Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Recurrence mechanisms of non-muscle-invasive bladder cancer — a clinical perspective

Nature Reviews Urology volume 19, pages 280–294 (2022)Cite this article

Subjects

Abstract

Non-muscle-invasive bladder cancer (NMIBC) is an early-stage cancer without invasion into the detrusor muscle layer. Transurethral resection of bladder tumour (TURBT) is a diagnostic and potentially curative procedure for NMIBC, but has some limitations, including difficulties in ascertaining complete tumour removal upon piecemeal resection and the possibility of tumour re-implantation after the procedure. The oncological control of NMIBC is far from satisfactory, with a 1-year recurrence rate of 15–61%, and a 5-year recurrence rate of 31–78%. Various recurrence mechanisms have been described for NMIBC, such as undetected tumours upon cystoscopy, incomplete resection during TURBT, tumour re-implantation after TURBT, drop metastasis from upper tract urothelial carcinoma and field change cancerization. Understanding the recurrence mechanisms from a clinical perspective has strong implications for the optimization of NMIBC oncological outcomes, as a cure for patients with NMIBC can only be achieved by tackling all possible recurrence mechanisms in a comprehensive manner.

Key points

  • Undetected cancer upon cystoscopy, local residual disease after transurethral resection and tumour re-implantation might cause early disease recurrence of non-muscle-invasive bladder cancer (NMIBC), whereas field change cancerization effects could lead to late disease recurrence.

  • Drop metastasis from upper tract urothelial carcinoma can cause NMIBC recurrence, although it is unlikely to be the predominant recurrence mechanism.

  • Recurrence mechanisms should be managed in a comprehensive manner in order to optimize the oncological outcomes of NMIBC.

  • Molecular classification of NMIBC as well as treatment with immunotherapy and other novel therapeutic agents might have important implications in the future management of NMIBC.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Conventional transurethral resection of bladder tumour and non-muscle-invasive bladder cancer recurrence.
Fig. 2: En bloc resection and NMIBC recurrence.
Fig. 3: Field change cancerization effect.

References

  1. Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394–424 (2018).

    Article  PubMed  Google Scholar 

  2. Teoh, J. Y. et al. Global trends of bladder cancer incidence and mortality, and their associations with tobacco use and gross domestic product per capita. Eur. Urol. 78, 893–906 (2020).

    Article  PubMed  Google Scholar 

  3. Pasin, E., Josephson, D. Y., Mitra, A. P., Cote, R. J. & Stein, J. P. Superficial bladder cancer: an update on etiology, molecular development, classification, and natural history. Rev. Urol. 10, 31–43 (2008).

    PubMed  PubMed Central  Google Scholar 

  4. Babjuk, M. et al. European Association of Urology guidelines on non-muscle-invasive bladder cancer (TaT1 and carcinoma in situ) 2019 update. Eur. Urol. 76, 639–657 (2019).

    Article  CAS  PubMed  Google Scholar 

  5. Khadhouri, S. et al. The IDENTIFY study: the investigation and detection of urological neoplasia in patients referred with suspected urinary tract cancer - a multicentre observational study. BJU Int. 128, 440–450 (2021).

    Article  PubMed  Google Scholar 

  6. Jones, H. C. & Swinney, J. The treatment of tumours of the bladder by transurethral resection. Br. J. Urol. 34, 215–220 (1962).

    Article  CAS  PubMed  Google Scholar 

  7. Mariappan, P. Attention to detail and a permissive set-up: crucial for an effective TURBT. Nat. Rev. Urol. 18, 253–254 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Sylvester, R. J. 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. 49, 466-5 (2006).

    Article  Google Scholar 

  9. Cheung, G., Sahai, A., Billia, M., Dasgupta, P. & Khan, M. S. Recent advances in the diagnosis and treatment of bladder cancer. BMC Med. 11, 13 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  10. van den Bosch, S. & Alfred Witjes, J. Long-term cancer-specific survival in patients with high-risk, non-muscle-invasive bladder cancer and tumour progression: a systematic review. Eur. Urol. 60, 493–500 (2011).

    Article  PubMed  Google Scholar 

  11. Bryan, R. T. et al. Mechanisms of recurrence of Ta/T1 bladder cancer. Ann. R. Coll. Surg. Engl. 92, 519–524 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Kamat, A. M. et al. BCG-unresponsive non-muscle-invasive bladder cancer: recommendations from the IBCG. Nat. Rev. Urol. 14, 244–255 (2017).

    Article  PubMed  Google Scholar 

  13. O’Sullivan, D. C. & Chilton, C. P. Flexible cystoscopy. Br. J. Hosp. Med. 51, 340–345 (1994).

    PubMed  Google Scholar 

  14. Lerner, S. P. & Goh, A. Novel endoscopic diagnosis for bladder cancer. Cancer 121, 169–178 (2015).

    Article  PubMed  Google Scholar 

  15. Nese, N., Gupta, R., Bui, M. H. & Amin, M. B. Carcinoma in situ of the urinary bladder: review of clinicopathologic characteristics with an emphasis on aspects related to molecular diagnostic techniques and prognosis. J. Natl Compr. Canc Netw. 7, 48–57 (2009).

    Article  PubMed  Google Scholar 

  16. Amin, M. B. & Young, R. H. Intraepithelial lesions of the urinary bladder with a discussion of the histogenesis of urothelial neoplasia. Semin. Diagn. Pathol. 14, 84–97 (1997).

    CAS  PubMed  Google Scholar 

  17. Bryan, R. T., Billingham, L. J. & Wallace, D. M. Narrow-band imaging flexible cystoscopy in the detection of recurrent urothelial cancer of the bladder. BJU Int. 101, 702–705 (2008).

    Article  PubMed  Google Scholar 

  18. Zheng, C., Lv, Y., Zhong, Q., Wang, R. & Jiang, Q. Narrow band imaging diagnosis of bladder cancer: systematic review and meta-analysis. BJU Int. 110, E680–E687 (2012).

    Article  PubMed  Google Scholar 

  19. Cauberg, E. C., Mamoulakis, C., de la Rosette, J. J. & de Reijke, T. M. Narrow band imaging-assisted transurethral resection for non-muscle invasive bladder cancer significantly reduces residual tumour rate. World J. Urol. 29, 503–509 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Naito, S. 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. 70, 506–515 (2016).

    Article  PubMed  Google Scholar 

  21. Kausch, I. et al. Photodynamic diagnosis in non-muscle-invasive bladder cancer: a systematic review and cumulative analysis of prospective studies. Eur. Urol. 57, 595–606 (2010).

    Article  PubMed  Google Scholar 

  22. Inoue, K. 5-Aminolevulinic acid-mediated photodynamic therapy for bladder cancer. Int. J. Urol. 24, 97–101 (2017).

    Article  CAS  PubMed  Google Scholar 

  23. Liberti, M. V. & Locasale, J. W. The Warburg effect: how does it benefit cancer cells? Trends Biochem. Sci. 41, 211–218 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Burger, M. et al. 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 (2013).

    Article  PubMed  Google Scholar 

  25. Ishizuka, M. et al. Novel development of 5-aminolevurinic acid (ALA) in cancer diagnoses and therapy. Int. Immunopharmacol. 11, 358–365 (2011).

    Article  CAS  PubMed  Google Scholar 

  26. Chou, R. 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. 197, 548–558 (2017).

    Article  PubMed  Google Scholar 

  27. Sari Motlagh, R. et al. Impact of enhanced optical techniques at time of transurethral resection of bladder tumour, with or without single immediate intravesical chemotherapy, on recurrence rate of non-muscle-invasive bladder cancer: a systematic review and network meta-analysis of randomized trials. BJU Int. https://doi.org/10.1111/bju.15383 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Kamphuis, G. et al. Storz professional image enhancement system: a new technique to improve endoscopic bladder imaging. J. Cancer Sci. Ther. 8, 71–77 (2016).

    Google Scholar 

  29. Ramponi, G., Strobel, N., Mitra, S. & Yu, T.-H. Nonlinear unsharp masking methods for image contrast enhancement. J. Electron. Imaging 5, 353–366 (1996).

    Article  Google Scholar 

  30. Wang, L. V. & Wu, H. Biomedical Optics: Principles and Imaging (John Wiley & Sons., 2007).

  31. Sid-Ahmed, M. A. Image Processing: Theory, Algorithms, and Architectures Int. edn (McGraw-Hill, 1995).

  32. Howard, J. M., Woldu, S. L., Daneshmand, S. & Lotan, Y. Enhanced endoscopy with IMAGE1 S CHROMA improves detection of nonmuscle invasive bladder cancer during transurethral resection. J. Endourol. 35, 647–651 (2021).

    Article  PubMed  Google Scholar 

  33. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02252549 (2021).

  34. Cumberbatch, M. G. K. et al. Repeat transurethral resection in non-muscle-invasive bladder cancer: a systematic review. Eur. Urol. 73, 925–933 (2018).

    Article  PubMed  Google Scholar 

  35. Herr, H. W. Restaging transurethral resection of high risk superficial bladder cancer improves the initial response to bacillus Calmette-Guerin therapy. J. Urol. 174, 2134–2137 (2005).

    Article  PubMed  Google Scholar 

  36. Divrik, R. T., Sahin, A. F., Yildirim, U., Altok, M. & Zorlu, F. 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 (2010).

    Article  PubMed  Google Scholar 

  37. Novara, G. & Ficarra, V. Does routine second transurethral resection affect the long-term outcome of patients with T1 bladder cancer? Why a flawed randomized controlled trial cannot address the issue. Eur. Urol. 58, 193–194 (2010).

    Article  PubMed  Google Scholar 

  38. Divrik, R. T., Sahin, A. F. & Ergor, G. Reply from authors re: Marko Babjuk. Second resection for non-muscle-invasive bladder carcinoma: current role and future perspectives. Eur Urol 2010;58:191–2 and Giacomo Novara, Vincenzo Ficarra. Does routine second transurethral resection affect the long-term outcome of patients with T1 bladder cancer? Why a flawed randomized controlled trial cannot address the issue. Eur Urol 2010;58:193–4. Eur. Urol. 58, 195–196 (2010).

    Article  PubMed  Google Scholar 

  39. Kitamura, K., Kataoka, K., Fujioka, H. & Kashiwai, K. Transurethral resection of a bladder tumor by the use of a polypectomy snare. J. Urol. 124, 808–809 (1980).

    Article  CAS  PubMed  Google Scholar 

  40. Teoh, J. Y. et al. An international collaborative consensus statement on en bloc resection of bladder tumour incorporating two systematic reviews, a two-round Delphi Survey, and a Consensus Meeting. Eur. Urol. 78, 546–569 (2020).

    Article  PubMed  Google Scholar 

  41. Teoh, J. Y., Chan, E. S., Yee, C. H., Hou, S. S. & Ng, C. F. Bipolar transurethral en-bloc resection of bladder tumour: clinical and pathologic considerations. Surgical Pract. 20, 13 (2016).

    Article  Google Scholar 

  42. Chan, V. W.-S., Ng, C.-F. & Teoh, J. Y.-C. The impact of transurethral en bloc resection of bladder tumour on pathological and oncological outcomes. AME Med. J. 5, 29 (2020).

    Article  Google Scholar 

  43. Teoh, J. Y. et al. En-bloc resection of bladder tumour as primary treatment for patients with non-muscle-invasive bladder cancer: routine implementation in a multi-centre setting. World J. Urol. https://doi.org/10.1007/s00345-021-03675-9 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  44. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02993211 (2021).

  45. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02555163 (2020).

  46. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02951078 (2016).

  47. Teoh, J. Y. C., Herrmann, T. R. W. & Babjuk, M. Re: Valeria Panebianco, Yoshifumi Narumi, Ersan Altun, et al. Multiparametric magnetic resonance imaging for bladder cancer: development of VI-RADS (Vesical Imaging-Reporting and Data System). Eur Urol 74, 2018, 294–306. Eur. Urol. 75, e27–e28 (2019).

    Article  PubMed  Google Scholar 

  48. Panebianco, V. et al. Multiparametric magnetic resonance imaging for bladder cancer: development of VI-RADS (Vesical Imaging-Reporting and Data System). Eur. Urol. https://doi.org/10.1016/j.eururo.2018.04.029 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  49. Carando, R. et al. The effectiveness of multiparametric magnetic resonance imaging in bladder cancer (Vesical Imaging-Reporting and Data System): a systematic review. Arab. J. Urol. 18, 67–71 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Del Giudice, F. et al. Preoperative detection of Vesical Imaging-Reporting and Data System (VI-RADS) score 5 reliably identifies extravesical extension of urothelial carcinoma of the urinary bladder and predicts significant delayed time to cystectomy: time to reconsider the need for primary deep transurethral resection of bladder tumour in cases of locally advanced disease? BJU Int. 126, 610–619 (2020).

    Article  PubMed  CAS  Google Scholar 

  51. Ueno, Y. et al. VI-RADS: multiinstitutional multireader diagnostic accuracy and interobserver agreement study. AJR Am. J. Roentgenol. 216, 1257–1266 (2021).

    Article  PubMed  Google Scholar 

  52. Gore, J. L. et al. Mortality increases when radical cystectomy is delayed more than 12 weeks: results from a Surveillance, Epidemiology, and End Results-Medicare analysis. Cancer 115, 988–996 (2009).

    Article  PubMed  Google Scholar 

  53. Bryan, R. T. et al. Comparing an imaging-guided pathway with the standard pathway for staging muscle-invasive bladder cancer: preliminary data from the BladderPath Study. Eur. Urol. 80, 12–15 (2021).

    Article  PubMed  Google Scholar 

  54. Del Giudice, F. et al. Prospective assessment of vesical imaging reporting and data system (VI-RADS) and its clinical impact on the management of high-risk non-muscle-invasive bladder cancer patients candidate for repeated transurethral resection. Eur. Urol. 77, 101–109 (2020).

    Article  PubMed  Google Scholar 

  55. Mariappan, P., Zachou, A., Grigor, K. M. & Edinburgh Uro-Oncology, G. Detrusor muscle in the first, apparently complete transurethral resection of bladder tumour specimen is a surrogate marker of resection quality, predicts risk of early recurrence, and is dependent on operator experience. Eur. Urol. 57, 843–849 (2010).

    Article  PubMed  Google Scholar 

  56. Poletajew, S. et al. The learning curve for transurethral resection of bladder tumour: how many is enough to be independent, safe and effective surgeon? J. Surg. Educ. 77, 978–985 (2020).

    Article  PubMed  Google Scholar 

  57. Teoh, J. Y. et al. A newly developed porcine training model for transurethral piecemeal and en bloc resection of bladder tumour. World J. Urol. 37, 1879–1887 (2019).

    Article  PubMed  Google Scholar 

  58. Kruck, S. et al. Virtual bladder tumor transurethral resection: an objective evaluation tool to overcome learning curves with and without photodynamic diagnostics. Urol. Int. 87, 138–142 (2011).

    Article  PubMed  Google Scholar 

  59. Mariappan, P. et al. Enhanced quality and effectiveness of transurethral resection of bladder tumour in non-muscle-invasive bladder cancer: a multicentre real-world experience from Scotland’s quality performance indicators programme. Eur. Urol. 78, 520–530 (2020).

    Article  PubMed  Google Scholar 

  60. Simon, R. et al. Cytogenetic analysis of multifocal bladder cancer supports a monoclonal origin and intraepithelial spread of tumor cells. Cancer Res. 61, 355–362 (2001).

    CAS  PubMed  Google Scholar 

  61. Sidransky, D. et al. Clonal origin of bladder cancer. N. Engl. J. Med. 326, 737–740 (1992).

    Article  CAS  PubMed  Google Scholar 

  62. Acar, O. et al. Determining the origin of synchronous multifocal bladder cancer by exome sequencing. BMC Cancer 15, 871 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Dahse, R., Gartner, D., Werner, W., Schubert, J. & Junker, K. P53 mutations as an identification marker for the clonal origin of bladder tumors and its recurrences. Oncol. Rep. 10, 2033–2037 (2003).

    CAS  PubMed  Google Scholar 

  64. Babjuk, M. et al. Indication for a single postoperative instillation of chemotherapy in non-muscle-invasive bladder cancer: what factors should be considered? Eur. Urol. Focus. 4, 525–528 (2018).

    Article  PubMed  Google Scholar 

  65. Pan, J. S. et al. Inhibition of implantation of murine bladder tumor by thiotepa in cauterized bladder. J. Urol. 142, 1589–1593 (1989).

    Article  CAS  PubMed  Google Scholar 

  66. Sylvester, R. J. 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. 69, 231–244 (2016).

    Article  PubMed  Google Scholar 

  67. Zhou, Z. et al. Meta-analysis of efficacy and safety of continuous saline bladder irrigation compared with intravesical chemotherapy after transurethral resection of bladder tumors. World J. Urol. 37, 1075–1084 (2019).

    Article  PubMed  Google Scholar 

  68. Onishi, T., Sasaki, T., Hoshina, A. & Yabana, T. Continuous saline bladder irrigation after transurethral resection is a prophylactic treatment choice for non-muscle invasive bladder tumor. Anticancer. Res. 31, 1471–1474 (2011).

    PubMed  Google Scholar 

  69. Maekawa, S. et al. [Continuous intravesical instillation of epirubicin immediately after transurethral resection of superficial bladder cancer: a prospective controlled study]. Hinyokika Kiyo 46, 301–306 (2000).

    CAS  PubMed  Google Scholar 

  70. Onishi, T. et al. Randomized controlled study of the efficacy and safety of continuous saline bladder irrigation after transurethral resection for the treatment of non-muscle-invasive bladder cancer. BJU Int. 119, 276–282 (2017).

    Article  CAS  PubMed  Google Scholar 

  71. Panahi, M. H. Letter to the Editor regarding the article “Meta-analysis of efficacy and safety of continuous saline bladder irrigation compared with intravesical chemotherapy after transurethral resection of bladder tumors”. World J. Urol. 38, 513 (2020).

    Article  PubMed  Google Scholar 

  72. Tse, R. T. et al. In vitro assessment of intra-operative and post-operative environment in reducing bladder cancer recurrence. Sci. Rep. 12, 22 (2022).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Fechner, G., Pocha, K., Schmidt, D. & Muller, S. C. Reducing recurrence and costs in superficial bladder cancer: preclinical evaluation of osmotic cytolysis by distilled water vs. mitomycin. Int. J. Clin. Pract. 60, 1178–1180 (2006).

    Article  CAS  PubMed  Google Scholar 

  74. Bijalwan, P., Pooleri, G. K. & Thomas, A. Comparison of sterile water irrigation versus intravesical mitomycin C in preventing recurrence of nonmuscle invasive bladder cancer after transurethral resection. Indian. J. Urol. 33, 144–148 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Audenet, F. et al. Clonal relatedness and mutational differences between upper tract and bladder urothelial carcinoma. Clin. Cancer Res. 25, 967–976 (2019).

    Article  CAS  PubMed  Google Scholar 

  76. van Doeveren, T. et al. Synchronous and metachronous urothelial carcinoma of the upper urinary tract and the bladder: are they clonally related? A systematic review. Urol. Oncol. 38, 590–598 (2020).

    Article  PubMed  CAS  Google Scholar 

  77. Cosentino, M. et al. Upper urinary tract urothelial cell carcinoma: location as a predictive factor for concomitant bladder carcinoma. World J. Urol. 31, 141–145 (2013).

    Article  PubMed  Google Scholar 

  78. Palou, J. et al. Multivariate analysis of clinical parameters of synchronous primary superficial bladder cancer and upper urinary tract tumor. J. Urol. 174, 859–861 (2005).

    Article  PubMed  Google Scholar 

  79. Millan-Rodriguez, F., Chechile-Toniolo, G., Salvador-Bayarri, J., Huguet-Perez, J. & Vicente-Rodriguez, J. Upper urinary tract tumors after primary superficial bladder tumors: prognostic factors and risk groups. J. Urol. 164, 1183–1187 (2000).

    Article  CAS  PubMed  Google Scholar 

  80. Khadhouri, S. et al. The IDENTIFY Study: the investigation and detection of urological neoplasia in patients referred with suspected urinary tract cancer; a multicentre observational study. BJU Int. https://doi.org/10.1111/bju.15483 (2021).

    Article  PubMed  Google Scholar 

  81. Janisch, F. et al. Diagnostic performance of multidetector computed tomographic (MDCTU) in upper tract urothelial carcinoma (UTUC): a systematic review and meta-analysis. World J. Urol. 38, 1165–1175 (2020).

    Article  PubMed  Google Scholar 

  82. Jinzaki, M. et al. Comparison of CT urography and excretory urography in the detection and localization of urothelial carcinoma of the upper urinary tract. AJR Am. J. Roentgenol. 196, 1102–1109 (2011).

    Article  PubMed  Google Scholar 

  83. Cowan, N. C., Turney, B. W., Taylor, N. J., McCarthy, C. L. & Crew, J. P. Multidetector computed tomography urography for diagnosing upper urinary tract urothelial tumour. BJU Int. 99, 1363–1370 (2007).

    Article  PubMed  Google Scholar 

  84. Razavi, S. A., Sadigh, G., Kelly, A. M. & Cronin, P. Comparative effectiveness of imaging modalities for the diagnosis of upper and lower urinary tract malignancy: a critically appraised topic. Acad. Radiol. 19, 1134–1140 (2012).

    Article  PubMed  Google Scholar 

  85. O’Connor, O. J., McLaughlin, P. & Maher, M. M. MR urography. AJR Am. J. Roentgenol. 195, W201–W206 (2010).

    Article  PubMed  Google Scholar 

  86. Woolen, S. A. et al. Risk of nephrogenic systemic fibrosis in patients with stage 4 or 5 chronic kidney disease receiving a group II gadolinium-based contrast agent: a systematic review and meta-analysis. JAMA Intern. Med. 180, 223–230 (2020).

    Article  CAS  PubMed  Google Scholar 

  87. Tan, W. S. et al. Can renal and bladder ultrasound replace computerized tomography urogram in patients investigated for microscopic hematuria? J. Urol. 200, 973–980 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Cumberbatch, M. G. K. et al. Epidemiology of bladder cancer: a systematic review and contemporary update of risk factors in 2018. Eur. Urol. 74, 784–795 (2018).

    Article  PubMed  Google Scholar 

  89. Mushtaq, J., Thurairaja, R. & Nair, R. Bladder cancer. Surgery 37, 529–537 (2019).

    Google Scholar 

  90. Slaughter, D. P., Southwick, H. W. & Smejkal, W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 6, 963–968 (1953).

    Article  CAS  PubMed  Google Scholar 

  91. Dakubo, G. D., Jakupciak, J. P., Birch-Machin, M. A. & Parr, R. L. Clinical implications and utility of field cancerization. Cancer Cell Int. 7, 2 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Jones, T. D. et al. Molecular evidence supporting field effect in urothelial carcinogenesis. Clin. Cancer Res. 11, 6512 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Burger, M. et al. Epidemiology and risk factors of urothelial bladder cancer. Eur. Urol. 63, 234–241 (2013).

    Article  PubMed  Google Scholar 

  94. van Osch, F. H., Jochems, S. H., van Schooten, F. J., Bryan, R. T. & Zeegers, M. P. Quantified relations between exposure to tobacco smoking and bladder cancer risk: a meta-analysis of 89 observational studies. Int. J. Epidemiol. 45, 857–870 (2016).

    Article  PubMed  Google Scholar 

  95. Lammers, R. J. et al. Smoking status is a risk factor for recurrence after transurethral resection of non-muscle-invasive bladder cancer. Eur. Urol. 60, 713–720 (2011).

    Article  PubMed  Google Scholar 

  96. Rink, M. et al. Smoking reduces the efficacy of intravesical bacillus Calmette-Guerin immunotherapy in non-muscle-invasive bladder cancer. Eur. Urol. 62, 1204–1206 (2012).

    Article  PubMed  Google Scholar 

  97. Sfakianos, J. P., Shariat, S. F., Favaretto, R. L., Rioja, J. & Herr, H. W. Impact of smoking on outcomes after intravesical bacillus Calmette-Guerin therapy for urothelial carcinoma not invading muscle of the bladder. BJU Int. 108, 526–530 (2011).

    Article  CAS  PubMed  Google Scholar 

  98. Sopori, M. Effects of cigarette smoke on the immune system. Nat. Rev. Immunol. 2, 372–377 (2002).

    Article  CAS  PubMed  Google Scholar 

  99. Andrade, D. L., Moretti, T. B. C., Neto, W. A., Benedetti, J. & Reis, L. O. Smoke load prognostic impact on bacillus Calmette-Guerin (BCG) treated non-muscle invasive bladder cancer. Int. Urol. Nephrol. 52, 1471–1476 (2020).

    Article  CAS  PubMed  Google Scholar 

  100. Mori, K. et al. Smoking and bladder cancer: review of the recent literature. Curr. Opin. Urol. 30, 720–725 (2020).

    Article  PubMed  Google Scholar 

  101. World Health Organization. Global NCD target: reducing tobacco use. WHO https://www.who.int/beat-ncds/take-action/ncd-tobacco-target.pdf (2020).

  102. Pettenati, C. & Ingersoll, M. A. Mechanisms of BCG immunotherapy and its outlook for bladder cancer. Nat. Rev. Urol. 15, 615–625 (2018).

    Article  CAS  PubMed  Google Scholar 

  103. Kawai, K., Miyazaki, J., Joraku, A., Nishiyama, H. & Akaza, H. Bacillus Calmette-Guerin (BCG) immunotherapy for bladder cancer: current understanding and perspectives on engineered BCG vaccine. Cancer Sci. 104, 22–27 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Fuge, O., Vasdev, N., Allchorne, P. & Green, J. S. Immunotherapy for bladder cancer. Res. Rep. Urol. 7, 65–79 (2015).

    PubMed  PubMed Central  Google Scholar 

  105. Zlotta, A. R. et al. What is the optimal regimen for BCG intravesical therapy? Are six weekly instillations necessary? Eur. Urol. 37, 470–477 (2000).

    Article  CAS  PubMed  Google Scholar 

  106. Böhle, A. & Bock, P. R. Intravesical bacille Calmette-Guérin versus mitomycin C in superficial bladder cancer: formal meta-analysis of comparative studies on tumor progression. Urology 63, 682–686 (2004).

    Article  PubMed  Google Scholar 

  107. Han, R. F. & Pan, J. G. Can intravesical bacillus Calmette-Guerin reduce recurrence in patients with superficial bladder cancer? A meta-analysis of randomized trials. Urology 67, 1216–1223 (2006).

    Article  PubMed  Google Scholar 

  108. Oddens, J. 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. 63, 462–472 (2013).

    Article  PubMed  Google Scholar 

  109. Grimm, M. O. et al. Treatment of high-grade non-muscle-invasive bladder carcinoma by standard number and dose of BCG instillations versus reduced number and standard dose of BCG instillations: results of the European Association of Urology Research Foundation randomised phase III clinical trial “NIMBUS”. Eur. Urol. 78, 690–698 (2020).

    Article  PubMed  Google Scholar 

  110. Shang, P. F. et al. Intravesical Bacillus Calmette-Guerin versus epirubicin for Ta and T1 bladder cancer. Cochrane Database Syst. Rev. https://doi.org/10.1002/14651858.CD006885.pub2 (2011).

    Article  PubMed  Google Scholar 

  111. Malmstrom, P. U. et al. An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin C versus bacillus Calmette-Guerin for non-muscle-invasive bladder cancer. Eur. Urol. 56, 247–256 (2009).

    Article  PubMed  CAS  Google Scholar 

  112. Huncharek, M., Geschwind, J. F., Witherspoon, B., McGarry, R. & Adcock, D. Intravesical chemotherapy prophylaxis in primary superficial bladder cancer: a meta-analysis of 3703 patients from 11 randomized trials. J. Clin. Epidemiol. 53, 676–680 (2000).

    Article  CAS  PubMed  Google Scholar 

  113. Joice, G. A., Bivalacqua, T. J. & Kates, M. Optimizing pharmacokinetics of intravesical chemotherapy for bladder cancer. Nat. Rev. Urol. 16, 599–612 (2019).

    Article  PubMed  Google Scholar 

  114. Walker, M. C., Masters, J. R., Parris, C. N., Hepburn, P. J. & English, P. J. Intravesical chemotherapy: in vitro studies on the relationship between dose and cytotoxicity. Urol. Res. 14, 137–140 (1986).

    CAS  PubMed  Google Scholar 

  115. Prescott, S., Jackson, A. M., Hawkyard, S. J., Alexandroff, A. B. & James, K. Mechanisms of action of intravesical bacille Calmette-Guérin: local immune mechanisms. Clin. Infect. Dis. 31, S91–S93 (2000).

    Article  CAS  PubMed  Google Scholar 

  116. Sylvester, R. J., Oosterlinck, W. & Witjes, J. A. The schedule and duration of intravesical chemotherapy in patients with non-muscle-invasive bladder cancer: a systematic review of the published results of randomized clinical trials. Eur. Urol. 53, 709–719 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Tan, W. S. & Kelly, J. D. Intravesical device-assisted therapies for non-muscle-invasive bladder cancer. Nat. Rev. Urol. 15, 667–685 (2018).

    Article  CAS  PubMed  Google Scholar 

  118. Westra, A. & Dewey, W. C. Variation in sensitivity to heat shock during the cell-cycle of Chinese hamster cells in vitro. Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med. 19, 467–477 (1971).

    Article  CAS  PubMed  Google Scholar 

  119. Mantso, T. et al. Effects of hyperthermia as a mitigation strategy in DNA damage-based cancer therapies. Semin. Cancer Biol. 37-38, 96–105 (2016).

    Article  CAS  PubMed  Google Scholar 

  120. Lefor, A. T., Makohon, S. & Ackerman, N. B. The effects of hyperthermia on vascular permeability in experimental liver metastasis. J. Surg. Oncol. 28, 297–300 (1985).

    Article  CAS  PubMed  Google Scholar 

  121. Song, C. W. Effect of hyperthermia on vascular functions of normal tissues and experimental tumors; brief communication. J. Natl Cancer Inst. 60, 711–713 (1978).

    Article  CAS  PubMed  Google Scholar 

  122. Kampinga, H. H. Cell biological effects of hyperthermia alone or combined with radiation or drugs: a short introduction to newcomers in the field. Int. J. Hyperth. 22, 191–196 (2006).

    Article  CAS  Google Scholar 

  123. Milani, V. et al. Heat shock protein 70: role in antigen presentation and immune stimulation. Int. J. Hyperth. 18, 563–575 (2002).

    Article  CAS  Google Scholar 

  124. Arends, T. J. et al. Results of a randomised controlled trial comparing intravesical chemohyperthermia with mitomycin C versus Bacillus Calmette-Guerin for adjuvant treatment of patients with intermediate- and high-risk non-muscle-invasive bladder cancer. Eur. Urol. 69, 1046–1052 (2016).

    Article  CAS  PubMed  Google Scholar 

  125. Tan, W. S. et al. Radiofrequency-induced thermo-chemotherapy effect versus a second course of Bacillus Calmette-Guerin or institutional standard in patients with recurrence of non-muscle-invasive bladder cancer following induction or maintenance Bacillus Calmette-Guerin Therapy (HYMN): a phase III, open-label, randomised controlled trial. Eur. Urol. 75, 63–71 (2019).

    Article  PubMed  Google Scholar 

  126. Hudson, M. A. & Herr, H. W. Carcinoma in situ of the bladder. J. Urol. 153, 564–572 (1995).

    Article  CAS  PubMed  Google Scholar 

  127. Fankhauser, C. D., Teoh, J. Y. & Mostafid, H. Treatment options and results of adjuvant treatment in nonmuscle-invasive bladder cancer (NMIBC) during the Bacillus Calmette-Guerin shortage. Curr. Opin. Urol. https://doi.org/10.1097/MOU.0000000000000739 (2020).

    Article  PubMed  Google Scholar 

  128. Teoh, J. Y. C., Roupret, M., Shariat, S. F. & Herrmann, T. Intravesical therapy for bladder cancer in the pandemic of Covid-19. World J. Urol. https://doi.org/10.1007/s00345-020-03218-8 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Shore, N. D. et al. Non-muscle-invasive bladder cancer: an overview of potential new treatment options. Urol. Oncol. 39, 642–663 (2021).

    Article  CAS  PubMed  Google Scholar 

  130. Balar, A. V. et al. Keynote 057: phase II trial of pembrolizumab (pembro) for patients (pts) with high-risk (HR) nonmuscle invasive bladder cancer (NMIBC) unresponsive to bacillus Calmette-Guérin (BCG). J. Clin. Oncol. 37, 350–350 (2019).

    Article  Google Scholar 

  131. Black, P. C. et al. Phase II trial of atezolizumab in BCG-unresponsive non-muscle invasive bladder cancer: SWOG S1605 (NCT #02844816). J. Clin. Oncol. 38, 5022–5022 (2020).

    Article  Google Scholar 

  132. Boorjian, S. A. et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. 22, 107–117 (2021).

    Article  CAS  PubMed  Google Scholar 

  133. Kawahara, T. et al. PD-1 and PD-L1 are more highly expressed in high-grade bladder cancer than in low-grade cases: PD-L1 might function as a mediator of stage progression in bladder cancer. BMC Urol. 18, 97 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Hashizume, A. et al. Enhanced expression of PD-L1 in non-muscle-invasive bladder cancer after treatment with Bacillus Calmette-Guerin. Oncotarget 9, 34066–34078 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Wright, K. M. FDA approves pembrolizumab for BCG-unresponsive NMIBC. Oncology 34, 44 (2020).

    PubMed  Google Scholar 

  136. Benedict, W. F. et al. Intravesical Ad-IFNalpha causes marked regression of human bladder cancer growing orthotopically in nude mice and overcomes resistance to IFN-alpha protein. Mol. Ther. 10, 525–532 (2004).

    Article  CAS  PubMed  Google Scholar 

  137. Tao, Z. et al. Efficacy of a single intravesical treatment with Ad-IFN/Syn 3 is dependent on dose and urine IFN concentration obtained: implications for clinical investigation. Cancer Gene Ther. 13, 125–130 (2006).

    Article  CAS  PubMed  Google Scholar 

  138. Connor, R. J., Anderson, J. M., Machemer, T., Maneval, D. C. & Engler, H. Sustained intravesical interferon protein exposure is achieved using an adenoviral-mediated gene delivery system: a study in rats evaluating dosing regimens. Urology 66, 224–229 (2005).

    Article  PubMed  Google Scholar 

  139. Yamashita, M. et al. Syn3 provides high levels of intravesical adenoviral-mediated gene transfer for gene therapy of genetically altered urothelium and superficial bladder cancer. Cancer Gene Ther. 9, 687–691 (2002).

    Article  CAS  PubMed  Google Scholar 

  140. Di Paolo, C. et al. A recombinant immunotoxin derived from a humanized epithelial cell adhesion molecule-specific single-chain antibody fragment has potent and selective antitumor activity. Clin. Cancer Res. 9, 2837–2848 (2003).

    PubMed  Google Scholar 

  141. Balzar, M., Winter, M. J., de Boer, C. J. & Litvinov, S. V. The biology of the 17-1A antigen (Ep-CAM). J. Mol. Med. 77, 699–712 (1999).

    Article  CAS  PubMed  Google Scholar 

  142. Munz, M. et al. The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation. Oncogene 23, 5748–5758 (2004).

    Article  PubMed  CAS  Google Scholar 

  143. Beverley, P., Olabiran, Y., Ledermann, J., Bobrow, L. & Souhami, L. Results of central data analysis. Br. J. Cancer Suppl. 14, 10–19 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Oppenheimer, N. J. & Bodley, J. W. Diphtheria toxin. Site and configuration of ADP-ribosylation of diphthamide in elongation factor 2. J. Biol. Chem. 256, 8579–8581 (1981).

    Article  CAS  PubMed  Google Scholar 

  145. Kowalski, M. et al. A phase II study of oportuzumab monatox: an immunotoxin therapy for patients with noninvasive urothelial carcinoma in situ previously treated with bacillus Calmette-Guerin. J. Urol. 188, 1712–1718 (2012).

    Article  CAS  PubMed  Google Scholar 

  146. Pietzak, E. J. et al. Next-generation sequencing of nonmuscle invasive bladder cancer reveals potential biomarkers and rational therapeutic targets. Eur. Urol. 72, 952–959 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Garczyk, S. et al. Next-generation sequencing reveals potential predictive biomarkers and targets of therapy for urothelial carcinoma in situ of the urinary bladder. Am. J. Pathol. 190, 323–332 (2020).

    Article  PubMed  Google Scholar 

  148. van Kessel, K. E. M. et al. Molecular markers increase precision of the European Association of Urology Non-Muscle-Invasive Bladder Cancer Progression Risk Groups. Clin. Cancer Res. 24, 1586–1593 (2018).

    Article  PubMed  CAS  Google Scholar 

  149. van Rhijn, B. W. 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. 21, 1912–1921 (2003).

    Article  PubMed  CAS  Google Scholar 

  150. Bakkar, A. A. et al. FGFR3 and TP53 gene mutations define two distinct pathways in urothelial cell carcinoma of the bladder. Cancer Res. 63, 8108–8112 (2003).

    CAS  PubMed  Google Scholar 

  151. Turner, N. & Grose, R. Fibroblast growth factor signalling: from development to cancer. Nat. Rev. Cancer 10, 116–129 (2010).

    Article  CAS  PubMed  Google Scholar 

  152. Kandimalla, R. et al. Genome-wide analysis of CpG island methylation in bladder cancer identified TBX2, TBX3, GATA2, and ZIC4 as pTa-specific prognostic markers. Eur. Urol. 61, 1245–1256 (2012).

    Article  CAS  PubMed  Google Scholar 

  153. Hurst, C. D., Platt, F. M., Taylor, C. F. & Knowles, M. A. Novel tumor subgroups of urothelial carcinoma of the bladder defined by integrated genomic analysis. Clin. Cancer Res. 18, 5865–5877 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Hurst, C. D. et al. Genomic subtypes of non-invasive bladder cancer with distinct metabolic profile and female gender bias in KDM6A mutation frequency. Cancer Cell 32, 701–715.e7 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Petljak, M. et al. Characterizing mutational signatures in human cancer cell lines reveals episodic APOBEC mutagenesis. Cell 176, 1282–1294.e20 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Venkatesan, S. et al. Perspective: APOBEC mutagenesis in drug resistance and immune escape in HIV and cancer evolution. Ann. Oncol. 29, 563–572 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Law, E. K. et al. APOBEC3A catalyzes mutation and drives carcinogenesis in vivo. J. Exp. Med. https://doi.org/10.1084/jem.20200261 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Lipponen, P. K., Eskelinen, M. J., Jauhiainen, K., Harju, E. & Terho, R. Tumour infiltrating lymphocytes as an independent prognostic factor in transitional cell bladder cancer. Eur. J. Cancer 29A, 69–75 (1992).

    CAS  PubMed  Google Scholar 

  160. Patschan, O. et al. A molecular pathologic framework for risk stratification of stage T1 urothelial carcinoma. Eur. Urol. 68, 824–832 (2015).

    Article  CAS  PubMed  Google Scholar 

  161. Ayari, C. et al. High level of mature tumor-infiltrating dendritic cells predicts progression to muscle invasion in bladder cancer. Hum. Pathol. 44, 1630–1637 (2013).

    Article  CAS  PubMed  Google Scholar 

  162. Lindskrog, S. V. et al. An integrated multi-omics analysis identifies prognostic molecular subtypes of non-muscle-invasive bladder cancer. Nat. Commun. 12, 2301 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. S.H. Ho Urology Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China

    Jeremy Yuen-Chun Teoh

  2. European Association of Urology-Young Academic Urologists (EAU-YAU) Urothelial Cancer Working Group, Amsterdam, Netherlands

    Jeremy Yuen-Chun Teoh

  3. The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Ashish M. Kamat

  4. Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada

    Peter C. Black

  5. Division of Oncology, Department of Medicine, University of Washington, Washington, USA

    Petros Grivas

  6. Fred Hutchinson Cancer Research Center, Seattle Cancer Care Alliance, Seattle, WA, USA

    Petros Grivas

  7. Department of Urology, Medical University of Vienna, Vienna, Austria

    Shahrokh F. Shariat & Marek Babjuk

  8. Department of Urology, Weill Cornell Medical College, New York, NY, USA

    Shahrokh F. Shariat

  9. Department of Urology, University of Texas Southwestern, Dallas, TX, USA

    Shahrokh F. Shariat

  10. Institute for Urology and Reproductive Health, Sechenov University, Moscow, Russia

    Shahrokh F. Shariat

  11. Hourani Center for Applied Scientific Research, Al-Ahliyya Amman University, Amman, Jordan

    Shahrokh F. Shariat

  12. Department of Urology, 2nd Faculty of Medicine, Hospital Motol, Charles University, Prague, Czech Republic

    Shahrokh F. Shariat & Marek Babjuk

Authors
  1. Jeremy Yuen-Chun Teoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ashish M. Kamat
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter C. Black
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Petros Grivas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shahrokh F. Shariat
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marek Babjuk
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

J.Y.-C.T. researched data for the article. All authors contributed substantially to discussion of the content. All authors wrote the article. All authors reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Jeremy Yuen-Chun Teoh.

Ethics declarations

Competing interests

J.Y.-C.T. holds investigator grants from Baxter, Bristol-Myers Squibb, Janssen, Ferring, Merck Sharp & Dohme, Storz and Olympus, is an advisory board member for Astellas, Ferring and Janssen, is a consultant for Astellas, Ferring, Janssen and MRI PRO and received an honorarium from Astellas, Boston Scientific, Combat Medical, Ferring, Janssen, Olympus and Sanofi. A.M.K. holds investigator grants from FKD Industries, Merck, Photocure, BMS, SWOG, NIH, AIBCCR, Heat Biologics, Adolor, Alere, Pacific Edge, Telesta, Celgene, TetraLogic and FAMRI and is an advisory board member for Merck, BMS, Eisai, Arquer, MDx Health, Photocure, AstraZeneca, Abbott Molecular, US Biotest, Ferring, BioClin, FKD Industries, Genentech, Allergan, Incyte, Telesta, Aurasence, Taris, Oncogenex, Sanofi, Pfizer, Theralase, Cepheid, Medac, Asieris, Synergo, Combat and Imagin. P.C.B. holds investigator grants from iProgen, GSK and GenomeDx Biosciences, is an advisory board member for Astellas, AbbVie, AstraZeneca, Bayer, Biosyent, BMS, Ferring, Janssen, MDxHealth, Merck, Roche, Sanofi and UroGen and is a consultant for Bayer, Janssen, Roche and Sanofi. P.G. holds investigator grants from Bavarian Nordic, Bristol Myers Squibb, Clovis Oncology, Debiopharm, EMD Serono, GlaxoSmithKline, Immunomedics/Gilead, Merck, Mirati Therapeutics, Pfizer, QED Therapeutics and G1 Therapeutics, and is a consultant for AstraZeneca, Astellas Pharma, Bayer, Bristol Myers Squibb, Clovis Oncology, Dyania Health, EMD Serono, Exelixis, Foundation Medicine, Genentech/Roche, Genzyme, GlaxoSmithKline, Guardant Health, Immunomedics/Gilead, Infinity Pharmaceuticals, Janssen, Merck, Mirati Therapeutics, Pfizer, QED Therapeutics, Regeneron Pharmaceuticals, Seattle Genetics, 4D Pharma PLC and UroGen. S.F.S., is a consultant for Olympus and Janssen and received an honorarium from Astellas, AstraZeneca, Bayer, BMS, Cepheid, Ferring, Ipsen, Janssen, Lilly and UroGen Pharma. M.B. is a consultant for Astellas and Ipsen and received an honorarium from Ipsen, Janssen, Olympus and Astellas.

Peer review

Peer review information

Nature Reviews Urology thanks P. U. Malmstrom, M. Oya and M. O’Donnell for their contribution to the peer review of this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Teoh, J.YC., Kamat, A.M., Black, P.C. et al. Recurrence mechanisms of non-muscle-invasive bladder cancer — a clinical perspective. Nat Rev Urol 19, 280–294 (2022). https://doi.org/10.1038/s41585-022-00578-1

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41585-022-00578-1

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing