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.

  • Review Article
  • Published:

Low-grade non-muscle-invasive bladder cancer: molecular landscape, treatment strategies and emerging therapies

Nature Reviews Urology volume 22, pages 846–861 (2025)Cite this article

Subjects

Abstract

Low-grade non-muscle invasive bladder cancer is a specific category of bladder cancer with a favourable prognosis; however, its management presents several challenges. The risk of stage progression is very low, but approximately half of patients will experience recurrence within the first 5 years after diagnosis. This high propensity for recurrence, coupled with the threat of progression, mandates ongoing surveillance. However, the optimal frequency and duration of follow-up monitoring remain undefined. Current management strategies for low-grade non-muscle invasive bladder cancer rely heavily on routine office cystoscopy, with few advances in diagnostic and treatment options over the past 25 years. Our basic understanding of disease biology has substantially advanced. However, at present, considerable variations in clinical practice exist, with implications for increased financial and treatment burden for patients and health care systems. Molecular signatures and biomarker discoveries are crucial to understand disease behaviour and inform novel treatment strategies. Emerging therapies, such as advanced drug-delivery systems, immunomodulatory agents and targeted therapies, offer the potential to improve patient outcomes, streamline management and reduce the need for surveillance cystoscopies. Actionable avenues for future research in the field include prospective validation of novel biomarkers and therapies with the ultimate aim of optimizing patient care and reducing health care costs.

Key points

  • Tumour grade is one of the most important prognostic features in non-muscle invasive bladder cancer (NMIBC) and low-grade disease accounts for half of patients with NMIBC at presentation. Low-grade tumours are characterized by a high propensity to recur, with a lifetime average of 6.6 recurrences per patient. The risk of recurrence is highest within the first 5 years following diagnosis and reduces thereafter. This feature of disease contributes to the overall high cost of bladder cancer care.

  • Low-grade NMIBC is associated with a low rate of progression to an increased stage or grade (3–19%). Risk of progression to muscle-invasive bladder cancer is 1.6% overall but can be as high as 8.3% in patients who have multiple risk factors as defined by the International Bladder Cancer Group intermediate-risk NMIBC scoring system.

  • Current management challenges in low-grade NMIBC reflect the lack of consensus of the most optimal surveillance frequency and intensity. High use of surveillance cystoscopy results in escalating health care costs without affecting disease outcome.

  • Low-grade NMIBC exhibits relative molecular homogeneity and low tumour mutational burden compared with high-grade NMIBC and MIBC, with increased prevalence of gain-of-function alterations in FGFR3, RAS and PIK3CA. Low-grade NMIBC lacks molecular aberrations in commonly mutated genes prevalent in advanced disease (TP53, CDKN1A, RB1, ERCC2, ERBB3 and FBXW7). These differences highlight distinct pathways of oncogenesis and hint at differences in therapeutic strategies.

  • Bladder cancer is unique in that tumour cells and associated proteins are continuously in contact with and shed into the urine, which can be leveraged using non-invasive urine-based biomarkers. Urine cytology remains one of the only biomarkers endorsed by professional guidelines in NMIBC surveillance algorithms, but has low sensitivity, especially for low-grade disease.

  • Emerging therapies and innovations in drug delivery, immunomodulation and targeted treatments offer promising avenues to enhance the efficacy of treatment while potentially reducing the need for invasive follow-up procedures.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

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

Fig. 1: Genetic pathway for low-grade and high-grade non-muscle-invasive bladder cancer.
Fig. 2: Clinical de-escalation pathway in low-grade non-muscle-invasive bladder cancer.

Similar content being viewed by others

References

  1. Zhang, Y. et al. The global landscape of bladder cancer incidence and mortality in 2020 and projections to 2040. J. Glob. Health 13, 04109 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Jubber, I. et al. Epidemiology of bladder cancer in 2023: a systematic review of risk factors. Eur. Urol. 84, 176–190 (2023).

    Article  PubMed  Google Scholar 

  3. Lopez-Beltran, A., Cookson, M. S., Guercio, B. J. & Cheng, L. Advances in diagnosis and treatment of bladder cancer. BMJ 384, e076743 (2024).

    Article  CAS  PubMed  Google Scholar 

  4. van Rhijn, B. W. G. et al. Prognostic value of the WHO1973 and WHO2004/2016 classification systems for grade in primary Ta/T1 non-muscle-invasive bladder cancer: a multicenter European Association of Urology non-muscle-invasive bladder cancer guidelines panel study. Eur. Urol. Oncol. 4, 182–191 (2021).

    Article  PubMed  Google Scholar 

  5. Falke, J. & Witjes, J. A. Contemporary management of low-risk bladder cancer. Nat. Rev. Urol. 8, 42–49 (2011).

    Article  PubMed  Google Scholar 

  6. Messing, E. M. et al. Effect of intravesical instillation of gemcitabine vs saline immediately following resection of suspected low-grade non-muscle-invasive bladder cancer on tumor recurrence: SWOG S0337 randomized clinical trial. JAMA 319, 1880–1888 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Joyce, D. D., Sharma, V. & Williams, S. B. Cost-effectiveness and economic impact of bladder cancer management: an updated review of the literature. Pharmacoeconomics 41, 751–769 (2023).

    Article  PubMed  Google Scholar 

  8. Holzbeierlein, J. M. et al. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline: 2024 amendment. J. Urol. 211, 533–538 (2024).

    Article  PubMed  Google Scholar 

  9. Sylvester, R. J. et al. European Association of Urology (EAU) prognostic factor risk groups for non-muscle-invasive bladder cancer (NMIBC) incorporating the WHO 2004/2016 and WHO 1973 classification systems for grade: an update from the EAU NMIBC guidelines panel. Eur. Urol. 79, 480–488 (2021).

    Article  PubMed  Google Scholar 

  10. Bree, K. K. et al. Management, surveillance patterns, and costs associated with low-grade papillary stage Ta non-muscle-invasive bladder cancer among older adults, 2004–2013. JAMA Netw. Open. 5, e223050–e223050 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  11. Jung, A. et al. Quality of life in non-muscle-invasive bladder cancer survivors: a systematic review. Cancer Nurs. 42, E21–E33 (2019).

    Article  PubMed  Google Scholar 

  12. Koo, K. et al. The burden of cystoscopic bladder cancer surveillance: anxiety, discomfort, and patient preferences for decision making. Urology 108, 122–128 (2017).

    Article  PubMed  Google Scholar 

  13. Chang, S. S. et al. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline. J. Urol. 196, 1021–1029 (2016).

    Article  PubMed  Google Scholar 

  14. Babjuk, M. et al. EAU guidelines on non-muscle-invasive urothelial carcinoma of the bladder: update 2016. Eur. Urol. 71, 447–461 (2017).

    Article  PubMed  Google Scholar 

  15. Gontero, P. et al. European Association of Urology guidelines on non-muscle-invasive bladder cancer (TaT1 and carcinoma in situ) — a summary of the 2024 guidelines update. Eur. Urol. 86, 531–549 (2024).

    Article  PubMed  Google Scholar 

  16. Raspollini, M. R. et al. News in the classification of WHO 2022 bladder tumors. Pathologica 115, 32–40 (2022).

    PubMed  Google Scholar 

  17. Barkan, G. A. et al. The Paris system for reporting urinary cytology: the quest to develop a standardized terminology. Acta Cytol. 60, 185–197 (2016).

    Article  PubMed  Google Scholar 

  18. Humphrey, P. A. Tumor amount in prostatic tissues in relation to patient outcome and management. Am. J. Clin. Pathol. 131, 7–10 (2009).

    Article  PubMed  Google Scholar 

  19. Reis, L. O. et al. Significance of a minor high-grade component in a low-grade noninvasive papillary urothelial carcinoma of bladder. Hum. Pathol. 47, 20–25 (2016).

    Article  PubMed  Google Scholar 

  20. US National Library of Medicine. ClinicalTrials.gov https://Clinicaltrials.Gov/Study/NCT06319820 (2025).

  21. Matulay, J. T. et al. Risk-adapted management of low-grade bladder tumours: recommendations from the International Bladder Cancer Group (IBCG). BJU Int. 125, 497–505 (2020).

    Article  PubMed  Google Scholar 

  22. 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, 466–465 (2006). discussion 475–477.

    Article  PubMed  Google Scholar 

  23. Soria, F. et al. Clinical validation of the intermediate-risk non-muscle-invasive bladder cancer scoring system and substratification model proposed by the International Bladder Cancer Group: a multicenter young academic urologists urothelial working group collaboration. Eur. Urol. Oncol. 7, 1497–1503 (2024).

    Article  PubMed  Google Scholar 

  24. Ma, J. et al. Long-term recurrence rates of low-risk non-muscle-invasive bladder cancer-how long is cystoscopic surveillance necessary? Eur. Urol. Focus. 10, 189–196 (2024).

    Article  PubMed  Google Scholar 

  25. Miyamoto, H. et al. Low-grade papillary urothelial carcinoma of the urinary bladder: a clinicopathologic analysis of a post-World Health Organization/International Society of Urological Pathology classification cohort from a single academic center. Arch. Pathol. Lab. Med. 134, 1160–1163 (2010).

    Article  PubMed  Google Scholar 

  26. Herr, H. W., Donat, S. M. & Reuter, V. E. Management of low grade papillary bladder tumors. J. Urol. 178, 1201–1205 (2007). discussion 1205.

    Article  PubMed  Google Scholar 

  27. Fitzpatrick, J. M., West, A. B., Butler, M. R., Lane, V. & O’Flynn, J. D. Superficial bladder tumors (stage pTa, grades 1 and 2): the importance of recurrence pattern following initial resection. J. Urol. 135, 920–922 (1986).

    Article  CAS  PubMed  Google Scholar 

  28. Hernández, V. et al. Long-term oncological outcomes of an active surveillance program in recurrent low grade Ta bladder cancer. Urol. Oncol. 34, 165.e19–23 (2016).

    Article  PubMed  Google Scholar 

  29. Zhang, J. H. et al. National complication and cost burden of transurethral resection of bladder tumor for bladder cancer. Urol. Oncol. 43, 469.e1–469.e11 (2025).

    Article  PubMed  Google Scholar 

  30. Dyrskjøt, L. et al. Bladder cancer. Nat. Rev. Dis. Prim. 9, 58 (2023).

    Article  PubMed  Google Scholar 

  31. Van Batavia, J. et al. Bladder cancers arise from distinct urothelial sub-populations. Nat. Cell Biol. 16, 982–991 (2014). 1–5.

    Article  PubMed  Google Scholar 

  32. Acharya, P. et al. Distribution of the tight junction proteins ZO-1, occludin, and claudin-4, -8, and -12 in bladder epithelium. Am. J. Physiol. Renal Physiol. 287, F305–F318 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Wiessner, G. B., Plumber, S. A., Xiang, T. & Mendelsohn, C. L. Development, regeneration and tumorigenesis of the urothelium. Dev. Camb. Engl. 149, dev198184 (2022).

    CAS  Google Scholar 

  34. Shin, K. et al. Cellular origin of bladder neoplasia and tissue dynamics of its progression to invasive carcinoma. Nat. Cell Biol. 16, 469–478 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Papafotiou, G. et al. KRT14 marks a subpopulation of bladder basal cells with pivotal role in regeneration and tumorigenesis. Nat. Commun. 7, 11914 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Li, R. et al. Effects of thiazolidinedione in patients with active bladder cancer. BJU Int. 121, 244–251 (2018).

    Article  CAS  PubMed  Google Scholar 

  37. Warrick, J. I. et al. FOXA1, GATA3 and PPARɣ cooperate to drive luminal subtype in bladder cancer: a molecular analysis of established human cell lines. Sci. Rep. 6, 38531 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hedegaard, J. et al. Comprehensive transcriptional analysis of early-stage urothelial carcinoma. Cancer Cell 30, 27–42 (2016).

    Article  CAS  PubMed  Google Scholar 

  39. Tate, T. et al. Pparg signaling controls bladder cancer subtype and immune exclusion. Nat. Commun. 12, 6160 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Halstead, A. M. et al. Bladder-cancer-associated mutations in RXRA activate peroxisome proliferator-activated receptors to drive urothelial proliferation. eLife 6, e30862 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  41. 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 

  42. Erdmann, E., Harding, S., Lam, H. & Perez, A. Ten-year observational follow-up of PROactive: a randomized cardiovascular outcomes trial evaluating pioglitazone in type 2 diabetes. Diabetes Obes. Metab. 18, 266–273 (2016).

    Article  CAS  PubMed  Google Scholar 

  43. Lewis, J. D. et al. Pioglitazone use and risk of bladder cancer and other common cancers in persons with diabetes. JAMA 314, 265–277 (2015).

    Article  CAS  PubMed  Google Scholar 

  44. Tate, T. et al. Combined Mek inhibition and Pparg activation eradicates muscle invasive bladder cancer in a mouse model of BBN-induced carcinogenesis. BioRxiv Prepr. Serv. Biol. https://doi.org/10.1101/2023.08.19.553961 (2023).

  45. Sjödahl, G. et al. A molecular taxonomy for urothelial carcinoma. Clin. Cancer Res. 18, 3377–3386 (2012).

    Article  PubMed  Google Scholar 

  46. Guo, Y. et al. TSC1 involvement in bladder cancer: diverse effects and therapeutic implications. J. Pathol. 230, 17–27 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Hurst, C. D. & Knowles, M. A. Mutational landscape of non-muscle-invasive bladder cancer. Urol. Oncol. 40, 295–303 (2022).

    Article  CAS  PubMed  Google Scholar 

  48. Minner, S. et al. Y chromosome loss is a frequent early event in urothelial bladder cancer. Pathology 42, 356–359 (2010).

    Article  PubMed  Google Scholar 

  49. 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 

  50. Ascione, C. M. et al. Role of FGFR3 in bladder cancer: treatment landscape and future challenges. Cancer Treat. Rev. 115, 102530 (2023).

    Article  CAS  PubMed  Google Scholar 

  51. Wu, Y.-M. et al. Identification of targetable FGFR gene fusions in diverse cancers. Cancer Discov. 3, 636–647 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wang, C. G., Peiris, M. N., Meyer, A. N., Nelson, K. N. & Donoghue, D. J. Oncogenic driver FGFR3-TACC3 requires five coiled-coil heptads for activation and disulfide bond formation for stability. Oncotarget 14, 133–145 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. di Martino, E., L’Hôte, C. G., Kennedy, W., Tomlinson, D. C. & Knowles, M. A. Mutant fibroblast growth factor receptor 3 induces intracellular signaling and cellular transformation in a cell type- and mutation-specific manner. Oncogene 28, 4306–4316 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Tomlinson, D. C., Baldo, O., Harnden, P. & Knowles, M. A. FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer. J. Pathol. 213, 91–98 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hernández, S. et al. Prospective study of FGFR3 mutations as a prognostic factor in nonmuscle invasive urothelial bladder carcinomas. J. Clin. Oncol. 24, 3664–3671 (2006).

    Article  PubMed  Google Scholar 

  56. van Rhijn, B. W. et al. The fibroblast growth factor receptor 3 (FGFR3) mutation is a strong indicator of superficial bladder cancer with low recurrence rate. Cancer Res. 61, 1265–1268 (2001).

    PubMed  Google Scholar 

  57. Jebar, A. H. et al. FGFR3 and Ras gene mutations are mutually exclusive genetic events in urothelial cell carcinoma. Oncogene 24, 5218–5225 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Zhang, Z. T. et al. Role of Ha-ras activation in superficial papillary pathway of urothelial tumor formation. Oncogene 20, 1973–1980 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Mo, L. et al. Hyperactivation of Ha-ras oncogene, but not Ink4a/Arf deficiency, triggers bladder tumorigenesis. J. Clin. Invest. 117, 314–325 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Urakami, S. et al. Recurrent transitional cell carcinoma in a child with the Costello syndrome. J. Urol. 168, 1133–1134 (2002).

    Article  PubMed  Google Scholar 

  61. Hurst, C. D. et al. Stage-stratified molecular profiling of non-muscle-invasive bladder cancer enhances biological, clinical, and therapeutic insight. Cell Rep. Med. 2, 100472 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. López-Knowles, E. et al. PIK3CA mutations are an early genetic alteration associated with FGFR3 mutations in superficial papillary bladder tumors. Cancer Res. 66, 7401–7404 (2006).

    Article  PubMed  Google Scholar 

  63. Facchinetti, F. et al. Resistance to selective FGFR inhibitors in FGFR-driven urothelial cancer. Cancer Discov. 13, 1998–2011 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Wolff, E. M. et al. Unique DNA methylation patterns distinguish noninvasive and invasive urothelial cancers and establish an epigenetic field defect in premalignant tissue. Cancer Res. 70, 8169–8178 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Hu, D. et al. The MLL3/MLL4 branches of the COMPASS family function as major histone H3K4 monomethylases at enhancers. Mol. Cell. Biol. 33, 4745–4754 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Yoo, K. H. et al. Histone demethylase KDM6A controls the mammary luminal lineage through enzyme-independent mechanisms. Mol. Cell. Biol. 36, 2108–2120 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Barrows, D., Feng, L., Carroll, T. S. & Allis, C. D. Loss of UTX/KDM6A and the activation of FGFR3 converge to regulate differentiation gene-expression programs in bladder cancer. Proc. Natl Acad. Sci. USA 117, 25732–25741 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Babjuk, M. et al. European Association of Urology guidelines on non-muscle-invasive bladder cancer (Ta, T1, and carcinoma in situ). Eur. Urol. 81, 75–94 (2022).

    Article  PubMed  Google Scholar 

  69. Papanicolaou, G. N. Cytology of the urine sediment in neoplasms of the urinary tract. J. Urol. 57, 375–379 (1947).

    Article  CAS  PubMed  Google Scholar 

  70. Raab, S. S., Grzybicki, D. M., Vrbin, C. M. & Geisinger, K. R. Urine cytology discrepancies: frequency, causes, and outcomes. Am. J. Clin. Pathol. 127, 946–953 (2007).

    Article  PubMed  Google Scholar 

  71. Nguyen, G.-K. & Smith, R. Repair renal tubular cells: a potential false-positive diagnosis in urine cytology. Diagn. Cytopathol. 31, 342–346 (2004).

    Article  PubMed  Google Scholar 

  72. Brown, F. M. Urine cytology. It is still the gold standard for screening? Urol. Clin. North Am. 27, 25–37 (2000).

    Article  CAS  PubMed  Google Scholar 

  73. Choi, S.-Y., Kim, K.-H., Suh, K.-S. & Yeo, M.-K. Diagnostic significance of dual immunocytochemical staining of p53/cytokeratin20 on liquid-based urine cytology to detect urothelial carcinoma. Cytojournal 17, 3 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Yafi, F. A. et al. Prospective analysis of sensitivity and specificity of urinary cytology and other urinary biomarkers for bladder cancer. Urol. Oncol. 33, 66.e25–66.e31 (2015).

    Article  PubMed  Google Scholar 

  75. Matulay, J. T. et al. Variability in adherence to guidelines based management of nonmuscle invasive bladder cancer among Society of Urologic Oncology (SUO) members. Urol. Oncol. 38, 796.e1–796.e6 (2020).

    Article  PubMed  Google Scholar 

  76. Allard, P., Fradet, Y., Têtu, B. & Bernard, P. Tumor-associated antigens as prognostic factors for recurrence in 382 patients with primary transitional cell carcinoma of the bladder. Clin. Cancer Res. 1, 1195–1202 (1995).

    CAS  PubMed  Google Scholar 

  77. Comploj, E. et al. uCyt+/ImmunoCyt and cytology in the detection of urothelial carcinoma. Cancer Cytopathol. 121, 392–397 (2013).

    Article  PubMed  Google Scholar 

  78. Hirasawa, Y. et al. Diagnostic performance of OncuriaTM, a urinalysis test for bladder cancer. J. Transl. Med. 19, 141–141 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Wang, Z. et al. Evaluation of the NMP22 BladderChek test for detecting bladder cancer: a systematic review and meta-analysis. Oncotarget 8, 100648–100656 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Landman, J., Chang, Y., Kavaler, E., Droller, M. J. & Liu, B. C.-S. Sensitivity and specificity of NMP-22, telomerase, and BTA in the detection of human bladder cancer. Urology 52, 398–402 (1998).

    Article  CAS  PubMed  Google Scholar 

  81. Sarosdy, M. F. et al. Improved detection of recurrent bladder cancer using the Bard BTA stat Test. Urology 50, 349–353 (1997).

    Article  CAS  PubMed  Google Scholar 

  82. Thomas, L. et al. Multicenter trial of the quantitative BTA TRAK assay in the detection of bladder cancer. Clin. Chem. 45, 472–477 (1999).

    CAS  PubMed  Google Scholar 

  83. Darling, D., Luxmanan, C., O’Sullivan, P., Lough, T. & Suttie, J. Clinical utility of Cxbladder for the diagnosis of urothelial carcinoma. Adv. Ther. 34, 1087–1096 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Laukhtina, E. et al. Diagnostic accuracy of novel urinary biomarker tests in non-muscle-invasive bladder cancer: a systematic review and network meta-analysis. Eur. Urol. Oncol. 4, 927–942 (2021).

    Article  PubMed  Google Scholar 

  85. Kavalieris, L. et al. Performance characteristics of a multigene urine biomarker test for monitoring for recurrent urothelial carcinoma in a multicenter study. J. Urol. 197, 1419–1426 (2017).

    Article  PubMed  Google Scholar 

  86. Cancel-Tassin, G. et al. Assessment of Xpert bladder cancer monitor test performance for the detection of recurrence during non-muscle invasive bladder cancer follow-up. World J. Urol. 39, 3329–3335 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Sharma, G., Sharma, A., Krishna, M., Devana, S. K. & Singh, S. K. Xpert bladder cancer monitor in surveillance of bladder cancer: systematic review and meta-analysis. Urol. Oncol. Semin. Orig. Investig. 40, 163.e1–163.e9 (2022).

    Google Scholar 

  88. Witjes, J. A. et al. Performance of the bladder EpiCheckTM methylation test for patients under surveillance for non-muscle-invasive bladder cancer: results of a multicenter, prospective, blinded clinical trial. Eur. Urol. Oncol. 1, 307–313 (2018).

    Article  PubMed  Google Scholar 

  89. Beukers, W. et al. FGFR3, TERT and OTX1 as a urinary biomarker combination for surveillance of patients with bladder cancer in a large prospective multicenter study. J. Urol. 197, 1410–1418 (2017).

    Article  CAS  PubMed  Google Scholar 

  90. Moonen, P. M. J. et al. UroVysion compared with cytology and quantitative cytology in the surveillance of non-muscle-invasive bladder cancer. Eur. Urol. 51, 1275–1280 (2007).

    Article  PubMed  Google Scholar 

  91. Lotan, Y. et al. Evaluation of the fluorescence in situ hybridization test to predict recurrence and/or progression of disease after bacillus Calmette-Guérin for primary high grade nonmuscle invasive bladder cancer: results from a prospective multicenter trial. J. Urol. 202, 920–926 (2019).

    Article  PubMed  Google Scholar 

  92. HALLING, K. C. et al. A comparison of cytology and fluorescence in situ hybridization for the detection of urothelial carcinoma. J. Urol. 164, 1768–1775 (2000).

    Article  CAS  PubMed  Google Scholar 

  93. Dudley, J. C. et al. Detection and surveillance of bladder cancer using urine tumor DNA. Cancer Discov. 9, 500–509 (2019).

    Article  CAS  PubMed  Google Scholar 

  94. Salari, K. et al. Development and multicenter case-control validation of urinary comprehensive genomic profiling for urothelial carcinoma diagnosis, surveillance, and risk-prediction. Clin. Cancer Res. 29, 3668–3680 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507, 315–322 (2014).

    Article  Google Scholar 

  96. Prip, F. et al. Comprehensive genomic characterization of early-stage bladder cancer. Nat. Genet. 57, 115–125 (2025).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Huelster, H. L. et al. Novel use of circulating tumor DNA to identify muscle-invasive and non-organ-confined upper tract urothelial carcinoma. Eur. Urol. 85, 283–292 (2024).

    Article  CAS  PubMed  Google Scholar 

  98. Chauhan, P. S. et al. Urine tumor DNA detection of minimal residual disease in muscle-invasive bladder cancer treated with curative-intent radical cystectomy: a cohort study. PLoS Med. 18, e1003732 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Shkolyar, E. et al. Augmented bladder tumor detection using deep learning. Eur. Urol. 76, 714–718 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Compérat, E. M. et al. Grading of urothelial carcinoma and the new ‘World Health Organisation classification of tumours of the urinary system and male genital organs 2016’. Eur. Urol. Focus. 5, 457–466 (2019).

    Article  PubMed  Google Scholar 

  101. Jansen, I. et al. Automated detection and grading of non-muscle-invasive urothelial cell carcinoma of the bladder. Am. J. Pathol. 190, 1483–1490 (2020).

    Article  PubMed  Google Scholar 

  102. Rose, K. et al. Complimentary genomic, pathologic, and artificial intelligence analysis on low-grade noninvasive bladder cancer to predict downstream recurrence. J. Clin. Oncol. 41, 6 (2023).

    Article  Google Scholar 

  103. US National Library of Medicine. ClinicalTrials.gov https://Clinicaltrials.Gov/Study/NCT03988309 (2025).

  104. Chou, R. et al. Intravesical therapy for the treatment of nonmuscle invasive bladder cancer: a systematic review and meta-analysis. J. Urol. 197, 1189–1199 (2017).

    Article  PubMed  Google Scholar 

  105. Dalton, J. T., Wientjes, M. G., Badalament, R. A., Drago, J. R. & Au, J. L. Pharmacokinetics of intravesical mitomycin C in superficial bladder cancer patients. Cancer Res. 51, 5144–5152 (1991).

    CAS  PubMed  Google Scholar 

  106. Addeo, R. et al. Randomized phase III trial on gemcitabine versus mytomicin in recurrent superficial bladder cancer: evaluation of efficacy and tolerance. J. Clin. Oncol. 28, 543–548 (2010).

    Article  CAS  PubMed  Google Scholar 

  107. Sylvester, R. J., Oosterlinck, W. & van der Meijden, A. P. M. A single immediate postoperative instillation of chemotherapy decreases the risk of recurrence in patients with stage Ta T1 bladder cancer: a meta-analysis of published results of randomized clinical trials. J. Urol. 171, 2186–2190 (2004). quiz 2435.

    Article  PubMed  Google Scholar 

  108. 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 

  109. Gudjónsson, S. et al. Should all patients with non-muscle-invasive bladder cancer receive early intravesical chemotherapy after transurethral resection? The results of a prospective randomised multicentre study. Eur. Urol. 55, 773–780 (2009).

    Article  PubMed  Google Scholar 

  110. Bosschieter, J. 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. 73, 226–232 (2018).

    Article  CAS  PubMed  Google Scholar 

  111. Tan, W. S. et al. Intermediate-risk non-muscle-invasive bladder cancer: updated consensus definition and management recommendations from the International Bladder Cancer Group. Eur. Urol. Oncol. 5, 505–516 (2022).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  113. Böhle, A., Jocham, D. & Bock, P. R. Intravesical bacillus Calmette-Guerin versus mitomycin C for superficial bladder cancer: a formal meta-analysis of comparative studies on recurrence and toxicity. J. Urol. 169, 90–95 (2003).

    Article  PubMed  Google Scholar 

  114. Chen, S., Zhang, N., Shao, J. & Wang, X. Maintenance versus non-maintenance intravesical Bacillus Calmette-Guerin instillation for non-muscle invasive bladder cancer: a systematic review and meta-analysis of randomized clinical trials. Int. J. Surg. 52, 248–257 (2018).

    Article  PubMed  Google Scholar 

  115. Hinotsu, S. et al. Maintenance therapy with bacillus Calmette-Guérin Connaught strain clearly prolongs recurrence-free survival following transurethral resection of bladder tumour for non-muscle-invasive bladder cancer. BJU Int. 108, 187–195 (2011).

    Article  PubMed  Google Scholar 

  116. Malmström, 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-Guérin for non-muscle-invasive bladder cancer. Eur. Urol. 56, 247–256 (2009).

    Article  PubMed  Google Scholar 

  117. Marttila, T. et al. Intravesical Bacillus Calmette-Guérin versus combination of epirubicin and interferon-α2a in reducing recurrence of non-muscle-invasive bladder carcinoma: FinnBladder-6 study. Eur. Urol. 70, 341–347 (2016).

    Article  CAS  PubMed  Google Scholar 

  118. Ojea, A. et al. A multicentre, randomised prospective trial comparing three intravesical adjuvant therapies for intermediate-risk superficial bladder cancer: low-dose bacillus Calmette-Guerin (27 mg) versus very low-dose bacillus Calmette-Guerin (13.5 mg) versus mitomycin C. Eur. Urol. 52, 1398–1406 (2007).

    Article  CAS  PubMed  Google Scholar 

  119. Sylvester, R. J. 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. 57, 766–773 (2010).

    Article  PubMed  Google Scholar 

  120. Au, J. L. et al. Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial. J. Natl Cancer Inst. 93, 597–604 (2001).

    Article  CAS  PubMed  Google Scholar 

  121. Schmidt, S. et al. Intravesical Bacillus Calmette-Guérin versus mitomycin C for Ta and T1 bladder cancer: abridged summary of the Cochrane Review. Investig. Clin. Urol. 61, 349–354 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Tan, W. S. et al. Sequential intravesical gemcitabine and docetaxel is an alternative to Bacillus Calmette-Guérin for the treatment of intermediate-risk non-muscle-invasive bladder cancer. Eur. Urol. Oncol. 6, 531–534 (2023).

    Article  PubMed  Google Scholar 

  123. Contieri, R. et al. Deintensification of treatment for low-grade bladder tumors: a collaborative review by the international bladder cancer group (IBCG). Eur. Urol. Oncol. 8, 179–189 (2025).

    Article  PubMed  Google Scholar 

  124. Soloway, M. S., Bruck, D. S. & Kim, S. S. Expectant management of small, recurrent, noninvasive papillary bladder tumors. J. Urol. 170, 438–441 (2003).

    Article  PubMed  Google Scholar 

  125. Hernández, V. et al. Safety of active surveillance program for recurrent nonmuscle-invasive bladder carcinoma. Urology 73, 1306–1310 (2009).

    Article  PubMed  Google Scholar 

  126. Contieri, R. et al. Long-term follow-up and factors associated with active surveillance failure for patients with non-muscle-invasive bladder cancer: the bladder cancer Italian active surveillance (BIAS) experience. Eur. Urol. Oncol. 5, 251–255 (2022).

    Article  PubMed  Google Scholar 

  127. Tan, W. S. et al. International Bladder Cancer Group intermediate-risk nonmuscle-invasive bladder cancer scoring system predicts outcomes of patients on active surveillance. J. Urol. 210, 763–770 (2023).

    Article  PubMed  Google Scholar 

  128. Ge, P. et al. Oncological outcome of primary and secondary muscle-invasive bladder cancer: a systematic review and meta-analysis. Sci. Rep. 8, 7543 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Gofrit, O. N., Zorn, K. C., Shikanov, S. & Steinberg, G. D. Marker lesion experiments in bladder cancer-what have we learned? J. Urol. 183, 1678–1684 (2010).

    Article  CAS  PubMed  Google Scholar 

  130. Gregg, J. R. et al. Short term complications from transurethral resection of bladder tumor. Can. J. Urol. 23, 8198–8203 (2016).

    PubMed  Google Scholar 

  131. Gontero, P. et al. Phase II study to investigate the ablative efficacy of intravesical administration of gemcitabine in intermediate-risk superficial bladder cancer (SBC). Eur. Urol. 46, 339–343 (2004).

    Article  CAS  PubMed  Google Scholar 

  132. Colombo, R. et al. Neoadjuvant short-term intensive intravesical mitomycin C regimen compared with weekly schedule for low-grade recurrent non-muscle-invasive bladder cancer: preliminary results of a randomised phase 2 study. Eur. Urol. 62, 797–802 (2012).

    Article  CAS  PubMed  Google Scholar 

  133. Racioppi, M. et al. Chemoablation with intensive intravesical mitomycin C treatment: a new approach for non-muscle-invasive bladder cancer. Eur. Urol. Oncol. 2, 576–583 (2019).

    Article  PubMed  Google Scholar 

  134. Lindgren, M. S. et al. DaBlaCa-13 study: oncological outcome of short-term, intensive chemoresection with mitomycin in nonmuscle invasive bladder cancer: primary outcome of a randomized controlled trial. J. Clin. Oncol. 41, 206–211 (2023).

    Article  CAS  PubMed  Google Scholar 

  135. Mostafid, A. H. et al. CALIBER: a phase II randomized feasibility trial of chemoablation with mitomycin-C vs surgical management in low-risk non-muscle-invasive bladder cancer. BJU Int. 125, 817–826 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Chevli, K. K. et al. Primary chemoablation of low-grade intermediate-risk nonmuscle-invasive bladder cancer using UGN-102, a mitomycin-containing reverse thermal gel (Optima II): a phase 2b, open-label, single-arm trial. J. Urol. 207, 61–69 (2022).

    Article  PubMed  Google Scholar 

  137. Prasad, S. M. et al. Treatment of low-grade Intermediate-risk nonmuscle-invasive bladder cancer with UGN-102 ± transurethral resection of bladder tumor compared to transurethral resection of bladder tumor monotherapy: a randomized, controlled, phase 3 trial (ATLAS). J. Urol. 210, 619–629 (2023).

    Article  PubMed  Google Scholar 

  138. Prasad, S. M. et al. Primary chemoablation of recurrent low-grade intermediate-risk nonmuscle-invasive bladder cancer with UGN-102: a single-arm, open-label, phase 3 trial (ENVISION). J. Urol. 213, 205–216 (2025).

    Article  PubMed  Google Scholar 

  139. Stover, A. M. et al. Perceived impact on patient routines/responsibilities for surgery and a nonsurgical primary treatment option in recurrent low-grade intermediate-risk nonmuscle-invasive bladder cancer: findings from the ENVISION phase 3 trial. J. Urol. 214, 18–31 (2025).

    Article  PubMed  Google Scholar 

  140. Abufaraj, M., Mostafid, H., Shariat, S. F. & Babjuk, M. What to do during Bacillus Calmette–Guérin shortage? Valid strategies based on evidence. Curr. Opin. Urol. 28, 570–576 (2018).

    Article  PubMed  Google Scholar 

  141. Racioppi, M. et al. ElectroMotive drug administration (EMDA) of mitomycin C as first-line salvage therapy in high risk ‘BCG failure’ non muscle invasive bladder cancer: 3 years follow-up outcomes. BMC Cancer 18, 1224 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Arends, T. J. H. 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. 69, 1046–1052 (2016).

    Article  CAS  PubMed  Google Scholar 

  143. Slater, S. E. et al. The effects and effectiveness of electromotive drug administration and chemohyperthermia for treating non-muscle invasive bladder cancer. Ann. R. Coll. Surg. Engl. 96, 415–419 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Zazzara, M. et al. Electromotive drug administration of mitomycin C (EMDA/MMC) versus intravesical immunotherapy with Bacillus Calmette-Guérin (BCG) in intermediate and high risk non muscle invasive bladder cancer. Urol. Int. 107, 64–71 (2023).

    Article  CAS  PubMed  Google Scholar 

  145. Liem, E. I. M. L., Crezee, H., de la Rosette, J. J. & de Reijke, T. M. Chemohyperthermia in non-muscle-invasive bladder cancer: An overview of the literature and recommendations. Int. J. Hyperthermia 32, 363–373 (2016).

    Article  CAS  PubMed  Google Scholar 

  146. van der Heijden, A. G., Verhaegh, G., Jansen, C. F. J., Schalken, J. A. & Witjes, J. A. Effect of hyperthermia on the cytotoxicity of 4 chemotherapeutic agents currently used for the treatment of transitional cell carcinoma of the bladder: an in vitro study. J. Urol. 173, 1375–1380 (2005).

    Article  PubMed  Google Scholar 

  147. Colombo, R., Salonia, A., Leib, Z., Pavone-Macaluso, M. & Engelstein, D. 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. 107, 912–918 (2011).

    Article  CAS  PubMed  Google Scholar 

  148. Tan, W. S. et al. Adjuvant intravesical chemohyperthermia versus passive chemotherapy in patients with intermediate-risk non-muscle-invasive bladder cancer (HIVEC-II): a phase 2, open-label, randomised controlled trial. Eur. Urol. 83, 497–504 (2023).

    Article  CAS  PubMed  Google Scholar 

  149. Zhao, H. et al. Intravesical chemohyperthermia vs. Bacillus Calmette-Guerin instillation for intermediate- and high-risk non-muscle invasive bladder cancer: a systematic review and meta-analysis. Front. Surg. 8, 775527 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Vilaseca, A. et al. First safety and efficacy results of the TAR-210 erdafitinib (erda) intravesical delivery system in patients (pts) with non-muscle-invasive bladder cancer (NMIBC) with select FGFR alterations (alt). Ann. Oncol. 34, S1343 (2023).

    Article  Google Scholar 

  151. Tyson, M. D. et al. Safety, tolerability, and preliminary efficacy of TAR-200 in patients with muscle-invasive bladder cancer who refused or were unfit for curative-intent therapy: a phase 1 study. J. Urol. 209, 890–900 (2023).

    Article  PubMed  Google Scholar 

  152. Narayan, V. M. et al. Mechanism of action of nadofaragene firadenovec-vncg. Front. Oncol. 14, 1359725 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. 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 

  154. US National Library of Medicine. ClinicalTrials.gov https://Clinicaltrials.Gov/Study/NCT06510374 (2025).

  155. Svatek, R., Bivalacqua, T. & Daneshmand, S. PIVOT-006: A phase 3, randomized study of cretostimogene grenadenorepvec versus observation for the treatment of intermediate risk non-muscle invasive bladder cancer (IR-NMIBC) following transurethral resection of bladder tumor (TURBT). J. Clin. Oncol. 42, 4.

  156. US National Library of Medicine. ClinicalTrials.gov https://Clinicaltrials.Gov/Study/NCT06111235 (2025).

  157. Billerey, C. et al. Frequent FGFR3 mutations in papillary non-invasive bladder (pTa) tumors. Am. J. Pathol. 158, 1955–1959 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Valenza, C. et al. Emerging treatment landscape of non-muscle invasive bladder cancer. Expert. Opin. Biol. Ther. 22, 717–734 (2022).

    Article  CAS  PubMed  Google Scholar 

  159. Loriot, Y. et al. Erdafitinib or chemotherapy in advanced or metastatic urothelial carcinoma. N. Engl. J. Med. 389, 1961–1971 (2023).

    Article  CAS  PubMed  Google Scholar 

  160. US National Library of Medicine. ClinicalTrials.gov https://Clinicaltrials.Gov/Study/NCT02202044 (2019).

  161. US National Library of Medicine. ClinicalTrials.gov https://Clinicaltrials.Gov/Study/NCT06768346 (2025).

  162. US National Library of Medicine. ClinicalTrials.gov https://Clinicaltrials.Gov/Study/NCT00595088 (2019).

  163. US National Library of Medicine. ClinicalTrials.gov https://Clinicaltrials.Gov/Study/NCT05243550 (2024).

  164. US National Library of Medicine. ClinicalTrials.gov https://Clinicaltrials.Gov/Study/NCT02720367 (2020).

  165. US National Library of Medicine. ClinicalTrials.gov https://Clinicaltrials.Gov/Study/NCT05316155 (2025).

  166. US National Library of Medicine. ClinicalTrials.gov https://Clinicaltrials.Gov/Study/NCT03914794 (2025).

  167. US National Library of Medicine. ClinicalTrials.gov https://Clinicaltrials.Gov/Study/NCT03167151 (2020).

Download references

Author information

Author notes

  1. These authors contributed equally: Lexiaochuan Wen, Hiroko Miyagi.

Authors and Affiliations

  1. Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    Lexiaochuan Wen, Hiroko Miyagi, Philippe E. Spiess, Alice Yu & Roger Li

  2. Department of Urology, Columbia University, New York, NY, USA

    Cathy L. Mendelsohn

  3. Department of Urology, Department of Urology, Yale School of Medicine, New Haven, CT, USA

    Wei Shen Tan

  4. Division of Surgery and Interventional Science, University College London, London, UK

    Wei Shen Tan

  5. Department of Urology, University of Washington, Fred Hutchinson Cancer Center, Seattle, WA, USA

    Sarah P. Psutka

  6. Scott Department of Urology, Dan L Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA

    Seth P. Lerner

  7. Department of Pathology and Laboratory Medicine, Department of Surgery (Urology), Brown University Warren Alpert Medical School, the Legorreta Cancer Center at Brown University, Brown University Health, Providence, RI, USA

    Liang Cheng

  8. Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

    Lars Dyrskjøt

  9. Department of Urology, Feinberg School of Medicine, Chicago, IL, USA

    Joshua J. Meeks

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

    Shahrokh F. Shariat

  11. Department of Urology, University of Torino School of Medicine, Torino, Italy

    Paolo Gontero

  12. Department of Urology UROSUD, La Croix Du Sud Hospital, Quint Fonsegrives, France

    Benjamin Pradere

  13. Department of Urology, NYU Langone Health, New York, NY, USA

    Gary D. Steinberg

  14. Department of Urology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Ashish M. Kamat

Authors
  1. Lexiaochuan Wen
    View author publications

    Search author on:PubMed Google Scholar

  2. Hiroko Miyagi
    View author publications

    Search author on:PubMed Google Scholar

  3. Philippe E. Spiess
    View author publications

    Search author on:PubMed Google Scholar

  4. Alice Yu
    View author publications

    Search author on:PubMed Google Scholar

  5. Cathy L. Mendelsohn
    View author publications

    Search author on:PubMed Google Scholar

  6. Wei Shen Tan
    View author publications

    Search author on:PubMed Google Scholar

  7. Sarah P. Psutka
    View author publications

    Search author on:PubMed Google Scholar

  8. Seth P. Lerner
    View author publications

    Search author on:PubMed Google Scholar

  9. Liang Cheng
    View author publications

    Search author on:PubMed Google Scholar

  10. Lars Dyrskjøt
    View author publications

    Search author on:PubMed Google Scholar

  11. Joshua J. Meeks
    View author publications

    Search author on:PubMed Google Scholar

  12. Shahrokh F. Shariat
    View author publications

    Search author on:PubMed Google Scholar

  13. Paolo Gontero
    View author publications

    Search author on:PubMed Google Scholar

  14. Benjamin Pradere
    View author publications

    Search author on:PubMed Google Scholar

  15. Gary D. Steinberg
    View author publications

    Search author on:PubMed Google Scholar

  16. Ashish M. Kamat
    View author publications

    Search author on:PubMed Google Scholar

  17. Roger Li
    View author publications

    Search author on:PubMed Google Scholar

Contributions

L.W., H.M. and R.L. researched data for the article. All authors contributed substantially to discussion of the content. L.W., H.M. and R.L. wrote the article. All authors reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Lexiaochuan Wen.

Ethics declarations

Competing interests

S.P.L declares patent: TCGA classifier; clinical trials: Aura Bioscience, FKD, JBL (SWOG), Merck (Alliance), QED Therapeutics, Surge Therapeutics; advisory board/consulting fee: Aura Bioscience, Astra Zeneca, BMS, Pfizer/EMD Serono, Protara, Surge Therapeutics, Immunity Bio UroGen, Verity, Gilead, FKD, Viventa; honoraria: Grand Rounds Urology, UroToday. J.J.M. declares advisory boards/consulting: Merck, AstraZeneca, Janssen, BMS, UroGen, Prokarium, Imvax, Pfizer, Seagen/Astellas, Ferring, CG Oncology, Calibr, Immunity Bio, Protara, Photocure. S.P.P. declares research funding: National Institute on Aging, Bladder Cancer Advocacy Network, PRIME Education, Inc, Janssen; guidelines committee: American Urological Association: Upper Tract Urothelial Carcinoma Guidelines 2023 and AUA Practice Guidelines Committee; advisory/consulting: Janssen (SunRise-4 Global Co-PI), Immunity Bio, Merck, CG Oncology, Pfizer; editorial boards: European Urology, Bladder Cancer; steering committees/leadership: Bladder Cancer Advocacy Network, KCCure/Kidney Cancer Association/International Kidney Cancer Society; educational company presentations given: PeerView, MedScape, UroToday. A.M.K. declares patent: CyPRIT (Anderson Cancer Center #00043705); grants/contracts: FKD Therapies, Patient-Centered Outcomes Institute (PCORI), Photocure, Seagen, EnGene, Arquer Diagnostis, SWOG; advisory board/consulting: Astellas Pharma, Atonco Pharma, Biologic Dynamics, Bristol-Myers Squibb, CG Oncology, Cystotech, Eisai, EnGene, Ferring, Genentech, Imagin Medical, ImmunityBio, Imvax, Incyte, Janssen, Medac, Merk, Nonagen Bioscience, Pfizer, Photocure, Protara Therapeutics, Roche, Seagen, Sesen Bio, Theralase, urogen Pharma, US Biotest, Valar Labs, Vivet Therapeutics; boards/committee: IBCG, European Urology Oncology, Journal of Urology, UroToday, World Bladder Cancer patient Coalition, American Urological Association. L.D. declares funding agreement: 2i Genomics, Veracyte, Natera, AstraZeneca, Photocure and Ferring; advisory/consulting: Ferring, MSD, Cystotech, AstraZeneca and UroGen; honoraria: AstraZeneca, Pfizer and Roche and travel support from MSD. R.L. declares research support: Predicine; Valar labs; Johnson & Johnson; scientific adviser/consultant: BMS, Merck, CG Oncology, ImmunityBio, Pfizer, Johnson & Johnson, AstraZeneca, enGene, Valar Labs; honoraria: UroToday, IBCG, MashUP Media, MJH Lifesciences; travel: Predicine, CG Oncology, Johnson & Johnson. P.E.S. declares vice-chair of the NCCN bladder and penile cancer panel. All other authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Urology thanks Marco Paciotti and Xuan-Mei Piao 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

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wen, L., Miyagi, H., Spiess, P.E. et al. Low-grade non-muscle-invasive bladder cancer: molecular landscape, treatment strategies and emerging therapies. Nat Rev Urol 22, 846–861 (2025). https://doi.org/10.1038/s41585-025-01072-0

Download citation

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41585-025-01072-0

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