microbe 2018;23:89-100.e5. doi:10.1016/j.chom.2017.12.010.

8. Hegarty PK, Sfakianos JP, Giannarini G, DiNardo AR, Kamat AM. Coronavirus disease 2019 (Covid-19) and Bacillus Calmette-Guérin (BCG): what is the link? Eur Urol Oncol 2020 in press

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 situ hybridization (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

Published Date: April 16th, 2019

Written by: Justin T. Matulay, MD and Ashish Kamat, MD, MBBS
References: 1. Khadra MH, Pickard RS, Charlton M, et al. A prospective analysis of 1,930 patients with hematuria to evaluate current diagnostic practice. J Urol. 2000;163(2):524-527.
2. Mishriki SF, Nabi G, Cohen NP. Diagnosis of urologic malignancies in patients with asymptomatic dipstick hematuria: prospective study with 13 years' follow-up. Urology. 2008;71(1):13-16.
3. Divrik RT, Yildirim U, Zorlu F, et al. The effect of repeat transurethral resection on recurrence and progression rates in patients with T1 tumors of the bladder who received intravesical mitomycin: a prospective, randomized clinical trial. J Urol. 2006;175(5):1641-1644.
4. Gendy R, Delprado W, Brenner P, et al. Repeat transurethral resection for non-muscle-invasive bladder cancer: a contemporary series. BJU Int. 2016;117 Suppl 4:54-59.
5. Lazica DA, Roth S, Brandt AS, et al. Second transurethral resection after Ta high-grade bladder tumor: a 4.5-year period at a single university center. Urol Int. 2014;92(2):131-135.
6. Cumberbatch MGK, Foerster B, Catto JWF, et al. Repeat Transurethral Resection in Non-muscle-invasive Bladder Cancer: A Systematic Review. Eur Urol. 2018.
7. Babjuk M, Bohle A, Burger M, et al. EAU Guidelines on Non-Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2016. Eur Urol. 2017;71(3):447-461.
8. Chang SS, Boorjian SA, Chou R, et al. Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline. J Urol. 2016;196(4):1021-1029.
9. Chang TC, Marcq G, Kiss B, et al. Image-Guided Transurethral Resection of Bladder Tumors - Current Practice and Future Outlooks. Bladder Cancer. 2017;3(3):149-159.
10. O'Brien T, Ray E, Chatterton K, et al. Prospective randomized trial of hexylaminolevulinate photodynamic-assisted transurethral resection of bladder tumour (TURBT) plus single-shot intravesical mitomycin C vs conventional white-light TURBT plus mitomycin C in newly presenting non-muscle-invasive bladder cancer. BJU Int. 2013;112(8):1096-1104.
11. Schumacher MC, Holmang S, Davidsson T, et al. Transurethral resection of non-muscle-invasive bladder transitional cell cancers with or without 5-aminolevulinic Acid under visible and fluorescent light: results of a prospective, randomised, multicentre study. Eur Urol. 2010;57(2):293-299.
12. Yuan H, Qiu J, Liu L, 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.
13. Herr HH. Narrow band imaging cystoscopy. Urol Oncol. 2011;29(4):353-357.
14. Kang W, Cui Z, Chen Q, et al. Narrow band imaging-assisted transurethral resection reduces the recurrence risk of non-muscle invasive bladder cancer: A systematic review and meta-analysis. Oncotarget. 2017;8(14):23880-23890.
15. Barkan GA, Wojcik EM, Nayar R, et al. The Paris System for Reporting Urinary Cytology: The Quest to Develop a Standardized Terminology. Adv Anat Pathol. 2016;23(4):193-201.
16. Lotan Y, Roehrborn CG. Sensitivity and specificity of commonly available bladder tumor markers versus cytology: results of a comprehensive literature review and meta-analyses. Urology. 2003;61(1):109-118; discussion 118.
17. Schmitz-Drager BJ, Droller M, Lokeshwar VB, et al. Molecular markers for bladder cancer screening, early diagnosis, and surveillance: the WHO/ICUD consensus. Urol Int. 2015;94(1):1-24.
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.
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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.
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Safe and Efficacious Therapies Urgently Needed for the Difficult to Treat Non-muscle Invasive Bladder Cancer Patient Population

A newly published systematic review and meta-analysis: Evidence-based Assessment of Current and Emerging Bladder-sparing Therapies for Non–muscle-invasive Bladder Cancer After Bacillus Calmette-Guerin Therapy: A Systematic Review and Meta-analysis 

Written by: Catherine Ryan

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 haematobium has 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.

Published Date: April 16th, 2019

Written by: Justin T. Matulay, MD, and Ashish Kamat, MD, MBBS
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Mapping Progress in Bladder Cancer

For those of us who take care of patients with the sixth most common malignancy in the United States and the seventh most common cause of cancer-related death,it was disheartening that, as recently as 2015, patients with advanced bladder cancer had no effective alternatives to cisplatinum-based chemotherapy, a status quo that had persisted for three decades.2
Written by: Ashish Kamat, MD, MBBS
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