Selection of patients and benefit of immediate radical cystectomy for non-muscle invasive bladder cancer
Review Article

Selection of patients and benefit of immediate radical cystectomy for non-muscle invasive bladder cancer

Karl H. Pang1, Aidan P. Noon2*; on behalf of the EAU Young Academic Urologists—Urothelial Cancer Working party

1Academic Urology Unit, University of Sheffield, Sheffield, UK; 2Department of Urology, Royal Hallamshire Hospital, Sheffield, UK

Contributions: (I) Conception and design: All authors; (II) Administrative support: None; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: None; (V) Data analysis and interpretation: None; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

*Only AP Noon is in this group.

Correspondence to: Mr. Aidan P. Noon. Consultant Urological Surgeon, Department of Urology, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK. Email: a.noon@sheffield.ac.uk.

Abstract: Bladder cancer (BC) is a common disease in both sexes and majority of cases present as non-muscle invasive BC (NMIBC). The percentage of NMIBC progressing to muscle invasive BC (MIBC) varies between 25% and 75% and currently there are no reliable molecular markers that may predict the outcome of high-risk (HR) NMIBC. Transurethral resection of the bladder tumour (TURBT) with intravesical bacillus Calmette-Guérin (BCG) or immediate radical cystectomy (RC) are the current gold standard treatment options. The European Association of Urology (EAU) guidelines recommend immediate or delayed RC for HR- and a subgroup of “highest-risk” NMIBC. These cases include pT1, carcinoma in-situ (CIS), multifocal disease, histological variants such as micropapillary and sarcomatoid, and patients who have contraindications to, or have failed with BCG. The comparative risks between maintenance BCG (mBCG) and immediate RC are unclear. However, RC may give patients the best oncological outcome.

Keywords: Immediate radical cystectomy; primary cystectomy; bladder cancer; non-muscle invasive bladder cancer (NMIBC)


Submitted Aug 10, 2018. Accepted for publication Sep 12, 2018.

doi: 10.21037/tau.2018.09.06


Introduction

Bladder cancer (BC) is the seventh most common malignancy in men and the eleventh most common in both sexes (1). BC is one of the most expensive malignancy to manage as patient’s with non-muscle invasive bladder cancer (NMIBC) managed with bladder-sparing approaches require long-term follow-up with flexible cystoscopy, and often require repeated treatment for recurrences (2). Approximately 75% of cases present as NMIBC, which include mucosal lesions (pTa), lamina propria invasion (pT1) or CIS (3). Tobacco smoking and occupational exposure to polycyclic aromatic hydrocarbons and aromatic amines are the most important risk factors for BC (4,5).

Management of low-risk disease (G1, pTa) focuses on preventing recurrence or progression to high-risk NMIBC (HR-NMIBC) (G3, pT1, CIS) or MIBC (pT2+). The management of HR-NMIBC is aimed at preventing both recurrence and progression to muscle invasive (pT2+) BC (MIBC). Recurrence is a common event in HR-NMIBC and results in significant morbidity and costs. Patients with HR-NMIBC may reduce their risk of disease progression by undergoing immediate RC or bladder-sparing approaches using intravesical immunotherapy such as mBCG (6,7). Although the European Organisation for the Research and Treatment of Cancer-Genito-Urinary Cancer Group (EORTC-GUCG) developed scoring system/risk tables to predict risks of disease recurrence and progression in individual patients, the incidence of HR-NMIBC progressing to MIBC varies significantly (25–75%). It is known that progression increases the risk of metastasis and disease-specific mortality (DSM), therefore the care of patients with HR disease is aimed at preventing, or the early detection of MIBC (8). However, the poor precision in identifying which patients with HR-NMIBC should be offered mBCG or immediate RC produces a major challenge. In addition, the comparative risks between the two curative treatment options are unclear. Here, we discuss the role of immediate RC in HR-NMIBC.


EAU recommendation on primary RC

The current EAU guidelines recommend immediate RC for HR tumours including CIS alone, multiple, recurrent and large (>3 cm) G1-2pTa, G3pT1 associated with concurrent bladder and or prostatic urethra CIS, and multiple and/or large G3pT1 (6) (Table 1). Lymphovascular invasion (LVI) in transurethral resection of the bladder tumour (TURBT) specimens is associated with an increased risk of pathological upstaging and a poor prognostic factor in pT1 tumours. A meta-analysis studied 3,905 patients, 18% with LVI and showed significant associations with upstaging [odds ratio (OR): 2.21, 95% CI: 1.44–3.39] and progression-free survival (hazard ratio: 2.28, 95% CI: 1.45–3.58) and disease-specific survival (hazard ratio: 1.35, 95% CI: 1.01–1.81). Hence, immediate RC is recommended in tumours with LVI (9,10).

Table 1
Table 1 EAU recommendations for immediate/delated RC in HR-NMIBC
Full table

Immediate RC is also recommended for variants of urothelial cell carcinoma (UCC) that have been reported to have a worse prognosis than classical UCC, such as micropapillary, small cell, squamous, glandular, plasmacytoid and sarcomatoid. Variants of UCC represent approximately 25% of RC histologies and are associated with advanced tumour stage, LVI and lymph node metastasis (11,12).

The UK National Institute for Health and Care Excellence (NICE) guidelines also recommend immediate RC as an alternative treatment option to BCG in managing HR-NMIBC (13). The UK national RC (bladder removal) against intravesical BCG immunotherapy for HR-NMIBC (BRAVO) randomised controlled feasibility study initially aimed to compare RC with BCG, however, it failed to recruit target numbers, therefore level 1 evidence is still unavailable (14).


Bladder-sparing treatment for HR-NMIBC

It has been estimated that the DSM of patients with HR-NMIBC is approximately 20–25% (8). The use of post TURBT intravesical immunotherapy such as BCG, mitomycin C (MMC) or epirubicin may reduce both recurrence and progression. Intravesical immunotherapy aims to induce an immune response against the tumour to reduce recurrence or progression. BCG treatment requires an induction phase followed by a maintenance phase of 3 years. Studies have confirmed the superiority of BCG in preventing tumour recurrence over MMC alone, epirubicin alone or a combination of epirubicin and interferon (15-17). A meta-analysis analysed 4,767 patients and showed that the addition of BCG reduced the risk of recurrence compared to TURBT alone (OR: 0.5, 95% CI: 0.33–0.75, P=0.0008) (18). Progression rate was also reduced in BCG therapy compared to TURBT alone when 4863 patients were analysed in another meta-analysis (OR: 0.73, P=0.001) (17). Although mBCG is a bladder-sparing treatment option, it subjects patients to risk of disease recurrence and progression and may impact quality of life (QoL) through local symptoms and potential severe BCG-toxicity, such as BCG sepsis with tuberculosis infection (19). In addition, there is the risk of BCG intolerability and failure. BCG-failure can be a result of MIBC detected during follow-up [progression rate of ~9.8% (17)] or BCG-refractory defined as high-grade NMIBC detected at 3 months or during BCG treatment [recurrence rate of ~40.5%) (18)], and detection of CIS at both 3 and 6 months (6). Patients with late BCG relapse (>1–2 years after last BCG exposure) and who are reluctant or unfit for RC can have a trial of salvage intravesical treatment with repeat BCG, BCG with interferon alpha-2a, gemcitabine or valrubicin (20,21). Device-assisted therapies such as electromotive drug administration and thermochemotherapy are also treatment options following BCG-failure (22). There is a current worldwide shortage of BCG due to problems in manufacturing and alternative therapies are needed to manage this challenging group of patients with HR-NMIBC (23,24).

New immunotherapeutic agents are being tested. A new international randomised-controlled trial (RCT) started in May 2018 is comparing Durvalumab [monoclonal antibody directed against programmed cell death-1 ligand 1 (PD-L1)] plus BCG with BCG alone in managing NMIBC [Assessment of Efficacy and Safety of Durvalumab Plus BCG Compared to the Standard Therapy with BCG in NMIBC (POTOMAC)] (ClinicalTrials.gov, NCT03528694).


Immediate RC for HR-NMIBC

Around 27–51% of pT1 tumours diagnosed through TURBT are upstaged to MIBC at RC (25-27). Patients with NMIBC who experience disease progression to MIBC have reduced 10-year recurrence-free survival (progression, 36% vs. MIBC, 43%, P=0.01), overall (progression, 28 vs. MIBC, 35%, P=0.03) and disease-specific survival (progression, 37% vs. MIBC, 43%, P=0.01) compared to those who present with MIBC (28). Patients with CIS have a progression rate to MIBC of ~54% if untreated (29) and ~41–100% if only managed by biopsy/fulguration (30).

RC includes bladder and adjacent organ removal, pelvic lymphadenectomy and reconstruction of urinary drainage through an ileal conduit or neobladder. A number of reports have evaluated robotic-assisted RC (RARC) as an alternative to open RC (ORC). RARC provides longer operative time (additional 1–1.5 hours), major costs, but shorter hospital length of stay (LOS) and less blood loss compared to ORC. The grade 3 90-day complication rate appears to be lower with RARC, but the intermediate-term oncological and QoL outcomes are not different between RARC and ORC (31-33). The US national RARC vs. ORC in patients with BC (RAZOR) RCT concluded that RARC was non-inferior to ORC for 2-year progression-free survival (RARC, 72.3% vs. ORC, 71.6%, non-inferiority P=0.001) (34). The ongoing UK robot-assisted radical cystectomy with intracorporeal urinary diversion versus open radical cystectomy (iROC) RCT aim to evaluate recovery times and complications (35).

RC eliminates the risk of local progression and may provide the best oncological outcomes but may be associated with over-treatment for non-progressing disease, short- and long-term post-operative complications and reduction in QoL. However, some patients are found to have extra-vesical (~43%) and metastatic regional lymph node disease (~23%) at the time of surgery (36). The 5-year progression-free survival exceeds 75% in HR-NMIBC (36). Post-operative complications requiring intervention occurs in around 20% of cases (37). With the introduction of enhanced recovery after surgery (ERAS) protocols, patients have shorter hospital LOS, reduced time-to-bowel function and experience lower rate of post-operative complications when compared with standard care (38,39). In younger patients, urinary incontinence and sexual function may be of concern following radical surgery and QoL discussion is important when counselling for immediate RC (40). Recurrence-free survival of ~79% at 10 years following immediate RC for HR-NMIBC appears superior when compared with mBCG (41).

The comparative risks and benefits of mBCG and immediate RC are unclear, therefore, clinicians and patients face the uncertainty of potential under- or over-treatment. An RCT would provide more data on QoL and oncological outcomes that could help clinicians make treatment decisions. However, there are difficulties with conducting an RCT, such as eligibility and recruitment. The CRUK-SPARE trial comparing surgical and non-surgical treatments for BC is an example reflecting difficulties in recruitment (42).

The NICE guidelines highlighted that comparison of BCG with RC as one of the research priorities in BC (13). The BRAVO multicentre RCT aimed to compare RC and mBCG for HR-NMIBC. The BRAVO feasibility study planned to assess whether a target sample size of n=506 for the full RCT can be met by first randomising 60 patients. Unfortunately, the study failed to recruit and has been closed. Therefore, the comparative outcomes between RC and BCG are still unclear (14,43).


Patient selection for immediate RC

Immediate RC is recommended for HR-NMIBC due to the risk of progression and BCG failure, and subsequent poor survival outcomes. Patients who have HR-NMIBC and who are fit for surgery should be offered immediate RC, but the potential benefits must be weighed against its potential risks, morbidity and impact on QoL. Immediate RC should also be considered in surgically fit patients with absolute and relative contraindications to BCG.

The clinicopathologic characteristics of HR disease such as grade 3, pathological stage 1, CIS, large tumours, histological variants increase the risk of progression with or without BCG. Recently there has been evolving evidence on molecular markers that may predict BCG-failure and progression. This knowledge may help clinicians identify those who may not respond to BCG and better select patients for immediate RC. Therefore, patients who are unable to have BCG or “predicted” to unlikely to benefit from BCG should be considered for immediate RC. In addition, patients who were deemed fit for RC at diagnosis of HR-NMIBC, may not be fit when found to have progression to MIBC following 3 years plus of initial mBCG and surveillance. This may be the case for the elderly cohort and should be considered when discussing immediate RC versus intravesical mBCG.

Cigarette smoking is a modifiable risk factor for urothelial BC development. Smoking status and lifetime smoking exposure at BC diagnosis and at different periods during treatment appear to affect disease recurrence, progression and survival. However, the evidence is heterogenous and further evaluation is needed (44). It may be important to emphasize to patient undergoing RC the importance of smoking cessation in order to maximise the benefits of RC.


Molecular and clinicopathological factors in predicting BCG response

Next-generation sequencing (NGS) data have shown several genetic and epigenetic alterations that are associated with disease progression such as FGFR3 mutation, high urinary tumour DNA levels and increased expression of long non-coding RNA H19 (45-48). ARID1A mutations were associated with an increased risk of recurrence after BCG (hazard ratio: 3.14, 95% CI: 1.51–6.51, P=0.002) when 105 NMIBC formalin-fixed paraffin-embedded (FFPE) samples were analysed (49).

A recent systematic review analysed “definitely useful”, “probably useful” and “emerging” factors in predicting BCG response (50). Clinicopathologic features (stage, grade, recurrent tumours, multiplicity, CIS, female gender, age) were classified as “definitely useful” and remain the most effective predictors of BCG response in keeping with the EORTC risk scores. Urinary fluorescent in-situ hybridization (FISH, UroVysion) is a molecular cytogenetic test for detecting chromosomal abnormalities and is a “definitely useful” tool for predicting failure after BCG (51,52). There are numerous tumour molecular biomarkers that are “probably useful” in predicting BCG response. These include cell cycle regulator Rb; apoptosis inhibitors surviving, bcl-2; cell adhesion molecules E-cadherin, ezrin, sialyl-Tn, sialyl-6-T; proliferation index Ki-67; and growth factor FGFR3. Urinary cytokines such as TNF-α, IL-12 and TRALI (cytokine panel for response to intravesical therapy, CyPRIT nomogram) (53) and immunity markers such as leukocyturia (improved response), CD4+ and CD8+ T-cells are “probably useful” in predicting BCG response during treatment. There is currently no single molecular strategy that can predict BCG response. Identifying molecular subtypes of NMIBC have been proposed and the use of NGS has appeared to be important in developing ‘emerging strategies’ in predicting BCG response (50,54).


Conclusions

BC is expensive to manage due to the need for active surveillance following treatment of NMIBC. Treatment options for HR-NMIBC include immediate RC or bladder-sparing intravesical agents. Innovations in bladder-sparing approaches such as thermochemotherapy immunotherapy and gene therapy may offer alternatives for patients who are not fit for RC or who fail mBCG. Patients who undergo RC for MIBC progressed from HR-NMIBC have a worse prognosis than those who receive immediate RC for HR-NMIBC. Immediate RC is now a much safer and less morbid procedure that currently offers the best chance of preventing progression of disease. It is important to identify those with HR-NMIBC who are likely to progress or fail with mBCG treatment and offer this group of patients immediate RC to provide the best survival outcomes. There are Clinicopathologic features that may predict progression, and although research into molecular markers in this context appear promising, better strategies of identifying patients at risk of failure of bladder-sparing treatments are needed.


Acknowledgements

None.


Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.


References

  1. Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. Lyon, France: International Agency for Research on Cancer, 2013.
  2. Sievert KD, Amend B, Nagele U, et al. Economic aspects of bladder cancer: what are the benefits and costs? World J Urol 2009;27:295-300. [Crossref] [PubMed]
  3. Moch H, Humphrey P, Ulbright T, et al. WHO Classification of Tumours of the Urinary System and Male Genital Organs. 4th edition. Lyon: IARCC Press, 2016.
  4. Cumberbatch MG, Rota M, Catto JWF, et al. The Role of Tobacco Smoke in Bladder and Kidney Carcinogenesis: A Comparison of Exposures and Meta-analysis of Incidence and Mortality Risks. Eur Urol 2016;70:458-66. [Crossref] [PubMed]
  5. Cumberbatch MG, Cox A, Teare D, et al. Contemporary Occupational Carcinogen Exposure and Bladder Cancer. JAMA Oncol 2015;1:1282. [Crossref] [PubMed]
  6. Babjuk M, Böhle A, Burger M, et al. EAU Guidelines on Non–Muscle-invasive Urothelial Carcinoma of the Bladder: Update 2016. Eur Urol 2017;71:447-61. [Crossref] [PubMed]
  7. Denzinger S, Fritsche HM, Otto W, et al. Early Versus Deferred Cystectomy for Initial High-Risk pT1G3 Urothelial Carcinoma of the Bladder: Do Risk Factors Define Feasibility of Bladder-Sparing Approach? Eur Urol 2008;53:146-52. [Crossref] [PubMed]
  8. Sylvester RJ, van der Meijden AP, Oosterlinck W, et al. Predicting recurrence and progression in individual patients with stage Ta T1 bladder cancer using EORTC risk tables: a combined analysis of 2596 patients from seven EORTC trials. Eur Urol 2006;49:466-5; discussion 475-7.
  9. Tilki D, Shariat SF, Lotan Y, et al. Lymphovascular invasion is independently associated with bladder cancer recurrence and survival in patients with final stage T1 disease and negative lymph nodes after radical cystectomy. BJU Int 2013;111:1215-21. [Crossref] [PubMed]
  10. Kim HS, Kim M, Jeong CW, et al. Presence of lymphovascular invasion in urothelial bladder cancer specimens after transurethral resections correlates with risk of upstaging and survival: A systematic review and meta-analysis. Urol Oncol 2014;32:1191-9. [Crossref] [PubMed]
  11. Xylinas E, Rink M, Robinson BD, et al. Impact of histological variants on oncological outcomes of patients with urothelial carcinoma of the bladder treated with radical cystectomy. Eur J Cancer 2013;49:1889-97. [Crossref] [PubMed]
  12. Moschini M, Dell’Oglio P, Luciano’ R, et al. Incidence and effect of variant histology on oncological outcomes in patients with bladder cancer treated with radical cystectomy. Urol Oncol 2017;35:335-41. [Crossref] [PubMed]
  13. NICE. Bladder cancer: diagnosis and management. Guidance and guidelines. National Institute for Health and Care Excellence 2015.
  14. Oughton JB, Poad H, Twiddy M, et al. Radical cystectomy (bladder removal) against intravesical BCG immunotherapy for high-risk non-muscle invasive bladder cancer (BRAVO): a protocol for a randomised controlled feasibility study. BMJ Open 2017;7:e017913. [Crossref] [PubMed]
  15. Järvinen R, Kaasinen E, Sankila A, et al. Long-term efficacy of maintenance bacillus Calmette-Guérin versus maintenance mitomycin C instillation therapy in frequently recurrent TaT1 tumours without carcinoma in situ: a subgroup analysis of the prospective, randomised FinnBladder I study with a 20-year follow-up. Eur Urol 2009;56:260-5. [Crossref] [PubMed]
  16. Shang PF, Kwong J, Wang ZP, et al. Intravesical Bacillus Calmette-Guérin versus epirubicin for Ta and T1 bladder cancer. Cochrane Database Syst Rev 2011.CD006885. [PubMed]
  17. Sylvester RJ, van der Meijden APM, Lamm DL. Intravesical bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol 2002;168:1964-70. [Crossref] [PubMed]
  18. Han RF, Pan JG. Can intravesical bacillus Calmette-Guérin reduce recurrence in patients with superficial bladder cancer? A meta-analysis of randomized trials. Urology 2006;67:1216-23. [Crossref] [PubMed]
  19. Brausi M, Oddens J, Sylvester R, et al. Side Effects of Bacillus Calmette-Guérin (BCG) in the Treatment of Intermediate- and High-risk Ta, T1 Papillary Carcinoma of the Bladder: Results of the EORTC Genito-Urinary Cancers Group Randomised Phase 3 Study Comparing One-third Dose with Full Dose and 1 Year with 3 Years of Maintenance BCG. Eur Urol 2014;65:69-76. [Crossref] [PubMed]
  20. Kamat AM, Hahn NM, Efstathiou JA, et al. Bladder cancer. Lancet 2016;388:2796-810. [Crossref] [PubMed]
  21. Packiam VT, Johnson SC, Steinberg GD. Non-muscle-invasive bladder cancer: Intravesical treatments beyond Bacille Calmette-Guérin. Cancer 2017;123:390-400. [Crossref] [PubMed]
  22. Yates DR, Rouprêt M. Failure of bacille Calmette-Guérin in patients with high risk non-muscle-invasive bladder cancer unsuitable for radical cystectomy: an update of available treatment options. BJU Int 2010;106:162-7. [Crossref] [PubMed]
  23. Mostafid AH, Palou Redorta J, Sylvester R, et al. Therapeutic Options in High-risk Non-muscle-invasive Bladder Cancer During the Current Worldwide Shortage of Bacille Calmette-Guérin. Eur Urol 2015;67:359-60. [Crossref] [PubMed]
  24. Veeratterapillay R, Heer R, Johnson MI, et al. High-Risk Non-Muscle-Invasive Bladder Cancer—Therapy Options During Intravesical BCG Shortage. Curr Urol Rep 2016;17:68. [Crossref] [PubMed]
  25. Svatek RS, Shariat SF, Novara G, et al. Discrepancy between clinical and pathological stage: external validation of the impact on prognosis in an international radical cystectomy cohort. BJU Int 2011;107:898-904. [Crossref] [PubMed]
  26. Turker P, Bostrom PJ, Wroclawski ML, et al. Upstaging of urothelial cancer at the time of radical cystectomy: factors associated with upstaging and its effect on outcome. BJU Int 2012;110:804-11. [Crossref] [PubMed]
  27. Fritsche HM, Burger M, Svatek RS, et al. Characteristics and Outcomes of Patients with Clinical T1 Grade 3 Urothelial Carcinoma Treated with Radical Cystectomy: Results from an International Cohort. Eur Urol 2010;57:300-9. [Crossref] [PubMed]
  28. Moschini M, Sharma V, Dell’oglio P, et al. Comparing long-term outcomes of primary and progressive carcinoma invading bladder muscle after radical cystectomy. BJU Int 2016;117:604-10. [Crossref] [PubMed]
  29. Lamm D, Herr H, Jakse G, et al. Updated concepts and treatment of carcinoma in situ. Urol Oncol 1998;4:130-8. [Crossref] [PubMed]
  30. Casey RG, Catto JWF, Cheng L, et al. Diagnosis and Management of Urothelial Carcinoma In Situ of the Lower Urinary Tract: A Systematic Review. Eur Urol 2015;67:876-88. [Crossref] [PubMed]
  31. Bochner BH, Dalbagni G, Sjoberg DD, et al. Comparing Open Radical Cystectomy and Robot-assisted Laparoscopic Radical Cystectomy: A Randomized Clinical Trial. Eur Urol 2015;67:1042-50. [Crossref] [PubMed]
  32. Yuh B, Wilson T, Bochner B, et al. Systematic Review and Cumulative Analysis of Oncologic and Functional Outcomes After Robot-assisted Radical Cystectomy. Eur Urol 2015;67:402-22. [Crossref] [PubMed]
  33. Novara G, Catto JWF, Wilson T, et al. Systematic Review and Cumulative Analysis of Perioperative Outcomes and Complications After Robot-assisted Radical Cystectomy. Eur Urol 2015;67:376-401. [Crossref] [PubMed]
  34. Parekh DJ, Reis IM, Castle EP, et al. Robot-assisted radical cystectomy versus open radical cystectomy in patients with bladder cancer (RAZOR): an open-label, randomised, phase 3, non-inferiority trial. Lancet 2018;391:2525-36. [Crossref] [PubMed]
  35. Catto JW, Khetrapal P, Ambler G, et al. Multidomain Quantitative Recovery Following Radical Cystectomy for Patients Within the Robot-assisted Radical Cystectomy with Intracorporeal Urinary Diversion Versus Open Radical Cystectomy Randomised Controlled Trial: The First 30 Patients. Eur Urol 2018;74:531-4. [Crossref] [PubMed]
  36. Shariat SF, Karakiewicz PI, Palapattu GS, et al. Outcomes of Radical Cystectomy for Transitional Cell Carcinoma of the Bladder: A Contemporary Series From the Bladder Cancer Research Consortium. J Urol 2006;176:2414-22. [Crossref] [PubMed]
  37. Shabsigh A, Korets R, Vora KC, et al. Defining Early Morbidity of Radical Cystectomy for Patients with Bladder Cancer Using a Standardized Reporting Methodology. Eur Urol 2009;55:164-74. [Crossref] [PubMed]
  38. Pang KH, Groves R, Venugopal S, et al. Prospective Implementation of Enhanced Recovery After Surgery Protocols to Radical Cystectomy. Eur Urol 2017. [Epub ahead of print]. [PubMed]
  39. Tyson MD, Chang SS. Enhanced Recovery Pathways Versus Standard Care After Cystectomy: A Meta-analysis of the Effect on Perioperative Outcomes. Eur Urol 2016;70:995-1003. [Crossref] [PubMed]
  40. Gellhaus PT, Cary C, Kaimakliotis HZ, et al. Long-term Health-related Quality of Life Outcomes Following Radical Cystectomy. Urology 2017;106:82-6. [Crossref] [PubMed]
  41. Hautmann RE, Volkmer BG, Gust K. Quantification of the survival benefit of early versus deferred cystectomy in high-risk non-muscle invasive bladder cancer (T1 G3). World J Urol 2009;27:347-51. [Crossref] [PubMed]
  42. Huddart RA, Birtle A, Maynard L, et al. Clinical and patient-reported outcomes of SPARE - a randomised feasibility study of selective bladder preservation versus radical cystectomy. BJU Int 2017;120:639-50. [Crossref] [PubMed]
  43. Pang KH, Noon AP. Re: Radical Cystectomy (Bladder Removal) Against Intravesical BCG Immunotherapy for High-risk Non-muscle Invasive Bladder Cancer (BRAVO): A Protocol for a Randomised Controlled Feasibility Study. Eur Urol 2018;73:636. [Crossref] [PubMed]
  44. Rink M, Crivelli JJ, Shariat SF, et al. Smoking and Bladder Cancer: A Systematic Review of Risk and Outcomes. Eur Urol Focus 2015;1:17-27. [Crossref] [PubMed]
  45. Pang KH, Esperto F, Noon AP, et al. Opportunities of next-generation sequencing in non-muscle invasive bladder cancer outcome prediction. Transl Androl Urol 2017;6:1043-8. [Crossref] [PubMed]
  46. Birkenkamp-Demtröder K, Nordentoft I, Christensen E, et al. Genomic Alterations in Liquid Biopsies from Patients with Bladder Cancer. Eur Urol 2016;70:75-82. [Crossref] [PubMed]
  47. Noon AP, Catto JWF. Noncoding RNA in bladder cancer: a specific focus upon high-risk nonmuscle invasive disease. Curr Opin Urol 2014;24:506-11. [Crossref] [PubMed]
  48. Dyrskjøt L, Zieger K, Real FX, et al. Gene Expression Signatures Predict Outcome in Non-Muscle-Invasive Bladder Carcinoma: A Multicenter Validation Study. Clin Cancer Res 2007;13:3545-51. [Crossref] [PubMed]
  49. 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;72:952-9. [Crossref] [PubMed]
  50. Kamat AM, Li R, O'Donnell MA, et al. Predicting Response to Intravesical Bacillus Calmette-Guérin Immunotherapy: Are We There Yet? A Systematic Review. Eur Urol 2018;73:738-48. [Crossref] [PubMed]
  51. Yoder BJ, Skacel M, Hedgepeth R, et al. Reflex UroVysion Testing of Bladder Cancer Surveillance Patients With Equivocal or Negative Urine Cytology. Am J Clin Pathol 2007;127:295-301. [Crossref] [PubMed]
  52. Kamat AM, Dickstein RJ, Messetti F, et al. Use of Fluorescence In Situ Hybridization to Predict Response to Bacillus Calmette-Guérin Therapy for Bladder Cancer: Results of a Prospective Trial. J Urol 2012;187:862-7. [Crossref] [PubMed]
  53. Kamat AM, Briggman J, Urbauer DL, et al. Cytokine Panel for Response to Intravesical Therapy (CyPRIT): Nomogram of Changes in Urinary Cytokine Levels Predicts Patient Response to Bacillus Calmette-Guérin. Eur Urol 2016;69:197-200. [Crossref] [PubMed]
  54. Hedegaard J, Lamy P, Nordentoft I, et al. Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma. Cancer Cell 2016;30:27-42. [Crossref] [PubMed]
Cite this article as: Pang KH, Noon AP; on behalf of the EAU Young Academic Urologists—Urothelial Cancer Working party. Selection of patients and benefit of immediate radical cystectomy for non-muscle invasive bladder cancer. Transl Androl Urol 2019;8(1):101-107. doi: 10.21037/tau.2018.09.06