Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Treatment of primary non-muscle invasive urothelial bladder cancer

Wassim Kassouf, MD, CM, FRCS
Peter Black, MD, FACS, FRCSC
Section Editor
Seth P Lerner, MD
Deputy Editor
Michael E Ross, MD


Globally, bladder cancer accounts for approximately 390,000 cases and 150,000 deaths each year [1]. In developed areas of the world, such as North America and Western Europe, these bladder cancers are predominantly urothelial (formerly called transitional cell). (See "Epidemiology and risk factors of urothelial (transitional cell) carcinoma of the bladder", section on 'Epidemiology'.)

Approximately 70 percent of new urothelial bladder cancer cases are classified as non-muscle invasive [2]. Non-muscle invasive bladder cancer includes Ta (papillary), T1 (submucosal invasive) tumors (table 1), and Tis (carcinoma in situ [CIS]), which account for approximately 70, 20, and 10 percent of non-muscle invasive cancers, respectively. (See "Pathology of bladder neoplasms", section on 'Noninvasive urothelial neoplasms'.)

The prognostic factors, risk stratification, and initial management of primary non-muscle invasive bladder cancer are discussed here, while the management of recurrent or persistent non-muscle invasive bladder cancer is discussed separately. (See "Management of recurrent or persistent non-muscle invasive bladder cancer".)

Other related topics include:

(See "Clinical presentation, diagnosis, and staging of bladder cancer".)

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Jul 31, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Antoni S, Ferlay J, Soerjomataram I, et al. Bladder Cancer Incidence and Mortality: A Global Overview and Recent Trends. Eur Urol 2017; 71:96.
  2. Kirkali Z, Chan T, Manoharan M, et al. Bladder cancer: epidemiology, staging and grading, and diagnosis. Urology 2005; 66:4.
  3. Thrasher JB, Frazier HA, Robertson JE, Paulson DF. Does of stage pT0 cystectomy specimen confer a survival advantage in patients with minimally invasive bladder cancer? J Urol 1994; 152:393.
  4. Pagano F, Bassi P, Galetti TP, et al. Results of contemporary radical cystectomy for invasive bladder cancer: a clinicopathological study with an emphasis on the inadequacy of the tumor, nodes and metastases classification. J Urol 1991; 145:45.
  5. Hall MC, Chang SS, Dalbagni G, et al. Guideline for the management of nonmuscle invasive bladder cancer (stages Ta, T1, and Tis): 2007 update. J Urol 2007; 178:2314.
  6. Babjuk M, Oosterlinck W, Sylvester R, et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder. Eur Urol 2008; 54:303.
  7. Lee SE, Jeong IG, Ku JH, et al. Impact of transurethral resection of bladder tumor: analysis of cystectomy specimens to evaluate for residual tumor. Urology 2004; 63:873.
  8. Herr HW. Restaging transurethral resection of high risk superficial bladder cancer improves the initial response to bacillus Calmette-Guerin therapy. J Urol 2005; 174:2134.
  9. Herr HW. The value of a second transurethral resection in evaluating patients with bladder tumors. J Urol 1999; 162:74.
  10. Klän R, Loy V, Huland H. Residual tumor discovered in routine second transurethral resection in patients with stage T1 transitional cell carcinoma of the bladder. J Urol 1991; 146:316.
  11. Dalbagni G, Herr HW, Reuter VE. Impact of a second transurethral resection on the staging of T1 bladder cancer. Urology 2002; 60:822.
  12. Sfakianos JP, Kim PH, Hakimi AA, Herr HW. The effect of restaging transurethral resection on recurrence and progression rates in patients with nonmuscle invasive bladder cancer treated with intravesical bacillus Calmette-Guérin. J Urol 2014; 191:341.
  13. Kausch I, Sommerauer M, Montorsi F, et al. Photodynamic diagnosis in non-muscle-invasive bladder cancer: a systematic review and cumulative analysis of prospective studies. Eur Urol 2010; 57:595.
  14. Daniltchenko DI, Riedl CR, Sachs MD, et al. Long-term benefit of 5-aminolevulinic acid fluorescence assisted transurethral resection of superficial bladder cancer: 5-year results of a prospective randomized study. J Urol 2005; 174:2129.
  15. Denzinger S, Burger M, Walter B, et al. Clinically relevant reduction in risk of recurrence of superficial bladder cancer using 5-aminolevulinic acid-induced fluorescence diagnosis: 8-year results of prospective randomized study. Urology 2007; 69:675.
  16. Filbeck T, Roessler W, Knuechel R, et al. Clinical results of the transurethreal resection and evaluation of superficial bladder carcinomas by means of fluorescence diagnosis after intravesical instillation of 5-aminolevulinic acid. J Endourol 1999; 13:117.
  17. Schmidbauer J, Witjes F, Schmeller N, et al. Improved detection of urothelial carcinoma in situ with hexaminolevulinate fluorescence cystoscopy. J Urol 2004; 171:135.
  18. Hungerhuber E, Stepp H, Kriegmair M, et al. Seven years' experience with 5-aminolevulinic acid in detection of transitional cell carcinoma of the bladder. Urology 2007; 69:260.
  19. Grossman HB, Gomella L, Fradet Y, 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. J Urol 2007; 178:62.
  20. Fradet Y, Grossman HB, Gomella L, 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. J Urol 2007; 178:68.
  21. Chou R, Selph S, Buckley DI, et al. Comparative Effectiveness of Fluorescent Versus White Light Cystoscopy for Initial Diagnosis or Surveillance of Bladder Cancer on Clinical Outcomes: Systematic Review and Meta-Analysis. J Urol 2017; 197:548.
  22. 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; 112:1096.
  23. Lee JY, Cho KS, Kang DH, et al. A network meta-analysis of therapeutic outcomes after new image technology-assisted transurethral resection for non-muscle invasive bladder cancer: 5-aminolaevulinic acid fluorescence vs hexylaminolevulinate fluorescence vs narrow band imaging. BMC Cancer 2015; 15:566.
  24. Zheng C, Lv Y, Zhong Q, et al. Narrow band imaging diagnosis of bladder cancer: systematic review and meta-analysis. BJU Int 2012; 110:E680.
  25. Naito S, Algaba F, Babjuk M, et al. The Clinical Research Office of the Endourological Society (CROES) Multicentre Randomised Trial of Narrow Band Imaging-Assisted Transurethral Resection of Bladder Tumour (TURBT) Versus Conventional White Light Imaging-Assisted TURBT in Primary Non-Muscle-invasive Bladder Cancer Patients: Trial Protocol and 1-year Results. Eur Urol 2016; 70:506.
  26. Soukup V, Čapoun O, Cohen D, et al. Prognostic Performance and Reproducibility of the 1973 and 2004/2016 World Health Organization Grading Classification Systems in Non-muscle-invasive Bladder Cancer: A European Association of Urology Non-muscle Invasive Bladder Cancer Guidelines Panel Systematic Review. Eur Urol 2017.
  27. 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.
  28. Cambier S, Sylvester RJ, Collette L, et al. EORTC Nomograms and Risk Groups for Predicting Recurrence, Progression, and Disease-specific and Overall Survival in Non-Muscle-invasive Stage Ta-T1 Urothelial Bladder Cancer Patients Treated with 1-3 Years of Maintenance Bacillus Calmette-Guérin. Eur Urol 2016; 69:60.
  29. Banerjee I, Yadav S, Priyadarshi S, Tomar V. Re: Clinical Outcomes of cT1 Micropapillary Bladder Cancer: D. L. Willis, M. I. Fernandez, R. J. Dickstein, S. Parikh, J. B. Shah, L. L. Pisters, C. C. Guo, S. Henderson, B. A. Czerniak, H. B. Grossman, C. P. Dinney and A. M. Kamat J Urol 2015;193:1129-1134. J Urol 2015; 194:1825.
  30. Spaliviero M, Dalbagni G, Bochner BH, et al. Clinical outcome of patients with T1 micropapillary urothelial carcinoma of the bladder. J Urol 2014; 192:702.
  31. Martin-Doyle W, Leow JJ, Orsola A, et al. Improving selection criteria for early cystectomy in high-grade t1 bladder cancer: a meta-analysis of 15,215 patients. J Clin Oncol 2015; 33:643.
  32. Cho KS, Seo HK, Joung JY, et al. Lymphovascular invasion in transurethral resection specimens as predictor of progression and metastasis in patients with newly diagnosed T1 bladder urothelial cancer. J Urol 2009; 182:2625.
  33. Resnick MJ, Bergey M, Magerfleisch L, et al. Longitudinal evaluation of the concordance and prognostic value of lymphovascular invasion in transurethral resection and radical cystectomy specimens. BJU Int 2011; 107:46.
  34. Streeper NM, Simons CM, Konety BR, et al. The significance of lymphovascular invasion in transurethral resection of bladder tumour and cystectomy specimens on the survival of patients with urothelial bladder cancer. BJU Int 2009; 103:475.
  35. Holmäng S, Andius P, Hedelin H, et al. Stage progression in Ta papillary urothelial tumors: relationship to grade, immunohistochemical expression of tumor markers, mitotic frequency and DNA ploidy. J Urol 2001; 165:1124.
  36. Bostwick DG. Natural history of early bladder cancer. J Cell Biochem Suppl 1992; 16I:31.
  37. Althausen AF, Prout GR Jr, Daly JJ. Non-invasive papillary carcinoma of the bladder associated with carcinoma in situ. J Urol 1976; 116:575.
  38. Pagano F, Garbeglio A, Milani C, et al. Prognosis of bladder cancer. I. Risk factors in superficial transitional cell carcinoma. Eur Urol 1987; 13:145.
  39. Tilki D, Reich O, Svatek RS, et al. Characteristics and outcomes of patients with clinical carcinoma in situ only treated with radical cystectomy: an international study of 243 patients. J Urol 2010; 183:1757.
  40. Chade DC, Shariat SF, Godoy G, et al. Clinical outcomes of primary bladder carcinoma in situ in a contemporary series. J Urol 2010; 184:74.
  41. Wallace DM, Hindmarsh JR, Webb JN, et al. The role of multiple mucosal biopsies in the management of patients with bladder cancer. Br J Urol 1979; 51:535.
  42. Farrow GM, Utz DC, Rife CC, Greene LF. Clinical observations on sixty-nine cases of in situ carcinoma of the urinary bladder. Cancer Res 1977; 37:2794.
  43. Herr HW, Jakse G, Sheinfeld J. The T1 bladder tumor. Semin Urol 1990; 8:254.
  44. Peyromaure M, Zerbib M. T1G3 transitional cell carcinoma of the bladder: recurrence, progression and survival. BJU Int 2004; 93:60.
  45. Alkhateeb SS, Van Rhijn BW, Finelli A, et al. Nonprimary pT1 nonmuscle invasive bladder cancer treated with bacillus Calmette-Guerin is associated with higher risk of progression compared to primary T1 tumors. J Urol 2010; 184:81.
  46. Segal R, Yafi FA, Brimo F, et al. Prognostic factors and outcome in patients with T1 high-grade bladder cancer: can we identify patients for early cystectomy? BJU Int 2012; 109:1026.
  47. Sylvester RJ, van der MEIJDEN AP, 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.
  48. Heney NM, Ahmed S, Flanagan MJ, et al. Superficial bladder cancer: progression and recurrence. J Urol 1983; 130:1083.
  49. Lutzeyer W, Rübben H, Dahm H. Prognostic parameters in superficial bladder cancer: an analysis of 315 cases. J Urol 1982; 127:250.
  50. Mariappan P, Smith G, Lamb AD, et al. Pattern of recurrence changes in noninvasive bladder tumors observed during 2 decades. J Urol 2007; 177:867.
  51. Lerman RI, Hutter RV, Whitmore WF Jr. Papilloma of the urinary bladder. Cancer 1970; 25:333.
  52. Oosterlinck W, Kurth KH, Schröder F, et al. A prospective European Organization for Research and Treatment of Cancer Genitourinary Group randomized trial comparing transurethral resection followed by a single intravesical instillation of epirubicin or water in single stage Ta, T1 papillary carcinoma of the bladder. J Urol 1993; 149:749.
  53. 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.
  54. Wu XR. Urothelial tumorigenesis: a tale of divergent pathways. Nat Rev Cancer 2005; 5:713.
  55. Knowles MA. Molecular subtypes of bladder cancer: Jekyll and Hyde or chalk and cheese? Carcinogenesis 2006; 27:361.
  56. Burger M, van der Aa MN, van Oers JM, et al. Prediction of progression of non-muscle-invasive bladder cancer by WHO 1973 and 2004 grading and by FGFR3 mutation status: a prospective study. Eur Urol 2008; 54:835.
  57. van Rhijn BW, Vis AN, van der Kwast TH, et al. Molecular grading of urothelial cell carcinoma with fibroblast growth factor receptor 3 and MIB-1 is superior to pathologic grade for the prediction of clinical outcome. J Clin Oncol 2003; 21:1912.
  58. Hernández S, López-Knowles E, Lloreta J, et al. Prospective study of FGFR3 mutations as a prognostic factor in nonmuscle invasive urothelial bladder carcinomas. J Clin Oncol 2006; 24:3664.
  59. Hartmann A, Schlake G, Zaak D, et al. Occurrence of chromosome 9 and p53 alterations in multifocal dysplasia and carcinoma in situ of human urinary bladder. Cancer Res 2002; 62:809.
  60. Moonen PM, van Balken-Ory B, Kiemeney LA, et al. Prognostic value of p53 for high risk superficial bladder cancer with long-term followup. J Urol 2007; 177:80.
  61. Shariat SF, Lotan Y, Karakiewicz PI, et al. p53 predictive value for pT1-2 N0 disease at radical cystectomy. J Urol 2009; 182:907.
  62. 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.
  63. Liu Y, Noon AP, Aguiar Cabeza E, et al. Next-generation RNA sequencing of archival formalin-fixed paraffin-embedded urothelial bladder cancer. Eur Urol 2014; 66:982.
  64. Patschan O, Sjödahl G, Chebil G, et al. A Molecular Pathologic Framework for Risk Stratification of Stage T1 Urothelial Carcinoma. Eur Urol 2015; 68:824.
  65. Hedegaard J, Lamy P, Nordentoft I, et al. Comprehensive Transcriptional Analysis of Early-Stage Urothelial Carcinoma. Cancer Cell 2016; 30:27.
  66. Chang SS, Boorjian SA, Chou R, et al. Diagnosis and Treatment of Non-Muscle Invasive Bladder Cancer: AUA/SUO Guideline. J Urol 2016; 196:1021.
  67. Kohjimoto Y, Kusumoto H, Nishizawa S, et al. External validation of European Organization for Research and Treatment of Cancer and Spanish Urological Club for Oncological Treatment scoring models to predict recurrence and progression in Japanese patients with non-muscle invasive bladder cancer treated with bacillus Calmette-Guérin. Int J Urol 2014; 21:1201.
  68. Fernandez-Gomez J, Madero R, Solsona E, et al. The EORTC tables overestimate the risk of recurrence and progression in patients with non-muscle-invasive bladder cancer treated with bacillus Calmette-Guérin: external validation of the EORTC risk tables. Eur Urol 2011; 60:423.
  69. http://www.eortc.be/tools/bladdercalculator/default.htm. (Accessed on February 25, 2011).
  70. Fernandez-Gomez J, Madero R, Solsona E, et al. Predicting nonmuscle invasive bladder cancer recurrence and progression in patients treated with bacillus Calmette-Guerin: the CUETO scoring model. J Urol 2009; 182:2195.
  71. Rosevear HM, Lightfoot AJ, Nepple KG, O'Donnell MA. Usefulness of the Spanish Urological Club for Oncological Treatment scoring model to predict nonmuscle invasive bladder cancer recurrence in patients treated with intravesical bacillus Calmette-Guérin plus interferon-α. J Urol 2011; 185:67.
  72. Oddens J, Brausi M, Sylvester R, et al. Final results of an EORTC-GU cancers group randomized study of maintenance bacillus Calmette-Guérin 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; 63:462.
  73. Kamat AM, Witjes JA, Brausi M, et al. Defining and treating the spectrum of intermediate risk nonmuscle invasive bladder cancer. J Urol 2014; 192:305.
  74. Sylvester RJ, van der Meijden AP, Witjes JA, Kurth K. Bacillus calmette-guerin versus chemotherapy for the intravesical treatment of patients with carcinoma in situ of the bladder: a meta-analysis of the published results of randomized clinical trials. J Urol 2005; 174:86.
  75. Martínez-Piñeiro JA, Jiménez León J, Martínez-Piñeiro L Jr, et al. Bacillus Calmette-Guerin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J Urol 1990; 143:502.
  76. Shelley MD, Court JB, Kynaston H, et al. Intravesical bacillus Calmette-Guerin versus mitomycin C for Ta and T1 bladder cancer. Cochrane Database Syst Rev 2003; :CD003231.
  77. Böhle A, Bock PR. Intravesical bacille Calmette-Guérin versus mitomycin C in superficial bladder cancer: formal meta-analysis of comparative studies on tumor progression. Urology 2004; 63:682.
  78. de Reijke TM, Kurth KH, Sylvester RJ, et al. Bacillus Calmette-Guerin versus epirubicin for primary, secondary or concurrent carcinoma in situ of the bladder: results of a European Organization for the Research and Treatment of Cancer--Genito-Urinary Group Phase III Trial (30906). J Urol 2005; 173:405.
  79. Kassouf W, Traboulsi SL, Kulkarni GS, et al. CUA guidelines on the management of non-muscle invasive bladder cancer. Can Urol Assoc J 2015; 9:E690.
  80. Böhle A, Jocham D, Bock PR. Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity. J Urol 2003; 169:90.
  81. Prescott S, Jackson AM, Hawkyard SJ, et al. Mechanisms of action of intravesical bacille Calmette-Guérin: local immune mechanisms. Clin Infect Dis 2000; 31 Suppl 3:S91.
  82. Böhle A, Brandau S. Immune mechanisms in bacillus Calmette-Guerin immunotherapy for superficial bladder cancer. J Urol 2003; 170:964.
  83. Mungan NA, Witjes JA. Bacille Calmette-Guérin in superficial transitional cell carcinoma. Br J Urol 1998; 82:213.
  84. Jackson A, Alexandroff A, Fleming D, et al. Bacillus-calmette-guerin (bcg) organisms directly alter the growth of bladder-tumor cells. Int J Oncol 1994; 5:697.
  85. Durek C, Richter E, Basteck A, et al. The fate of bacillus Calmette-Guerin after intravesical instillation. J Urol 2001; 165:1765.
  86. Catalona WJ, Ratliff TL. Bacillus Calmette-Guérin and superficial bladder cancer. Clinical experience and mechanism of action. Surg Annu 1990; 22:363.
  87. Martínez-Piñeiro JA, Martínez-Piñeiro L, Solsona E, et al. Has a 3-fold decreased dose of bacillus Calmette-Guerin the same efficacy against recurrences and progression of T1G3 and Tis bladder tumors than the standard dose? Results of a prospective randomized trial. J Urol 2005; 174:1242.
  88. Pagano F, Bassi P, Piazza N, et al. Improving the efficacy of BCG immunotherapy by dose reduction. Eur Urol 1995; 27 Suppl 1:19.
  89. Agrawal MS, Agrawal M, Bansal S, et al. The safety and efficacy of different doses of bacillus Calmette Guérin in superficial bladder transitional cell carcinoma. Urology 2007; 70:1075.
  90. Saint F, Irani J, Patard JJ, et al. Tolerability of bacille Calmette-Guérin maintenance therapy for superficial bladder cancer. Urology 2001; 57:883.
  91. Colombel M, Saint F, Chopin D, et al. The effect of ofloxacin on bacillus calmette-guerin induced toxicity in patients with superficial bladder cancer: results of a randomized, prospective, double-blind, placebo controlled, multicenter study. J Urol 2006; 176:935.
  92. Swietek N, Waldert M, Rom M, et al. The value of transurethral bladder biopsy after intravesical bacillus Calmette-Guérin instillation therapy for nonmuscle invasive bladder cancer: a retrospective, single center study and cumulative analysis of the literature. J Urol 2012; 188:748.
  93. Lamm DL, Blumenstein BA, Crissman JD, et al. Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group Study. J Urol 2000; 163:1124.
  94. Shelley MD, Court JB, Kynaston H, et al. Intravesical Bacillus Calmette-Guerin in Ta and T1 Bladder Cancer. Cochrane Database Syst Rev 2000; :CD001986.
  95. Herr HW, Schwalb DM, Zhang ZF, et al. Intravesical bacillus Calmette-Guérin therapy prevents tumor progression and death from superficial bladder cancer: ten-year follow-up of a prospective randomized trial. J Clin Oncol 1995; 13:1404.
  96. Davis JW, Sheth SI, Doviak MJ, Schellhammer PF. Superficial bladder carcinoma treated with bacillus Calmette-Guerin: progression-free and disease specific survival with minimum 10-year followup. J Urol 2002; 167:494.
  97. Margel D, Tal R, Golan S, et al. Long-term follow-up of patients with Stage T1 high-grade transitional cell carcinoma managed by Bacille Calmette-Guérin immunotherapy. Urology 2007; 69:78.
  98. Herr HW. Tumour progression and survival in patients with T1G3 bladder tumours: 15-year outcome. Br J Urol 1997; 80:762.
  99. Brake M, Loertzer H, Horsch R, Keller H. Long-term results of intravesical bacillus Calmette-Guérin therapy for stage T1 superficial bladder cancer. Urology 2000; 55:673.
  100. Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med 2000; 6:1399.
  101. Greenwood J, Steinman L, Zamvil SS. Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol 2006; 6:358.
  102. Hoffmann P, Roumeguère T, Schulman C, van Velthoven R. Use of statins and outcome of BCG treatment for bladder cancer. N Engl J Med 2006; 355:2705.
  103. Orsola A, Cecchini L, Bellmunt J. Statins and the effect of BCG on bladder cancer. N Engl J Med 2007; 356:1276; author reply 1276.
  104. Berglund RK, Savage CJ, Vora KC, et al. An analysis of the effect of statin use on the efficacy of bacillus calmette-guerin treatment for transitional cell carcinoma of the bladder. J Urol 2008; 180:1297.
  105. Au JL, Badalament RA, Wientjes MG, et al. Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial. J Natl Cancer Inst 2001; 93:597.
  106. Sylvester RJ, Oosterlinck W, Holmang 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; 69:231.
  107. Bosschieter J, Nieuwenhuijzen JA, van Ginkel T, et al. Value of an Immediate Intravesical Instillation of Mitomycin C in Patients with Non–muscle-invasive Bladder Cancer: A Prospective Multicentre Randomised Study in 2243 patients. Eur Urol 2017.
  108. Friedrich MG, Pichlmeier U, Schwaibold H, et al. Long-term intravesical adjuvant chemotherapy further reduces recurrence rate compared with short-term intravesical chemotherapy and short-term therapy with Bacillus Calmette-Guérin (BCG) in patients with non-muscle-invasive bladder carcinoma. Eur Urol 2007; 52:1123.
  109. Colombo R, Da Pozzo LF, Salonia A, et al. Multicentric study comparing intravesical chemotherapy alone and with local microwave hyperthermia for prophylaxis of recurrence of superficial transitional cell carcinoma. J Clin Oncol 2003; 21:4270.
  110. Colombo R, Salonia A, Leib Z, et al. Long-term outcomes of a randomized controlled trial comparing thermochemotherapy with mitomycin-C alone as adjuvant treatment for non-muscle-invasive bladder cancer (NMIBC). BJU Int 2011; 107:912.
  111. Alfred Witjes J, Hendricksen K, Gofrit O, et al. Intravesical hyperthermia and mitomycin-C for carcinoma in situ of the urinary bladder: experience of the European Synergo working party. World J Urol 2009; 27:319.
  112. Arends TJ, Nativ O, Maffezzini M, et al. Results of a Randomised Controlled Trial Comparing Intravesical Chemohyperthermia with Mitomycin C Versus Bacillus Calmette-Guérin for Adjuvant Treatment of Patients with Intermediate- and High-risk Non-Muscle-invasive Bladder Cancer. Eur Urol 2016; 69:1046.
  113. Di Stasi SM, Giannantoni A, Giurioli A, et al. Sequential BCG and electromotive mitomycin versus BCG alone for high-risk superficial bladder cancer: a randomised controlled trial. Lancet Oncol 2006; 7:43.
  114. Bachir BG, Dragomir A, Aprikian AG, et al. Contemporary cost-effectiveness analysis comparing sequential bacillus Calmette-Guerin and electromotive mitomycin versus bacillus Calmette-Guerin alone for patients with high-risk non-muscle-invasive bladder cancer. Cancer 2014; 120:2424.
  115. Di Stasi SM, Giannantoni A, Stephen RL, et al. Intravesical electromotive mitomycin C versus passive transport mitomycin C for high risk superficial bladder cancer: a prospective randomized study. J Urol 2003; 170:777.
  116. Thrasher JB, Crawford ED. Complications of intravesical chemotherapy. Urol Clin North Am 1992; 19:529.
  117. Colver GB, Inglis JA, McVittie E, et al. Dermatitis due to intravesical mitomycin C: a delayed-type hypersensitivity reaction? Br J Dermatol 1990; 122:217.
  118. Rajala P, Liukkonen T, Raitanen M, et al. Transurethral resection with perioperative instilation on interferon-alpha or epirubicin for the prophylaxis of recurrent primary superficial bladder cancer: a prospective randomized multicenter study--Finnbladder III. J Urol 1999; 161:1133.
  119. Berrum-Svennung I, Granfors T, Jahnson S, et al. A single instillation of epirubicin after transurethral resection of bladder tumors prevents only small recurrences. J Urol 2008; 179:101.
  120. van der Meijden AP, Brausi M, Zambon V, et al. Intravesical instillation of epirubicin, bacillus Calmette-Guerin and bacillus Calmette-Guerin plus isoniazid for intermediate and high risk Ta, T1 papillary carcinoma of the bladder: a European Organization for Research and Treatment of Cancer genito-urinary group randomized phase III trial. J Urol 2001; 166:476.
  121. Sylvester RJ, Brausi MA, Kirkels WJ, et al. Long-term efficacy results of EORTC genito-urinary group randomized phase 3 study 30911 comparing intravesical instillations of epirubicin, bacillus Calmette-Guérin, and bacillus Calmette-Guérin plus isoniazid in patients with intermediate- and high-risk stage Ta T1 urothelial carcinoma of the bladder. Eur Urol 2010; 57:766.
  122. Böhle A, Leyh H, Frei C, et al. Single postoperative instillation of gemcitabine in patients with non-muscle-invasive transitional cell carcinoma of the bladder: a randomised, double-blind, placebo-controlled phase III multicentre study. Eur Urol 2009; 56:495.
  123. Addeo R, Caraglia M, Bellini S, et al. Randomized phase III trial on gemcitabine versus mytomicin in recurrent superficial bladder cancer: evaluation of efficacy and tolerance. J Clin Oncol 2010; 28:543.
  124. Jones G, Cleves A, Wilt TJ, et al. Intravesical gemcitabine for non-muscle invasive bladder cancer. Cochrane Database Syst Rev 2012; 1:CD009294.
  125. Borden EC, Groveman DS, Nasu T, et al. Antiproliferative activities of interferons against human bladder carcinoma cell lines in vitro. J Urol 1984; 132:800.
  126. Hawkyard S, James K, Prescott S, et al. The effects of recombinant human interferon-gamma on a panel of human bladder cancer cell lines. J Urol 1991; 145:1078.
  127. Sargent ER, Williams RD. Immunotherapeutic alternatives in superficial bladder cancer. Interferon, interleukin-2, and keyhole-limpet hemocyanin. Urol Clin North Am 1992; 19:581.
  128. Jimenez-Cruz JF, Vera-Donoso CD, Leiva O, et al. Intravesical immunoprophylaxis in recurrent superficial bladder cancer (Stage T1): multicenter trial comparing bacille Calmette-Guérin and interferon-alpha. Urology 1997; 50:529.
  129. Nepple KG, Lightfoot AJ, Rosevear HM, et al. Bacillus Calmette-Guérin with or without interferon α-2b and megadose versus recommended daily allowance vitamins during induction and maintenance intravesical treatment of nonmuscle invasive bladder cancer. J Urol 2010; 184:1915.
  130. Joudi FN, Smith BJ, O'Donnell MA, National BCG-Interferon Phase 2 Investigator Group. Final results from a national multicenter phase II trial of combination bacillus Calmette-Guérin plus interferon alpha-2B for reducing recurrence of superficial bladder cancer. Urol Oncol 2006; 24:344.
  131. Lamm D, Brausi M, O'Donnell MA, Witjes JA. Interferon alfa in the treatment paradigm for non-muscle-invasive bladder cancer. Urol Oncol 2014; 32:35.e21.
  132. Prout GR Jr, Koontz WW Jr, Coombs LJ, et al. Long-term fate of 90 patients with superficial bladder cancer randomly assigned to receive or not to receive thiotepa. J Urol 1983; 130:677.
  133. Hollister D Jr, Coleman M. Hematologic effects of intravesicular thiotepa therapy for bladder carcinoma. JAMA 1980; 244:2065.
  134. Silberberg JM, Zarrabi MH. Acute nonlymphocytic leukemia after thiotepa instillation into the bladder: report of 2 cases and review of the literature. J Urol 1987; 138:402.
  135. Weiss C, Wolze C, Engehausen DG, et al. Radiochemotherapy after transurethral resection for high-risk T1 bladder cancer: an alternative to intravesical therapy or early cystectomy? J Clin Oncol 2006; 24:2318.
  136. Harland SJ, Kynaston H, Grigor K, et al. A randomized trial of radical radiotherapy for the management of pT1G3 NXM0 transitional cell carcinoma of the bladder. J Urol 2007; 178:807.
  137. Kassouf W, Traboulsi SL, Schmitz-Dräger B, et al. Follow-up in non-muscle-invasive bladder cancer-International Bladder Cancer Network recommendations. Urol Oncol 2016; 34:460.
  138. Schrag D, Hsieh LJ, Rabbani F, et al. Adherence to surveillance among patients with superficial bladder cancer. J Natl Cancer Inst 2003; 95:588.
  139. Sanderson KM, Cai J, Miranda G, et al. Upper tract urothelial recurrence following radical cystectomy for transitional cell carcinoma of the bladder: an analysis of 1,069 patients with 10-year followup. J Urol 2007; 177:2088.
  140. Schwartz CB, Bekirov H, Melman A. Urothelial tumors of upper tract following treatment of primary bladder transitional cell carcinoma. Urology 1992; 40:509.
  141. Hurle R, Losa A, Manzetti A, Lembo A. Upper urinary tract tumors developing after treatment of superficial bladder cancer: 7-year follow-up of 591 consecutive patients. Urology 1999; 53:1144.
  142. Canales BK, Anderson JK, Premoli J, Slaton JW. Risk factors for upper tract recurrence in patients undergoing long-term surveillance for stage ta bladder cancer. J Urol 2006; 175:74.
  143. Wright JL, Hotaling J, Porter MP. Predictors of upper tract urothelial cell carcinoma after primary bladder cancer: a population based analysis. J Urol 2009; 181:1035.
  144. Herr HW, Cookson MS, Soloway SM. Upper tract tumors in patients with primary bladder cancer followed for 15 years. J Urol 1996; 156:1286.
  145. Miller EB, Eure GR, Schellhammer PF. Upper tract transitional cell carcinoma following treatment of superficial bladder cancer with BCG. Urology 1993; 42:26.
  146. National Comprehensive Cancer Network (NCCN). NCCN Clinical practice guidelines in oncology. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (Accessed on February 27, 2016).
  147. Schwalb MD, Herr HW, Sogani PC, et al. Positive urinary cytology following a complete response to intravesical bacillus Calmette-Guerin therapy: pattern of recurrence. J Urol 1994; 152:382.
  148. Evans CP. Follow-up surveillance strategies for genitourinary malignancies. Cancer 2002; 94:2892.
  149. Rabbani F, Perrotti M, Russo P, Herr HW. Upper-tract tumors after an initial diagnosis of bladder cancer: argument for long-term surveillance. J Clin Oncol 2001; 19:94.
  150. Herr HW, Donat SM. Prostatic tumor relapse in patients with superficial bladder tumors: 15-year outcome. J Urol 1999; 161:1854.
  151. Huguet J, Crego M, Sabaté S, et al. Cystectomy in patients with high risk superficial bladder tumors who fail intravesical BCG therapy: pre-cystectomy prostate involvement as a prognostic factor. Eur Urol 2005; 48:53.