Emerging therapies in the management of high-risk non-muscle invasive bladder cancer (HRNMIBC)

  • Ryan P. WerntzEmail author
  • Brittany Adamic
  • Gary D. Steinberg
Topic Paper



BCG is the gold standard in management of high-risk non-muscle invasive bladder cancer (HRNMIBC). However, in patients who fail BCG, there are few effective intrasvesical options. This review aims to explore standard and emerging therapies in HRNMIBC.


A non-systematic literature review was performed using Medline and PubMed. Literature focused on HRNMIBC and BCG failure studies, with particular attention to Phase II and III clinical trials.


The only FDA approved therapy for BCG failure patients in Valrubicin. Patients with HRNMIBC and BCG failure patients are at increased risk for progression and death from bladder cancer. There are a variety of clinical trials exploring different therapeutic approaches such as immunotherapy, vaccines, radiotherapy, and gene therapy. These trials are showing some promise in the early reporting phase.


Despite limited intravesical treatment options in BCG failure patients, there are several promising therapies currently being developed and several with promising early results.


Non-muscle invasive bladder cancer BCG failure Immunotherapy Vaccines 


Author contributions

RW: Protocol/project development-yes, data collection or management-yes, data analysis-N/A, manuscript writing/editing-writing and editing. BA, M.D.: Protocol/project development-yes, data collection or management-yes, data analysis-N/A, manuscript writing/editing-writing and editing. GDS, M.D.: Protocol/project development-yes, data collection or management-no, data analysis-N/A, manuscript writing/editing-editing.

Compliance with ethical standards

Conflict of interest

Gary Steinberg: I am a scientific advisor/consultant for the following companies: Heat Biologics, Cold Genesys, PhotoCure, Merck, Roche/Genentech, Taris Biomedical, MDxHealth, Fidia Farmaceuticals, Urogen, Spectrum Pharmaceuticals, Biocancell, Epivax Oncology, Natera, FKD, Synergo, BMS, Boston Scientific, Ferring Pharmaceuticals, QED. Ryan Werntz: none. Brittany Adamic: none.


  1. 1.
    Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. CA: A Cancer J Clin 65:5–29Google Scholar
  2. 2.
    Sylvester RJ, van der Meijden APM, Oosterlinck W et al (2006) 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 49:466–475. (discussion 475–7) CrossRefPubMedGoogle Scholar
  3. 3.
    Fernandez-Gomez J, Madero R, Solsona E et al (2009) Predicting nonmuscle invasive bladder cancer recurrence and progression in patients treated with bacillus Calmette–Guerin: the CUETO scoring model. J Urol 182:2195–2203. CrossRefPubMedGoogle Scholar
  4. 4.
    Chang SS, Boorjian SA, Chou R et al (2016) Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline. J Urol 196:1021–1029. CrossRefPubMedGoogle Scholar
  5. 5.
    Herr HW (1999) The value of a second transurethral resection in evaluating patients with bladder tumors. J Urol 162:74–76. CrossRefPubMedGoogle Scholar
  6. 6.
    Divrik RT, Sahin AF, Yildirim U et al (2010) Impact of routine second transurethral resection on the long-term outcome of patients with newly diagnosed pT1 urothelial carcinoma with respect to recurrence, progression rate, and disease-specific survival: a prospective randomised clinical trial. Eur Urol 58:185–190. CrossRefPubMedGoogle Scholar
  7. 7.
    Gendy R, Delprado W, Brenner P et al (2016) Repeat transurethral resection for non-muscle-invasive bladder cancer: a contemporary series. BJU Int 117(Suppl 4):54–59. CrossRefPubMedGoogle Scholar
  8. 8.
    Tae BS, Jeong CW, Kwak C et al (2017) Pathology in repeated transurethral resection of a bladder tumor as a risk factor for prognosis of high-risk non-muscle-invasive bladder cancer. PLoS One 12:e0189354. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Herr HW, Donat SM, Dalbagni G (2007) Can restaging transurethral resection of T1 bladder cancer select patients for immediate cystectomy? J Urol 177:75–79. (discussion 79) CrossRefPubMedGoogle Scholar
  10. 10.
    Cookson MS, Herr HW, Zhang ZF et al (1997) The treated natural history of high risk superficial bladder cancer: 15-year outcome. J Urol 158:62–67. CrossRefPubMedGoogle Scholar
  11. 11.
    Dhir R (2007) 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. Yearb Pathol Lab Med 2007:192–193. CrossRefGoogle Scholar
  12. 12.
    Fernandez-Gomez J, Madero R, Solsona E et al (2011) 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 60:423–430. CrossRefPubMedGoogle Scholar
  13. 13.
    Martin-Doyle W, Leow JJ, Orsola A et al (2015) Improving selection criteria for early cystectomy in high-grade T1 bladder cancer: a meta-analysis of 15,215 patients. J Clin Oncol 33:643–650. CrossRefPubMedGoogle Scholar
  14. 14.
    Daniltchenko DI, Riedl CR, Sachs MD et al (2005) 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 174:2129–2133. (discussion 2133) CrossRefPubMedGoogle Scholar
  15. 15.
    Grossman HB, Gomella L, Fradet Y et al (2007) 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 178:62–67. CrossRefPubMedGoogle Scholar
  16. 16.
    Burger M, Grossman HB, Droller M et al (2013) Photodynamic diagnosis of non-muscle-invasive bladder cancer with hexaminolevulinate cystoscopy: a meta-analysis of detection and recurrence based on raw data. Eur Urol 64:846–854. CrossRefPubMedGoogle Scholar
  17. 17.
    Yuan H, Qiu J, Liu L et al (2013) 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 8:e74142. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Morales A, Eidinger D, Bruce AW (2017) Intracavitary Bacillus Calmette–Guerin in the treatment of superficial bladder tumors. J Urol 197:S142–S145. CrossRefPubMedGoogle Scholar
  19. 19.
    Babjuk M, Bohle A, Burger M et al (2017) EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016. Eur Urol 71:447–461. CrossRefPubMedGoogle Scholar
  20. 20.
    Lamm DL, Blumenstein BA, Crissman JD et al (2000) 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 163:1124–1129CrossRefPubMedGoogle Scholar
  21. 21.
    Oddens J, Brausi M, Sylvester R et al (2013) 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 63:462–472. CrossRefPubMedGoogle Scholar
  22. 22.
    Herr HW, Dalbagni G (2003) Defining bacillus Calmette–Guerin refractory superficial bladder tumors. J Urol 169:1706–1708. CrossRefPubMedGoogle Scholar
  23. 23.
    Mmeje CO, Guo CC, Shah JB et al (2016) Papillary recurrence of bladder cancer at first evaluation after induction Bacillus Calmette–Guérin therapy: implication for clinical trial design. Eur Urol 70:778–785. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Nadler RB, Catalona WJ, Hudson MA, Ratliff TL (1994) Durability of the tumor-free response for intravesical bacillus Calmette–Guerin therapy. J Urol 152:367–373CrossRefPubMedGoogle Scholar
  25. 25.
    Lamm DL (1992) Long-term results of intravesical therapy for superficial bladder cancer. Urol Clin N Am 19:573–580Google Scholar
  26. 26.
    Sarosdy MF, Lowe BA, Schellhammer PF et al (1996) Oral bropirimine immunotherapy of carcinoma in situ of the bladder: results of a phase II trial. Urology 48:21–27. CrossRefPubMedGoogle Scholar
  27. 27.
    Sarosdy MF, Manyak MJ, Sagalowsky AI et al (1998) Oral bropirimine immunotherapy of bladder carcinoma in situ after prior intravesical bacille Calmette–Guérin. Urology 51:226–231. CrossRefPubMedGoogle Scholar
  28. 28.
    Greenberg RE, Bahnson RR, Wood D et al (1997) Initial report on intraves1 cal administration of N-trifluoroacetyladriamycin-14-valerate (AD 32) to patients with refractory superficial transitional cell carcinoma of the urinary bladder. Urology 49:471–475. CrossRefPubMedGoogle Scholar
  29. 29.
    Dinney CPN, Greenberg RE, Steinberg GD (2013) Intravesical valrubicin in patients with bladder carcinoma in situ and contraindication to or failure after bacillus Calmette–Guérin. Urol Oncol 31:1635–1642. CrossRefPubMedGoogle Scholar
  30. 30.
    Steinberg G, Bahnson R, Brosman S et al (2000) 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 163:761–767CrossRefPubMedGoogle Scholar
  31. 31.
    Portillo J, Martin B, Hernandez R et al (1997) Results at 43 months’ follow-up of a double-blind, randomized, prospective clinical trial using intravesical interferon alpha-2b in the prophylaxis of stage pT1 transitional cell carcinoma of the bladder. Urology 49:187–190. CrossRefPubMedGoogle Scholar
  32. 32.
    Lam JS, Benson MC, O’Donnell MA et al (2003) Bacillus Calmete-Guérin plus interferon-alpha2B intravesical therapy maintains an extended treatment plan for superficial bladder cancer with minimal toxicity. Urol Oncol 21:354–360CrossRefPubMedGoogle Scholar
  33. 33.
    O’Donnell MA, Krohn J, DeWolf WC (2001) Salvage intravesical therapy with interferon-alpha 2b plus low dose bacillus Calmette–Guerin is effective in patients with superficial bladder cancer in whom bacillus Calmette–Guerin alone previously failed. J Urol 166:1300–1304 (discussion 1304–5) CrossRefPubMedGoogle Scholar
  34. 34.
    Punnen SP, Chin JL, Jewett MAS (2003) Management of bacillus Calmette–Guerin (BCG) refractory superficial bladder cancer: results with intravesical BCG and Interferon combination therapy. Can J Urol 10:1790–1795PubMedGoogle Scholar
  35. 35.
    Rosevear HM, Lightfoot AJ, Birusingh KK et al (2011) Factors affecting response to bacillus Calmette–Guérin plus interferon for urothelial carcinoma in situ. J Urol 186:817–823. CrossRefPubMedGoogle Scholar
  36. 36.
    Nativ O, Witjes JA, Hendricksen K et al (2009) Combined thermo-chemotherapy for recurrent bladder cancer after bacillus Calmette–Guerin. J Urol 182:1313–1317. CrossRefPubMedGoogle Scholar
  37. 37.
    Liu Z, Ye Y, Li X et al (2018) The effects of intra-arterial chemotherapy on bladder preservation in patients with T1 stage bladder cancer. World J Urol 36:1191–1200. CrossRefPubMedGoogle Scholar
  38. 38.
    Skinner EC, Goldman B, Sakr WA et al (2013) SWOG S0353: phase II trial of intravesical gemcitabine in patients with nonmuscle invasive bladder cancer and recurrence after 2 prior courses of intravesical bacillus Calmette–Guérin. J Urol 190:1200–1204. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Carosella ED, Ploussard G, LeMaoult J, Desgrandchamps F (2015) A systematic review of immunotherapy in urologic cancer: evolving roles for targeting of CTLA-4, PD-1/PD-L1, and HLA-G. Eur Urol 68:267–279. CrossRefPubMedGoogle Scholar
  40. 40.
    Pettenati C, Ingersoll MA (2018) Mechanisms of BCG immunotherapy and its outlook for bladder cancer. Nat Rev Urol 49:1374. CrossRefGoogle Scholar
  41. 41.
    Steinberg GD, Shore ND, Karsh LI et al (2017) Immune response results of vesigenurtacel-l (HS-410) in combination with BCG from a randomized phase II trial in patients with non-muscle invasive bladder cancer (NMIBC). J Clin Oncol 35:319. CrossRefGoogle Scholar
  42. 42.
    Sanford T, Donahue R, Jochems C et al (2017) MP15-10 immunologic response to a therapeutic cancer vaccine (PANVAC): initial results from a randomized phase 2 clinical trial. J Urol 197:e174. CrossRefGoogle Scholar
  43. 43.
    Dinney CPN, Fisher MB, Navai N et al (2013) Phase I trial of intravesical recombinant adenovirus mediated interferon-α2b formulated in Syn3 for Bacillus Calmette–Guérin failures in nonmuscle invasive bladder cancer. J Urol 190:850–856. CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Boorjian SA, Shore ND, Canter D et al (2017) Intravesical rad-IFNα/Syn3 for patients with high-grade, bacillus Calmette–Guérin (BCG) refractory or relapsed non-muscle invasive bladder cancer: a phase II randomized study. J Clin Oncol 35:279. CrossRefGoogle Scholar
  45. 45.
    Boehm BE, Svatek RS (2015) Novel therapeutic approaches for recurrent nonmuscle invasive bladder cancer. Urol Clin N Am 42:159–168. (vii) CrossRefGoogle Scholar
  46. 46.
    Packiam VT, Lamm DL, Barocas DA et al (2017) An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non-muscle-invasive bladder cancer: Interim results. Urologic oncology. CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Rayn KN, Hale GR, Grave GP-L, Agarwal PK (2018) New therapies in nonmuscle invasive bladder cancer treatment. Indian J Urol 34:11–19. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Robins DJ, Sui W, Matulay JT et al (2017) Long-term survival outcomes with intravesical nanoparticle albumin-bound paclitaxel for recurrent non-muscle-invasive bladder cancer after previous Bacillus Calmette–Guérin therapy. Urology 103:149–153. CrossRefPubMedGoogle Scholar
  49. 49.
    Premo C, Apolo AB, Agarwal PK, Citrin DE (2015) Trimodality therapy in bladder cancer. Urol Clin N Am 42:169–180. CrossRefGoogle Scholar
  50. 50.
    Raby SEM, Choudhury A (2018) Radiotherapy for high-grade T1 bladder cancer. Eur Urol Focus 4:506–508. CrossRefPubMedGoogle Scholar
  51. 51.
    Liu Y, Dong Y, Kong L et al (2018) Abscopal effect of radiotherapy combined with immune checkpoint inhibitors. J Hematol Oncol 11:104. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Ryan P. Werntz
    • 1
    Email author
  • Brittany Adamic
    • 1
  • Gary D. Steinberg
    • 1
  1. 1.Section of Urology, Department of SurgeryThe University of Chicago Medicine, ChicagoChicagoUSA

Personalised recommendations