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.

  • Primer
  • Published:

Bladder cancer

Nature Reviews Disease Primers volume 9, Article number: 58 (2023) Cite this article

Subjects

Abstract

Bladder cancer is a global health issue with sex differences in incidence and prognosis. Bladder cancer has distinct molecular subtypes with multiple pathogenic pathways depending on whether the disease is non-muscle invasive or muscle invasive. The mutational burden is higher in muscle-invasive than in non-muscle-invasive disease. Commonly mutated genes include TERT, FGFR3, TP53, PIK3CA, STAG2 and genes involved in chromatin modification. Subtyping of both forms of bladder cancer is likely to change considerably with the advent of single-cell analysis methods. Early detection signifies a better disease prognosis; thus, minimally invasive diagnostic options are needed to improve patient outcomes. Urine-based tests are available for disease diagnosis and surveillance, and analysis of blood-based cell-free DNA is a promising tool for the detection of minimal residual disease and metastatic relapse. Transurethral resection is the cornerstone treatment for non-muscle-invasive bladder cancer and intravesical therapy can further improve oncological outcomes. For muscle-invasive bladder cancer, radical cystectomy with neoadjuvant chemotherapy is the standard of care with evidence supporting trimodality therapy. Immune-checkpoint inhibitors have demonstrated benefit in non-muscle-invasive, muscle-invasive and metastatic bladder cancer. Effective management requires a multidisciplinary approach that considers patient characteristics and molecular disease characteristics.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Bladder cancer categories.
Fig. 2: Global incidence of bladder cancer.
Fig. 3: Global mortality of bladder cancer.
Fig. 4: Pathogenesis pathways.
Fig. 5: Histopathology of bladder cancer.
Fig. 6: Landmarks in understanding, diagnosis and treatment of bladder cancer.

Similar content being viewed by others

References

  1. Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71, 209–249 (2021).

    Article  PubMed  Google Scholar 

  2. Antoni, S. et al. Bladder cancer incidence and mortality: a global overview and recent trends. Eur. Urol. 71, 96–108 (2017).

    Article  PubMed  Google Scholar 

  3. IARC. Global Cancer Observatory: Cancer Tomorrow. WHO https://gco.iarc.fr/tomorrow/en (2023).

  4. Tran, L., Xiao, J.-F., Agarwal, N., Duex, J. E. & Theodorescu, D. Advances in bladder cancer biology and therapy. Nat. Rev. Cancer 21, 104–121 (2021).

    Article  CAS  PubMed  Google Scholar 

  5. Facchini, G. et al. Advanced/metastatic bladder cancer: current status and future directions. Eur. Rev. Med. Pharmacol. Sci. 24, 11536–11552 (2020).

    CAS  PubMed  Google Scholar 

  6. Dancik, G. M., Owens, C. R., Iczkowski, K. A. & Theodorescu, D. A cell of origin gene signature indicates human bladder cancer has distinct cellular progenitors. Stem Cell 32, 974–982 (2014).

    Article  CAS  Google Scholar 

  7. Partin, A. W., Peters, C. A., Kavoussi, L. R., Dmochowski, R. R. & Wein, A. J. Campbell-Walsh-Wein Urology Twelfth Edition Review (Elsevier Health Sciences, 2020).

  8. Freedman, N. D., Silverman, D. T., Hollenbeck, A. R., Schatzkin, A. & Abnet, C. C. Association between smoking and risk of bladder cancer among men and women. JAMA 306, 737–745 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wilhelm-Benartzi, C. S. et al. Association of secondhand smoke exposures with DNA methylation in bladder carcinomas. Cancer Causes Control 22, 1205–1213 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Bellamri, M. et al. DNA damage and oxidative stress of tobacco smoke condensate in human bladder epithelial cells. Chem. Res. Toxicol. 35, 1863–1880 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Matuszczak, M. & Salagierski, M. Diagnostic and prognostic potential of biomarkers CYFRA 21.1, ERCC1, p53, FGFR3 and TATI in bladder cancers. Int. J. Mol. Sci. 21, 3360 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Mertens, L. S. et al. Prognostic markers in invasive bladder cancer: FGFR3 mutation status versus P53 and KI-67 expression: a multi-center, multi-laboratory analysis in 1058 radical cystectomy patients. Urol. Oncol. 40, 110.e1–110.e9 (2022).

    Article  CAS  PubMed  Google Scholar 

  13. Theodorescu, D., Li, Z. & Li, X. Sex differences in bladder cancer: emerging data and call to action. Nat. Rev. Urol. 19, 447–449 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Bladder Cancer Statistics. WCRF International https://www.wcrf.org/cancer-trends/bladder-cancer-statistics/ (2022).

  15. Dobruch, J. et al. Gender and bladder cancer: a collaborative review of etiology, biology, and outcomes. Eur. Urol. 69, 300–310 (2016).

    Article  PubMed  Google Scholar 

  16. Hyldgaard, J. M. & Jensen, J. B. The inequality of females in bladder cancer. APMIS 129, 694–699 (2021).

    Article  PubMed  Google Scholar 

  17. Radkiewicz, C. et al. Sex differences in urothelial bladder cancer survival. Clin. Genitourin. Cancer 18, 26–34.e6 (2020).

    Article  PubMed  Google Scholar 

  18. You, S. et al. Characterizing molecular subtypes of high-risk non-muscle-invasive bladder cancer in African American patients. Urol. Oncol. 40, 410.e19–410.e27 (2022).

    Article  CAS  PubMed  Google Scholar 

  19. Saginala, K. et al. Epidemiology of bladder cancer. Med. Sci. 8, 15 (2020).

    CAS  Google Scholar 

  20. Richters, A., Aben, K. K. H. & Kiemeney, L. A. L. M. The global burden of urinary bladder cancer: an update. World J. Urol. 38, 1895–1904 (2020).

    Article  PubMed  Google Scholar 

  21. Safiri, S., Kolahi, A.-A. & Naghavi, M., Global Burden of Disease Bladder Cancer Collaborators. Global, regional and national burden of bladder cancer and its attributable risk factors in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease study 2019. BMJ Glob. Health 6, e004128 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Dai, X., Gakidou, E. & Lopez, A. D. Evolution of the global smoking epidemic over the past half century: strengthening the evidence base for policy action. Tob. Control 31, 129–137 (2022).

    Article  PubMed  Google Scholar 

  23. Flor, L. S., Reitsma, M. B., Gupta, V., Ng, M. & Gakidou, E. The effects of tobacco control policies on global smoking prevalence. Nat. Med. 27, 239–243 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ishida, K. & Hsieh, M. H. Understanding urogenital schistosomiasis-related bladder cancer: an update. Front. Med. 5, 223 (2018).

    Article  Google Scholar 

  25. Zaghloul, M. S., Zaghloul, T. M., Bishr, M. K. & Baumann, B. C. Urinary schistosomiasis and the associated bladder cancer: update. J. Egypt. Natl Canc. Inst. 32, 44 (2020).

    Article  PubMed  Google Scholar 

  26. Salem, S., Mitchell, R. E., El-Alim El-Dorey, A., Smith, J. A. & Barocas, D. A. Successful control of schistosomiasis and the changing epidemiology of bladder cancer in Egypt. BJU Int. 107, 206–211 (2011).

    Article  PubMed  Google Scholar 

  27. Martin, A., Woolbright, B. L., Umar, S., Ingersoll, M. A. & Taylor, J. A. 3rd Bladder cancer, inflammageing and microbiomes. Nat. Rev. Urol. 19, 495–509 (2022).

    Article  PubMed  Google Scholar 

  28. Lobo, N. et al. Epidemiology, screening, and prevention of bladder cancer. Eur. Urol. Oncol. 5, 628–639 (2022).

    Article  PubMed  Google Scholar 

  29. Letašiová, S. et al. Bladder cancer, a review of the environmental risk factors. Environ. Health 11, S11 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  30. van der Post, R. S. et al. Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers. J. Med. Genet. 47, 464–470 (2010).

    Article  PubMed  Google Scholar 

  31. Lindner, A. K. et al. Lynch syndrome: its impact on urothelial carcinoma. Int. J. Mol. Sci. 22, 531 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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). An update to the 2016 UROMOL consortium study, representing the largest multi-omics analysis to characterize the molecular landscape in early-stage bladder cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  34. 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 

  35. Sun, T. T., Zhao, H., Provet, J., Aebi, U. & Wu, X. R. Formation of asymmetric unit membrane during urothelial differentiation. Mol. Biol. Rep. 23, 3–11 (1996).

    Article  CAS  PubMed  Google Scholar 

  36. Varley, C. L. et al. PPARgamma-regulated tight junction development during human urothelial cytodifferentiation. J. Cell. Physiol. 208, 407–417 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Southgate, J., Harnden, P. & Trejdosiewicz, L. K. Cytokeratin expression patterns in normal and malignant urothelium: a review of the biological and diagnostic implications. Histol. Histopathol. 14, 657–664 (1999).

    CAS  PubMed  Google Scholar 

  38. Wezel, F., Pearson, J. & Southgate, J. Plasticity of in vitro-generated urothelial cells for functional tissue formation. Tissue Eng. Part. A 20, 1358–1368 (2014).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  40. Fishwick, C. et al. Heterarchy of transcription factors driving basal and luminal cell phenotypes in human urothelium. Cell Death Differ. 24, 809–818 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Curtius, K., Wright, N. A. & Graham, T. A. An evolutionary perspective on field cancerization. Nat. Rev. Cancer 18, 19–32 (2018).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  43. Höglund, M. On the origin of syn- and metachronous urothelial carcinomas. Eur. Urol. 51, 1185–1193 (2007).

    Article  PubMed  Google Scholar 

  44. Höglund, M. Bladder cancer, a two phased disease? Semin. Cancer Biol. 17, 225–232 (2007).

    Article  PubMed  Google Scholar 

  45. Lamy, P. et al. Paired exome analysis reveals clonal evolution and potential therapeutic targets in urothelial carcinoma. Cancer Res. 76, 5894–5906 (2016).

    Article  CAS  PubMed  Google Scholar 

  46. Bondaruk, J. et al. The origin of bladder cancer from mucosal field effects. iScience 25, 104551 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Strandgaard, T. et al. Field cancerization is associated with tumor development, T-cell exhaustion, and clinical outcomes in bladder cancer. Eur. Urol. https://doi.org/10.1016/j.eururo.2023.07.014 (2023).

    Article  PubMed  Google Scholar 

  48. Lawson, A. R. J. et al. Extensive heterogeneity in somatic mutation and selection in the human bladder. Science 370, 75–82 (2020).

    Article  CAS  PubMed  Google Scholar 

  49. Alexandrov, L. B. et al. The repertoire of mutational signatures in human cancer. Nature 578, 94–101 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Nordentoft, I. et al. Mutational context and diverse clonal development in early and late bladder cancer. Cell Rep. 7, 1649–1663 (2014).

    Article  CAS  PubMed  Google Scholar 

  51. Robertson, A. G. et al. Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell 171, 540–556 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Sandberg, A. A. Chromosome changes in bladder cancer: clinical and other correlations. Cancer Genet. Cytogenet. 19, 163–175 (1986).

    Article  CAS  PubMed  Google Scholar 

  54. 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). The authors defined two major genomic subtypes of primary-stage Ta tumors and found that more mutations in the histone lysine demethylase KDM6A were present in non-invasive tumours from women than in those from men, supporting the hypothesis that male and female bladder cancers have both common and different biological drivers.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ségal-Bendirdjian, E. & Geli, V. Non-canonical roles of telomerase: unraveling the imbroglio. Front. Cell Dev. Biol. 7, 332 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Agarwal, N. et al. TRIM28 is a transcriptional activator of the mutant TERT promoter in human bladder cancer. Proc. Natl Acad. Sci. USA 118, e2102423118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Borah, S. et al. Cancer. TERT promoter mutations and telomerase reactivation in urothelial cancer. Science 347, 1006–1010 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Nickerson, M. L. et al. Molecular analysis of urothelial cancer cell lines for modeling tumor biology and drug response. Oncogene 36, 35–46 (2017).

    Article  CAS  PubMed  Google Scholar 

  59. Nickerson, M. L. et al. Concurrent alterations in TERT, KDM6A, and the BRCA pathway in bladder cancer. Clin. Cancer Res. 20, 4935–4948 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 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 

  61. Allory, Y. et al. Telomerase reverse transcriptase promoter mutations in bladder cancer: high frequency across stages, detection in urine, and lack of association with outcome. Eur. Urol. 65, 360–366 (2014).

    Article  CAS  PubMed  Google Scholar 

  62. Stern, J. L., Theodorescu, D., Vogelstein, B., Papadopoulos, N. & Cech, T. R. Mutation of the TERT promoter, switch to active chromatin, and monoallelic TERT expression in multiple cancers. Genes Dev. 29, 2219–2224 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Shi, M.-J. et al. APOBEC-mediated mutagenesis as a likely cause of FGFR3 S249C mutation over-representation in bladder cancer. Eur. Urol. 76, 9–13 (2019).

    Article  CAS  PubMed  Google Scholar 

  64. 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 

  65. 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 

  66. Qiu, H. et al. KDM6A loss triggers an epigenetic switch that disrupts urothelial differentiation and drives cell proliferation in bladder cancer. Cancer Res. 83, 814–829 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Richart, L. et al. STAG2 loss-of-function affects short-range genomic contacts and modulates the basal-luminal transcriptional program of bladder cancer cells. Nucleic Acids Res. 49, 11005–11021 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Taylor, C. F., Platt, F. M., Hurst, C. D., Thygesen, H. H. & Knowles, M. A. Frequent inactivating mutations of STAG2 in bladder cancer are associated with low tumour grade and stage and inversely related to chromosomal copy number changes. Hum. Mol. Genet. 23, 1964–1974 (2014).

    Article  CAS  PubMed  Google Scholar 

  69. Gordon, N. S. et al. STAG2 protein expression in non-muscle-invasive bladder cancer: associations with sex, genomic and transcriptomic changes, and clinical outcomes. Eur. Urol. Open Sci. 38, 88–95 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Meeks, J. J. et al. Genomic heterogeneity in bladder cancer: challenges and possible solutions to improve outcomes. Nat. Rev. Urol. 17, 259–270 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Li, Q. et al. ERCC2 helicase domain mutations confer nucleotide excision repair deficiency and drive cisplatin sensitivity in muscle-invasive bladder cancer. Clin. Cancer Res. 25, 977–988 (2019).

    Article  CAS  PubMed  Google Scholar 

  72. Williams, S. V., Hurst, C. D. & Knowles, M. A. Oncogenic FGFR3 gene fusions in bladder cancer. Hum. Mol. Genet. 22, 795–803 (2013).

    Article  CAS  PubMed  Google Scholar 

  73. Tomlinson, D. C., Baxter, E. W., Loadman, P. M., Hull, M. A. & Knowles, M. A. FGFR1-induced epithelial to mesenchymal transition through MAPK/PLCγ/COX-2-mediated mechanisms. PLoS ONE 7, e38972 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Tomlinson, D. C. & Knowles, M. A. Altered splicing of FGFR1 is associated with high tumor grade and stage and leads to increased sensitivity to FGF1 in bladder cancer. Am. J. Pathol. 177, 2379–2386 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Rebouissou, S. et al. CDKN2A homozygous deletion is associated with muscle invasion in FGFR3-mutated urothelial bladder carcinoma. J. Pathol. 227, 315–324 (2012).

    Article  CAS  PubMed  Google Scholar 

  76. Huan, J., Grivas, P., Birch, J. & Hansel, D. E. Emerging roles for mammalian target of rapamycin (mTOR) complexes in bladder cancer progression and therapy. Cancers 14, 1555 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Miyata, Y., Sagara, Y., Kanda, S., Hayashi, T. & Kanetake, H. Phosphorylated hepatocyte growth factor receptor/c-Met is associated with tumor growth and prognosis in patients with bladder cancer: correlation with matrix metalloproteinase-2 and -7 and E-cadherin. Hum. Pathol. 40, 496–504 (2009).

    Article  CAS  PubMed  Google Scholar 

  78. Goriki, A. et al. Unravelling disparate roles of NOTCH in bladder cancer. Nat. Rev. Urol. 15, 345–357 (2018).

    Article  CAS  PubMed  Google Scholar 

  79. Gouin, K. H. III et al. An N-Cadherin 2 expressing epithelial cell subpopulation predicts response to surgery, chemotherapy and immunotherapy in bladder cancer. Nat. Commun. 12, 4906 (2021). To our knowledge, this is the first publication evaluating, through single-cell and spatial transcriptomics and proteomics, tumor heterogeneity in muscle-invasive bladder cancer and defines a new subtype architecture and specific tumor cell population whose presence predicts clinical outcomes after surgery and immunotherapy.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Su, S. et al. CD10+GPR77+ cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness. Cell 172, 841–856.e16 (2018).

    Article  CAS  PubMed  Google Scholar 

  81. Lee, Y.-C. et al. The dynamic roles of the bladder tumour microenvironment. Nat. Rev. Urol. 19, 515–533 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Qiu, S. et al. Tumor-associated macrophages promote bladder tumor growth through PI3K/AKT signal induced by collagen. Cancer Sci. 110, 2110–2118 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Mezheyeuski, A. et al. Fibroblasts in urothelial bladder cancer define stroma phenotypes that are associated with clinical outcome. Sci. Rep. 10, 281 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Long, X. et al. Cancer-associated fibroblasts promote cisplatin resistance in bladder cancer cells by increasing IGF-1/ERβ/Bcl-2 signalling. Cell Death Dis. 10, 375 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Tran, L. & Theodorescu, D. Determinants of resistance to checkpoint inhibitors. Int. J. Mol. Sci. 21, 1594 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Chen, Y. et al. Tumor-associated macrophages: an accomplice in solid tumor progression. J. Biomed. Sci. 26, 78 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  87. Tu, M. M. et al. Inhibition of the CCL2 receptor, CCR2, enhances tumor response to immune checkpoint therapy. Commun. Biol. 3, 720 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Tu, M. M. et al. Targeting DDR2 enhances tumor response to anti-PD-1 immunotherapy. Sci. Adv. 5, eaav2437 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Said, N., Sanchez-Carbayo, M., Smith, S. C. & Theodorescu, D. RhoGDI2 suppresses lung metastasis in mice by reducing tumor versican expression and macrophage infiltration. J. Clin. Invest. 122, 1503–1518 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wang, L. et al. Myeloid cell-associated resistance to PD-1/PD-L1 blockade in urothelial cancer revealed through bulk and single-cell RNA sequencing. Clin. Cancer Res. 27, 4287–4300 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Samstein, R. M. et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat. Genet. 51, 202–206 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Cristescu, R. et al. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 362, eaar3593 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  93. Pfannstiel, C. et al. The tumor immune microenvironment drives a prognostic relevance that correlates with bladder cancer subtypes. Cancer Immunol. Res. 7, 923–938 (2019).

    Article  CAS  PubMed  Google Scholar 

  94. Wang, L. et al. EMT- and stroma-related gene expression and resistance to PD-1 blockade in urothelial cancer. Nat. Commun. 9, 3503 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  95. You, S. et al. Discoidin domain receptor-driven gene signatures as markers of patient response to anti-PD-L1 immune checkpoint therapy. J. Natl Cancer Inst. 114, 1380–1391 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Kaneko, S. & Li, X. X chromosome protects against bladder cancer in females via a KDM6A-dependent epigenetic mechanism. Sci. Adv. 4, eaar5598 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Li, Z., Azar, J. H. & Rubinstein, M. P. Converting tumoral PD-L1 into a 4-1BB agonist for safer and more effective cancer immunotherapy. Cancer Discov. 12, 1184–1186 (2022).

    Article  CAS  PubMed  Google Scholar 

  98. Kwon, H. et al. Androgen conspires with the CD8+ T cell exhaustion program and contributes to sex bias in cancer. Sci. Immunol. 7, eabq2630 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Sottnik, J. L. et al. Androgen receptor regulates CD44 expression in bladder cancer. Cancer Res. 81, 2833–2846 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Calvete, J. et al. The coexpression of fibroblast activation protein (FAP) and basal-type markers (CK 5/6 and CD44) predicts prognosis in high-grade invasive urothelial carcinoma of the bladder. Hum. Pathol. 91, 61–68 (2019).

    Article  CAS  PubMed  Google Scholar 

  101. Bellmunt, J. Stem-like signature predicting disease progression in early stage bladder cancer. the role of E2F3 and SOX4. Biomedicines 6, 85 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Sottnik, J. L. & Theodorescu, D. CD44: a metastasis driver and therapeutic target. Oncoscience 3, 320–321 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Senbanjo, L. T. & Chellaiah, M. A. CD44: a multifunctional cell surface adhesion receptor is a regulator of progression and metastasis of cancer cells. Front. Cell Dev. Biol. 5, 18 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Miyamoto, H. et al. Promotion of bladder cancer development and progression by androgen receptor signals. J. Natl Cancer Inst. 99, 558–568 (2007).

    Article  CAS  PubMed  Google Scholar 

  105. Morales, E. E. et al. Finasteride reduces risk of bladder cancer in a large prospective screening study. Eur. Urol. 69, 407–410 (2016).

    Article  CAS  PubMed  Google Scholar 

  106. Sathianathen, N. J., Fan, Y., Jarosek, S. L., Lawrentschuk, N. L. & Konety, B. R. Finasteride does not prevent bladder cancer: a secondary analysis of the Medical Therapy for Prostatic Symptoms Study. Urol. Oncol. 36, 338.e13–338.e17 (2018).

    Article  CAS  PubMed  Google Scholar 

  107. Zhu, D. et al. Finasteride use and risk of bladder cancer in a multiethnic population. J. Urol. 206, 15–21 (2021).

    Article  PubMed  Google Scholar 

  108. Richard, A. et al. Racial variation in sex steroid hormone concentration in black and white men: a meta-analysis. Andrology 2, 428–435 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Giaquinto, A. N. et al. Cancer statistics for African American/Black People 2022. CA Cancer J. Clin. 72, 202–229 (2022).

    Article  PubMed  Google Scholar 

  110. Miyamoto, H. et al. Expression of androgen and oestrogen receptors and its prognostic significance in urothelial neoplasm of the urinary bladder. BJU Int. 109, 1716–1726 (2012).

    Article  CAS  PubMed  Google Scholar 

  111. Tripathi, A. & Gupta, S. Androgen receptor in bladder cancer: a promising therapeutic target. Asian J. Urol. 7, 284–290 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Xiang, P. et al. Impact of androgen suppression therapy on the risk and prognosis of bladder cancer: a systematic review and meta-analysis. Front. Oncol. 11, 784627 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Creta, M. et al. Inhibition of androgen signalling improves the outcomes of therapies for bladder cancer: results from a systematic review of preclinical and clinical evidence and meta-analysis of clinical studies. Diagnostics 11, 351 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Wu, S.-C. et al. Androgen suppression therapy is associated with lower recurrence of non-muscle-invasive bladder cancer. Eur. Urol. Focus 7, 142–147 (2021).

    Article  PubMed  Google Scholar 

  115. Maan, A. A. et al. The Y chromosome: a blueprint for men’s health? Eur. J. Hum. Genet. 25, 1181–1188 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Sano, S. et al. Hematopoietic loss of Y chromosome leads to cardiac fibrosis and heart failure mortality. Science 377, 292–297 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Forsberg, L. A. et al. Mosaic loss of chromosome Y in peripheral blood is associated with shorter survival and higher risk of cancer. Nat. Genet. 46, 624–628 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Kido, T. & Lau, Y.-F. C. Roles of the Y chromosome genes in human cancers. Asian J. Androl. 17, 373–380 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Brown, D. W. & Machiela, M. J. Why Y? Downregulation of chromosome Y genes potentially contributes to elevated cancer risk. J. Natl Cancer Inst. 112, 871–872 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Panani, A. D. & Roussos, C. Sex chromosome abnormalities in bladder cancer: Y polysomies are linked to PT1-grade III transitional cell carcinoma. Anticancer. Res. 26, 319–323 (2006).

    PubMed  Google Scholar 

  121. Fadl-Elmula, I. et al. Karyotypic characterization of urinary bladder transitional cell carcinomas. Genes Chromosomes Cancer 29, 256–265 (2000).

    Article  CAS  PubMed  Google Scholar 

  122. Sauter, G., Moch, H., Mihatsch, M. J. & Gasser, T. C. Molecular cytogenetics of bladder cancer progression. Eur. Urol. 33, 9–10 (1998).

    Article  PubMed  Google Scholar 

  123. Smeets, W., Pauwels, R., Laarakkers, L., Debruyne, F. & Geraedts, J. Chromosomal analysis of bladder cancer. III. Nonrandom alterations. Cancer Genet. Cytogenet. 29, 29–41 (1987).

    Article  CAS  PubMed  Google Scholar 

  124. Sauter, G. et al. Y chromosome loss detected by FISH in bladder cancer. Cancer Genet. Cytogenet. 82, 163–169 (1995).

    Article  CAS  PubMed  Google Scholar 

  125. Neuhaus, M. et al. Polysomies but not Y chromosome losses have prognostic significance in pTa/pT1 urinary bladder cancer. Hum. Pathol. 30, 81–86 (1999).

    Article  CAS  PubMed  Google Scholar 

  126. Powell, I., Tyrkus, M. & Kleer, E. Apparent correlation of sex chromosome loss and disease course in urothelial cancer. Cancer Genet. Cytogenet. 50, 97–101 (1990).

    Article  CAS  PubMed  Google Scholar 

  127. Siegel, R. L., Miller, K. D., Fuchs, H. E. & Jemal, A. Cancer statistics, 2022. CA Cancer J. Clin. 72, 7–33 (2022).

    Article  PubMed  Google Scholar 

  128. Johansson, S. L. & Cohen, S. M. Epidemiology and etiology of bladder cancer. Semin. Surg. Oncol. 13, 291–298 (1997).

    Article  CAS  PubMed  Google Scholar 

  129. Dumanski, J. P. et al. Mutagenesis. Smoking is associated with mosaic loss of chromosome Y. Science 347, 81–83 (2015).

    Article  CAS  PubMed  Google Scholar 

  130. Abdel-Hafiz, H. A. et al. Y chromosome loss in cancer drives growth by evasion of adaptive immunity. Nature 619, 624–631 (2023). To our knowledge, this is the first publication that mechanistically links cancer aggressiveness with LOY and shows that this is due to the cancer cell evading T cell-mediated immunity, opening up possibilities for biomarker and therapeutic development in cancer.

    Article  CAS  PubMed  Google Scholar 

  131. Cummings, K. B., Barone, J. G. & Ward, W. S. Diagnosis and staging of bladder cancer. Urol. Clin. North Am. 19, 455–465 (1992).

    Article  CAS  PubMed  Google Scholar 

  132. 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 

  133. Ghandour, R., Freifeld, Y., Singla, N. & Lotan, Y. Evaluation of hematuria in a large public health care system. Bladder Cancer 5, 119–129 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  134. Rai, B. P. et al. Systematic review of the incidence of and risk factors for urothelial cancers and renal cell carcinoma among patients with haematuria. Eur. Urol. 82, 182–192 (2022).

    Article  PubMed  Google Scholar 

  135. Ramirez, D. et al. Microscopic haematuria at time of diagnosis is associated with lower disease stage in patients with newly diagnosed bladder cancer. BJU Int. 117, 783–786 (2016).

    Article  PubMed  Google Scholar 

  136. Alanee, S. & Shukla, A. R. Bladder malignancies in children aged <18 years: results from the surveillance, epidemiology and end results database. BJU Int. 106, 557–560 (2010).

    Article  PubMed  Google Scholar 

  137. Kutarski, P. W. & Padwell, A. Transitional cell carcinoma of the bladder in young adults. Br. J. Urol. 72, 749–755 (1993).

    Article  CAS  PubMed  Google Scholar 

  138. Rezaee, M. E., Dunaway, C. M., Baker, M. L., Penna, F. J. & Chavez, D. R. Urothelial cell carcinoma of the bladder in pediatric patients: a systematic review and data analysis of the world literature. J. Pediatr. Urol. 15, 309–314 (2019).

    Article  CAS  PubMed  Google Scholar 

  139. Czech, A. K. et al. Diagnostic accuracy of bimanual palpation in bladder cancer patients undergoing cystectomy: a prospective study. Urol. Oncol. 41, 390.e27–390.e33 (2023).

    Article  PubMed  Google Scholar 

  140. Flaig, T. W. et al. Bladder cancer, version 3.2020, NCCN clinical practice guidelines in oncology. J. Natl Compr. Canc. Netw. 18, 329–354 (2020).

    Article  PubMed  Google Scholar 

  141. Ploeg, M. et al. Discrepancy between clinical staging through bimanual palpation and pathological staging after cystectomy. Urol. Oncol. 30, 247–251 (2012).

    Article  PubMed  Google Scholar 

  142. 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 

  143. Xing, J. & Reynolds, J. P. Diagnostic advances in urine cytology. Surg. Pathol. Clin. 11, 601–610 (2018).

    Article  PubMed  Google Scholar 

  144. Barkan, G. A. et al. The Paris system for reporting urinary cytology: the quest to develop a standardized terminology. Adv. Anat. Pathol. 23, 193–201 (2016).

    Article  PubMed  Google Scholar 

  145. Nikas, I. P. et al. The Paris system for reporting urinary cytology: a meta-analysis. J. Pers. Med. 12, 170 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  146. Saprykina, E. V. & Sal’nik, B. I. The role of lipid metabolism disorders in the mechanism of the hepatotoxic effects of rubomycin [Russian]. Antibiot. Khimioter. 33, 452–455 (1988).

    CAS  PubMed  Google Scholar 

  147. Guo, A. et al. Bladder tumour antigen (BTA stat) test compared to the urine cytology in the diagnosis of bladder cancer: a meta-analysis. Can. Urol. Assoc. J. 8, E347–E352 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  148. Dimashkieh, H. et al. Evaluation of urovysion and cytology for bladder cancer detection: a study of 1835 paired urine samples with clinical and histologic correlation. Cancer Cytopathol. 121, 591–597 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Zippe, C., Pandrangi, L. & Agarwal, A. NMP22 is a sensitive, cost-effective test in patients at risk for bladder cancer. J. Urol. 161, 62–65 (1999).

    Article  CAS  PubMed  Google Scholar 

  150. He, H., Han, C., Hao, L. & Zang, G. ImmunoCyt test compared to cytology in the diagnosis of bladder cancer: a meta-analysis. Oncol. Lett. 12, 83–88 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. 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 

  152. Jeong, S.-H. & Ku, J. H. Urinary markers for bladder cancer diagnosis and monitoring. Front. Cell Dev. Biol. 10, 892067 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Heitzer, E., Auinger, L. & Speicher, M. R. Cell-free DNA and apoptosis: how dead cells inform about the living. Trends Mol. Med. 26, 519–528 (2020).

    Article  CAS  PubMed  Google Scholar 

  154. Cherepanova, A. V., Tamkovich, S. N., Bryzgunova, O. E., Vlassov, V. V. & Laktionov, P. P. Deoxyribonuclease activity and circulating DNA concentration in blood plasma of patients with prostate tumors. Ann. N. Y. Acad. Sci. 1137, 218–221 (2008).

    Article  CAS  PubMed  Google Scholar 

  155. Tamkovich, S. N. et al. Circulating DNA and DNase activity in human blood. Ann. N. Y. Acad. Sci. 1075, 191–196 (2006).

    Article  CAS  PubMed  Google Scholar 

  156. Yu, S. C. Y. et al. High-resolution profiling of fetal DNA clearance from maternal plasma by massively parallel sequencing. Clin. Chem. 59, 1228–1237 (2013).

    Article  CAS  PubMed  Google Scholar 

  157. Khier, S. & Gahan, P. B. Hepatic clearance of cell-free DNA: possible impact on early metastasis diagnosis. Mol. Diagn. Ther. 25, 677–682 (2021).

    Article  CAS  PubMed  Google Scholar 

  158. Khier, S. & Lohan, L. Kinetics of circulating cell-free DNA for biomedical applications: critical appraisal of the literature. Future Sci. OA 4, FSO295 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Christensen, E. et al. Early detection of metastatic relapse and monitoring of therapeutic efficacy by ultra-deep sequencing of plasma cell-free DNA in patients with urothelial bladder carcinoma. J. Clin. Oncol. 37, 1547–1557 (2019). To our knowledge, this is the first larger prospective study showing that ctDNA measurements during chemotherapy and after cystectomy may be a very powerful biomarker for guiding treatment.

    Article  CAS  PubMed  Google Scholar 

  160. Christensen, E. et al. Cell-free urine and plasma DNA mutational analysis predicts neoadjuvant chemotherapy response and outcome in patients with muscle-invasive bladder cancer. Clin. Cancer Res. 14, 1582–1591 (2023).

    Article  Google Scholar 

  161. van Dorp, J. et al. High- or low-dose preoperative ipilimumab plus nivolumab in stage III urothelial cancer: the phase 1B NABUCCO trial. Nat. Med. 29, 588–592 (2023).

    Article  PubMed  Google Scholar 

  162. Powles, T. et al. ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature 595, 432–437 (2021).

    Article  CAS  PubMed  Google Scholar 

  163. Powles, T. et al. Updated overall survival by circulating tumor DNA status from the phase 3 IMvigor010 trial: adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma. Eur. Urol. https://doi.org/10.1016/j.eururo.2023.06.007 (2023).

    Article  PubMed  Google Scholar 

  164. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04660344 (2023).

  165. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04138628 (2022).

  166. Vandekerkhove, G. et al. Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer. Nat. Commun. 12, 184 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Vandekerkhove, G. et al. Circulating tumor DNA reveals clinically actionable somatic genome of metastatic bladder cancer. Clin. Cancer Res. 23, 6487–6497 (2017).

    Article  CAS  PubMed  Google Scholar 

  168. Moch, H. Urinary and Male Genital Tumours: WHO Classification of Tumours, 5th Edition, Volume 8. 576 (IARC Publications, 2022).

  169. 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 

  170. Ching, C. B. et al. HER2 gene amplification occurs frequently in the micropapillary variant of urothelial carcinoma: analysis by dual-color in situ hybridization. Mod. Pathol. 24, 1111–1119 (2011).

    Article  CAS  PubMed  Google Scholar 

  171. Willis, D. L. et al. Micropapillary bladder cancer: current treatment patterns and review of the literature. Urol. Oncol. 32, 826–832 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  172. Isharwal, S. et al. Intratumoral heterogeneity of ERBB2 amplification and HER2 expression in micropapillary urothelial carcinoma. Hum. Pathol. 77, 63–69 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Teo, M. Y. et al. Natural history, response to systemic therapy, and genomic landscape of plasmacytoid urothelial carcinoma. Br. J. Cancer 124, 1214–1221 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Edgerton, N., Sirintrapun, S. J., Munoz, M., Chen, Z. & Osunkoya, A. O. Micropapillary urothelial carcinoma of the urinary bladder: a clinicopathological analysis of 24 cases. Int. J. Urol. 18, 49–54 (2011).

    Article  PubMed  Google Scholar 

  175. Fernández, M. I. et al. Clinical risk stratification in patients with surgically resectable micropapillary bladder cancer. BJU Int. 119, 684–691 (2017).

    Article  PubMed  Google Scholar 

  176. Amin, M. B. et al. AJCC Cancer Staging Manual (Springer International Publishing, 2017).

  177. Leivo, M. Z. et al. Analysis of T1 bladder cancer on biopsy and transurethral resection specimens: comparison and ranking of T1 quantification approaches to predict progression to muscularis propria invasion. Am. J. Surg. Pathol. 42, e1–e10 (2018).

    Article  PubMed  Google Scholar 

  178. Soria, F., Dutto, D. & Gontero, P. Clinical and biological markers for risk-stratification of T1 high-grade non-muscle invasive bladder cancer. Curr. Opin. Urol. 32, 517–522 (2022).

    Article  PubMed  Google Scholar 

  179. Castaneda, P. R., Theodorescu, D., Rosser, C. J. & Ahdoot, M. Identifying novel biomarkers associated with bladder cancer treatment outcomes. Front. Oncol. 13, 1114203 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Chang, S. S. et al. Treatment of non-metastatic muscle-invasive bladder cancer: AUA/ASCO/ASTRO/SUO guideline. J. Urol. 198, 552–559 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Flaig, T. W. et al. NCCN guidelines® insights: bladder cancer, version 2.2022. J. Natl Compr. Canc. Netw. 20, 866–878 (2022).

    Article  PubMed  Google Scholar 

  182. Witjes, J. A. et al. European Association of Urology guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2020 guidelines. Eur. Urol. 79, 82–104 (2021).

    Article  CAS  PubMed  Google Scholar 

  183. Hensley, P. J. et al. Contemporary staging for muscle-invasive bladder cancer: accuracy and limitations. Eur. Urol. Oncol. 5, 403–411 (2022).

    Article  PubMed  Google Scholar 

  184. Mirmomen, S. M., Shinagare, A. B., Williams, K. E., Silverman, S. G. & Malayeri, A. A. Preoperative imaging for locoregional staging of bladder cancer. Abdom. Radiol. 44, 3843–3857 (2019).

    Article  Google Scholar 

  185. Tekes, A. et al. Dynamic MRI of bladder cancer: evaluation of staging accuracy. AJR Am. J. Roentgenol. 184, 121–127 (2005).

    Article  PubMed  Google Scholar 

  186. Cornelissen, S. W. E., Veenboer, P. W., Wessels, F. J. & Meijer, R. P. Diagnostic accuracy of multiparametric MRI for local staging of bladder cancer: a systematic review and meta-analysis. Urology 145, 22–29 (2020).

    Article  PubMed  Google Scholar 

  187. Gurram, S., Muthigi, A., Egan, J. & Stamatakis, L. Imaging in localized bladder cancer: can current diagnostic modalities provide accurate local tumor staging? Curr. Urol. Rep. 20, 82 (2019).

    Article  PubMed  Google Scholar 

  188. Panebianco, V. et al. Multiparametric magnetic resonance imaging for bladder cancer: development of VI-RADS (Vesical Imaging-Reporting And Data System). Eur. Urol. 74, 294–306 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  189. Bandini, M. et al. The value of multiparametric magnetic resonance imaging sequences to assist in the decision making of muscle-invasive bladder cancer. Eur. Urol. Oncol. 4, 829–833 (2021).

    Article  PubMed  Google Scholar 

  190. Furrer, M. A. et al. Routine preoperative bone scintigraphy has limited impact on the management of patients with invasive bladder cancer. Eur. Urol. Focus 7, 1052–1060 (2021).

    Article  PubMed  Google Scholar 

  191. Ha, H. K., Koo, P. J. & Kim, S.-J. Diagnostic accuracy of F-18 FDG PET/CT for preoperative lymph node staging in newly diagnosed bladder cancer patients: a systematic review and meta-analysis. Oncology 95, 31–38 (2018).

    Article  CAS  PubMed  Google Scholar 

  192. Mertens, L. S., Meijer, R. P. & Alfred Witjes, J. Positron emission tomography/computed tomography for staging of bladder cancer: a continuing clinical controversy. Eur. Urol. 83, 95–96 (2023).

    Article  PubMed  Google Scholar 

  193. Apolo, A. B. et al. Clinical value of fluorine-18 2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography in bladder cancer. J. Clin. Oncol. 28, 3973–3978 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  194. Kibel, A. S. et al. Prospective study of [18F]fluorodeoxyglucose positron emission tomography/computed tomography for staging of muscle-invasive bladder carcinoma. J. Clin. Oncol. 27, 4314–4320 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  195. 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  Google Scholar 

  196. Bellmunt, J. et al. Genomic predictors of good outcome, recurrence, or progression in high-grade T1 non-muscle-invasive bladder cancer. Cancer Res. 80, 4476–4486 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Dyrskjøt, L. et al. A molecular signature in superficial bladder carcinoma predicts clinical outcome. Clin. Cancer Res. 11, 4029–4036 (2005).

    Article  PubMed  Google Scholar 

  198. Dyrskjøt, L. et al. Prognostic impact of a 12-gene progression score in non-muscle-invasive bladder cancer: a prospective multicentre validation study. Eur. Urol. 72, 461–469 (2017).

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  200. Damrauer, J. S. et al. Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology. Proc. Natl Acad. Sci. USA 111, 3110–3115 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Sjödahl, G., Eriksson, P., Liedberg, F. & Höglund, M. Molecular classification of urothelial carcinoma: global mRNA classification versus tumour-cell phenotype classification. J. Pathol. 242, 113–125 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  202. Kamoun, A. et al. A consensus molecular classification of muscle-invasive bladder cancer. Eur. Urol. 77, 420–433 (2019). A consensus classification system for MIBC that includes six subtype classes, demonstrating differences in underlying oncogenic mechanisms, infiltration by immune and stromal cells, and histological and clinical characteristics, including outcomes.

    Article  PubMed  PubMed Central  Google Scholar 

  203. Kates, M. et al. Adaptive immune resistance to intravesical BCG in non-muscle invasive bladder cancer: implications for prospective BCG-unresponsive trials. Clin. Cancer Res. 26, 882–891 (2020).

    Article  CAS  PubMed  Google Scholar 

  204. Strandgaard, T. et al. Elevated T-cell exhaustion and urinary tumor DNA levels are associated with Bacillus Calmette-Guérin failure in patients with non-muscle-invasive bladder cancer. Eur. Urol. 82, 646–656 (2022).

    Article  CAS  PubMed  Google Scholar 

  205. de Jong, F. C. et al. Non-muscle-invasive bladder cancer molecular subtypes predict differential response to intravesical Bacillus Calmette-Guérin. Sci. Transl. Med. 15, eabn4118 (2023).

    Article  PubMed  Google Scholar 

  206. Van Allen, E. M. et al. Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma. Cancer Discov. 4, 1140–1153 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  207. Liu, D. et al. Clinical validation of chemotherapy response biomarker ERCC2 in muscle-invasive urothelial bladder carcinoma. JAMA Oncol. 2, 1094–1096 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  208. Magliocco, A. M., Moughan, J. & Miyamoto, D. T. Analysis of MRE11 and mortality among adults with muscle-invasive bladder cancer managed with trimodality therapy. JAMA Netw. Open 5, e2242378 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  209. Miyamoto, D. T., Mouw, K. W., Feng, F. Y., Shipley, W. U. & Efstathiou, J. A. Molecular biomarkers in bladder preservation therapy for muscle-invasive bladder cancer. Lancet Oncol. 19, e683–e695 (2018).

    Article  CAS  PubMed  Google Scholar 

  210. Kamran, S. C. et al. Genomic tumor correlates of clinical outcomes following organ-sparing chemoradiation therapy for bladder cancer. Clin. Cancer Res. https://doi.org/10.1158/1078-0432.CCR-23-0792 (2023).

    Article  Google Scholar 

  211. Geynisman, D. M. et al. A phase II trial of risk-enabled therapy after initiating neoadjuvant chemotherapy for bladder cancer (RETAIN). J. Clin. Orthod. 41, 438–438 (2023).

    Google Scholar 

  212. Mariathasan, S. et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature 554, 544 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Taber, A. et al. Molecular correlates of cisplatin-based chemotherapy response in muscle invasive bladder cancer by integrated multi-omics analysis. Nat. Commun. 11, 4858 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Sjödahl, G. et al. Different responses to neoadjuvant chemotherapy in urothelial carcinoma molecular subtypes. Eur. Urol. 81, 523–532 (2022).

    Article  PubMed  Google Scholar 

  215. Seiler, R. et al. Impact of molecular subtypes in muscle-invasive bladder cancer on predicting response and survival after neoadjuvant chemotherapy. Eur. Urol. 72, 544–554 (2017).

    Article  CAS  PubMed  Google Scholar 

  216. Efstathiou, J. A. et al. Impact of immune and stromal infiltration on outcomes following bladder-sparing trimodality therapy for muscle-invasive bladder cancer. Eur. Urol. 76, 59–68 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  217. Lindskrog, S. V. et al. Single-nucleus and spatially resolved intratumor subtype heterogeneity in bladder cancer. Eur. Urol. Open Sci. 51, 78–88 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  218. 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 

  219. 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 

  220. Yanagisawa, T. et al. Repeat transurethral resection for non-muscle-invasive bladder cancer: an updated systematic review and meta-analysis in the contemporary era. Eur. Urol. Focus https://doi.org/10.1016/j.euf.2023.07.002 (2023).

    Article  PubMed  Google Scholar 

  221. Kirk, P. S. et al. Impact of maximal transurethral resection on pathological outcomes at cystectomy in a large, multi-institutional cohort. J. Urol. 209, 882–889 (2023).

    Article  PubMed  Google Scholar 

  222. Giacalone, N. J. et al. Long-term outcomes after bladder-preserving tri-modality therapy for patients with muscle-invasive bladder cancer: an updated analysis of the massachusetts general hospital experience. Eur. Urol. 71, 952–960 (2017).

    Article  PubMed  Google Scholar 

  223. 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 

  224. Teoh, J. Y.-C. 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. 39, 3353–3358 (2021).

    Article  PubMed  Google Scholar 

  225. Gallioli, A. et al. En bloc versus conventional transurethral resection of bladder tumors: a single-center prospective randomized noninferiority trial. Eur. Urol. Oncol. 5, 440–448 (2022).

    Article  PubMed  Google Scholar 

  226. D’Andrea, D. et al. En bloc versus conventional resection of primary bladder tumor (eBLOC): a prospective, multicenter, open-label, phase 3 randomized controlled trial. Eur. Urol. Oncol. https://doi.org/10.1016/j.euo.2023.07.010 (2023).

    Article  PubMed  Google Scholar 

  227. Teoh, Y. C. J. et al. A0707 — Transurethral en bloc resection versus standard resection of bladder tumour: a multi-center randomized trial (EB-StaR Study). Eur. Urol. 83, S997–S998 (2023).

    Article  Google Scholar 

  228. 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 

  229. Mertens, L. S., Meinhardt, W., Rier, W. B., Nooter, R. I. & Horenblas, S. Extravasation of intravesical chemotherapy for non-muscle-invasive bladder cancer. Urol. Int. 89, 332–336 (2012).

    Article  CAS  PubMed  Google Scholar 

  230. Xu, Y. et al. Comparing the treatment outcomes of potassium-titanyl-phosphate laser vaporization and transurethral electroresection for primary nonmuscle-invasive bladder cancer: a prospective, randomized study. Lasers Surg. Med. 47, 306–311 (2015).

    Article  PubMed  Google Scholar 

  231. Planelles Gómez, J. et al. Holmium YAG photocoagulation: safe and economical alternative to transurethral resection in small nonmuscle-invasive bladder tumors. J. Endourol. 31, 674–678 (2017).

    Article  PubMed  Google Scholar 

  232. Gofrit, O. N., Pode, D., Lazar, A., Katz, R. & Shapiro, A. Watchful waiting policy in recurrent Ta G1 bladder tumors. Eur. Urol. 49, 303–306 (2006).

    Article  PubMed  Google Scholar 

  233. Morales, A., Eidinger, D. & Bruce, A. W. Intracavitary bacillus calmette-guerin in the treatment of superficial bladder tumors. J. Urol. 116, 180–183 (1976).

    Article  CAS  PubMed  Google Scholar 

  234. 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 

  235. Balasubramanian, A. et al. Adjuvant therapies for non-muscle-invasive bladder cancer: advances during BCG shortage. World J. Urol. 40, 1111–1124 (2022).

    Article  PubMed  Google Scholar 

  236. Ourfali, S. et al. Recurrence rate and cost consequence of the shortage of Bacillus Calmette-Guérin Connaught strain for bladder cancer patients. Eur. Urol. Focus 7, 111–116 (2021).

    Article  PubMed  Google Scholar 

  237. 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 

  238. Balar, A. V. et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol. 22, 919–930 (2021).

    Article  CAS  PubMed  Google Scholar 

  239. Shang, P. F. et al. Intravesical Bacillus Calmette-Guérin versus epirubicin for Ta and T1 bladder cancer. Cochrane Database Syst. Rev. 5, CD006885 (2011).

    Google Scholar 

  240. 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 

  241. 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 

  242. Gschwend, J. E. et al. Extended versus limited lymph node dissection in bladder cancer patients undergoing radical cystectomy: survival results from a prospective, randomized trial. Eur. Urol. 75, 604–611 (2019).

    Article  PubMed  Google Scholar 

  243. Lerner, S. P. et al. SWOG S1011: a phase III surgical trial to evaluate the benefit of a standard versus an extended lymphadenectomy performed at time of radical cystectomy for muscle invasive urothelial cancer. J. Clin. Orthod. 41, 4508–4508 (2023).

    Google Scholar 

  244. Lee, R. K. et al. Urinary diversion after radical cystectomy for bladder cancer: options, patient selection, and outcomes. BJU Int. 113, 11–23 (2014).

    Article  PubMed  Google Scholar 

  245. Kowalewski, K.-F. et al. Robotic-assisted versus laparoscopic versus open radical cystectomy-a systematic review and network meta-analysis of randomized controlled trials. Eur. Urol. Focus 9, 480–490 (2023).

    Article  PubMed  Google Scholar 

  246. Zhang, J. H. et al. Large single institution comparison of perioperative outcomes and complications of open radical cystectomy, intracorporeal robot-assisted radical cystectomy and robotic extracorporeal approach. J. Urol. 203, 512–521 (2020).

    Article  PubMed  Google Scholar 

  247. Teoh, J. Y.-C. et al. Perioperative outcomes of robot-assisted radical cystectomy with intracorporeal versus extracorporeal urinary diversion. Ann. Surg. Oncol. 28, 9209–9215 (2021).

    Article  PubMed  Google Scholar 

  248. Baumann, B. C. et al. Validating a local failure risk stratification for use in prospective studies of adjuvant radiation therapy for bladder cancer. Int. J. Radiat. Oncol. Biol. Phys. 95, 703–706 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  249. Baumann, B. C. et al. Development and validation of consensus contouring guidelines for adjuvant radiation therapy for bladder cancer after radical cystectomy. Int. J. Radiat. Oncol. Biol. Phys. 96, 78–86 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  250. Zaghloul, M. S. et al. Adjuvant sandwich chemotherapy plus radiotherapy vs adjuvant chemotherapy alone for locally advanced bladder cancer after radical cystectomy: a randomized phase 2 trial. JAMA Surg. 153, e174591 (2018).

    Article  PubMed  Google Scholar 

  251. Peak, T. C. & Hemal, A. Partial cystectomy for muscle-invasive bladder cancer: a review of the literature. Transl. Androl. Urol. 9, 2938–2945 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  252. Compérat, E. et al. Current best practice for bladder cancer: a narrative review of diagnostics and treatments. Lancet 400, 1712–1721 (2022).

    Article  PubMed  Google Scholar 

  253. Huddart, R. A., Hall, E., Lewis, R. & Birtle, A., SPARE Trial Management Group. Life and death of spare (selective bladder preservation against radical excision): reflections on why the spare trial closed. BJU Int. 106, 753–755 (2010).

    Article  PubMed  Google Scholar 

  254. Vashistha, V. et al. Radical cystectomy compared to combined modality treatment for muscle-invasive bladder cancer: a systematic review and meta-analysis. Int. J. Radiat. Oncol. Biol. Phys. 97, 1002–1020 (2017).

    Article  PubMed  Google Scholar 

  255. Mak, R. H. et al. Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233. J. Clin. Oncol. 32, 3801–3809 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  256. Kamran, S. C. & Efstathiou, J. A. The legacy of RTOG/NRG protocols in shaping current bladder preservation therapy in North America. Semin. Radiat. Oncol. 33, 26–34 (2023).

    Article  PubMed  Google Scholar 

  257. James, N. D. et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N. Engl. J. Med. 366, 1477–1488 (2012).

    Article  CAS  PubMed  Google Scholar 

  258. Zlotta, A. R. et al. Radical cystectomy versus trimodality therapy for muscle-invasive bladder cancer: a multi-institutional propensity score matched and weighted analysis. Lancet Oncol. 24, 669–681 (2023). In the absence of randomized trials, this is the most definitive work suggesting that trimodality therapy for muscle-invasive bladder cancer is of value and should be considered in patient management.

    Article  PubMed  Google Scholar 

  259. Coen, J. J. et al. Bladder preservation with twice-a-day radiation plus fluorouracil/cisplatin or once daily radiation plus gemcitabine for muscle-invasive bladder cancer: NRG/RTOG 0712 — a randomized phase II trial. J. Clin. Oncol. 37, 44–51 (2019).

    Article  CAS  PubMed  Google Scholar 

  260. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03775265 (2023).

  261. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04241185 (2023).

  262. Pieretti, A. et al. Complications and outcomes of salvage cystectomy after trimodality therapy. J. Urol. 206, 29–36 (2021).

    Article  PubMed  Google Scholar 

  263. Yerramilli, D., Moghanaki, D. M. & Efstathiou, J. A. Safeguarding autonomy of patients with bladder cancer. Int. J. Radiat. Oncol. Biol. Phys. 103, 81–83 (2019).

    Article  PubMed  Google Scholar 

  264. Dahl, D. M. et al. NRG oncology/RTOG 0926: phase II protocol for patients with stage T1 bladder cancer to evaluate selective bladder preserving treatment by radiation therapy concurrent with radiosensitizing chemotherapy following a thorough transurethral surgical re-staging. Int. J. Radiat. Oncol. Biol. Phys. 111, S133–S134 (2021).

    Article  Google Scholar 

  265. Seisen, T. et al. Efficacy of high-intensity local treatment for metastatic urothelial carcinoma of the bladder: a propensity score-weighted analysis from the national cancer data base. J. Clin. Oncol. 34, 3529–3536 (2016).

    Article  PubMed  Google Scholar 

  266. Fischer-Valuck, B. W. et al. Association between local radiation therapy to the primary bladder tumor and overall survival for patients with metastatic urothelial cancer receiving systemic chemotherapy. Eur. Urol. Oncol. 5, 246–250 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  267. Lehmann, J. et al. Surgery for metastatic urothelial carcinoma with curative intent: the German experience (AUO AB 30/05). Eur. Urol. 55, 1293–1299 (2009).

    Article  PubMed  Google Scholar 

  268. Palma, D. A. et al. Stereotactic ablative radiotherapy for the comprehensive treatment of oligometastatic cancers: long-term results of the SABR-COMET phase II randomized trial. J. Clin. Oncol. 38, 2830–2838 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  269. International Collaboration of Trialists et al. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle-invasive bladder cancer: long-term results of the BA06 30894 trial. J. Clin. Oncol. 29, 2171–2177 (2011).

    Article  PubMed Central  Google Scholar 

  270. Grossman, H. B. et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N. Engl. J. Med. 349, 859–866 (2003).

    Article  CAS  PubMed  Google Scholar 

  271. Advanced Bladder Cancer (ABC) Meta-analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and meta-analysis of individual patient data advanced bladder cancer (ABC) meta-analysis collaboration. Eur. Urol. 48, 202–205 (2005).

    Article  Google Scholar 

  272. Galsky, M. D. et al. Comparative effectiveness of gemcitabine plus cisplatin versus methotrexate, vinblastine, doxorubicin, plus cisplatin as neoadjuvant therapy for muscle-invasive bladder cancer. Cancer 121, 2586–2593 (2015).

    Article  CAS  PubMed  Google Scholar 

  273. Flaig, T. W. et al. A randomized phase II study of coexpression extrapolation (COXEN) with neoadjuvant chemotherapy for bladder cancer (SWOG S1314; NCT02177695). Clin. Cancer Res. 27, 2435–2441 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. Pfister, C. et al. Dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin or gemcitabine and cisplatin as perioperative chemotherapy for patients with nonmetastatic muscle-invasive bladder cancer: results of the GETUG-AFU V05 VESPER trial. J. Clin. Oncol. 40, 2013–2022 (2022).

    Article  CAS  PubMed  Google Scholar 

  275. Sternberg, C. N. et al. Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial. Lancet Oncol. 16, 76–86 (2015).

    Article  PubMed  Google Scholar 

  276. Galsky, M. D. et al. Effectiveness of adjuvant chemotherapy for locally advanced bladder cancer. J. Clin. Oncol. 34, 825–832 (2016).

    Article  CAS  PubMed  Google Scholar 

  277. Bajorin, D. F. et al. Adjuvant nivolumab versus placebo in muscle-invasive urothelial carcinoma. N. Engl. J. Med. 384, 2102–2114 (2021). This trial demonstrated an improvement in disease-free survival with adjuvant PD1 inhibition versus placebo as adjuvant therapy for patients with high-risk muscle-invasive urothelial cancer after radical resection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  278. Bellmunt, J. et al. Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 22, 525–537 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  279. Loehrer, P. J. Sr et al. A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J. Clin. Oncol. 10, 1066–1073 (1992).

    Article  PubMed  Google Scholar 

  280. Gabrilove, J. L. et al. Effect of granulocyte colony-stimulating factor on neutropenia and associated morbidity due to chemotherapy for transitional-cell carcinoma of the urothelium. N. Engl. J. Med. 318, 1414–1422 (1988).

    Article  CAS  PubMed  Google Scholar 

  281. Sternberg, C. N. et al. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur. J. Cancer 42, 50–54 (2006).

    Article  CAS  PubMed  Google Scholar 

  282. von der Maase, H. et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J. Clin. Oncol. 23, 4602–4608 (2005).

    Article  PubMed  Google Scholar 

  283. Galsky, M. D. et al. A consensus definition of patients with metastatic urothelial carcinoma who are unfit for cisplatin-based chemotherapy. Lancet Oncol. 12, 211–214 (2011).

    Article  PubMed  Google Scholar 

  284. De Santis, M. et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J. Clin. Oncol. 30, 191–199 (2012).

    Article  PubMed  Google Scholar 

  285. Sharma, P. et al. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 18, 312–322 (2017).

    Article  CAS  PubMed  Google Scholar 

  286. Patel, M. R. et al. Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN Solid Tumor): pooled results from two expansion cohorts of an open-label, phase 1 trial. Lancet Oncol. 19, 51–64 (2018).

    Article  CAS  PubMed  Google Scholar 

  287. Bellmunt, J. et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N. Engl. J. Med. 376, 1015–1026 (2017). This trial demonstrated an improvement in survival with PD1 inhibition versus chemotherapy in patients with metastatic urothelial cancer progressing despite prior platinum-based chemotherapy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  288. Balar, A. V. et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 18, 1483–1492 (2017).

    Article  CAS  PubMed  Google Scholar 

  289. Balar, A. V. et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 389, 67–76 (2017).

    Article  CAS  PubMed  Google Scholar 

  290. Galsky, M. D. et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet 395, 1547–1557 (2020).

    Article  CAS  PubMed  Google Scholar 

  291. Powles, T. et al. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 22, 931–945 (2021).

    Article  CAS  PubMed  Google Scholar 

  292. Galsky, M. D. et al. Randomized double-blind phase II study of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients with metastatic urothelial cancer. J. Clin. Oncol. 38, 1797–1806 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  293. Powles, T. et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N. Engl. J. Med. 383, 1218–1230 (2020). This trial demonstrated an improvement in survival with switch maintenance PDL1 inhibition versus surveillance after first-line chemotherapy in patients with metastatic urothelial cancer.

    Article  CAS  PubMed  Google Scholar 

  294. Rugo, H. S. et al. LBA76 Overall survival (OS) results from the phase III TROPiCS-02 study of sacituzumab govitecan (SG) vs treatment of physician’s choice (TPC) in patients (pts) with HR+/HER2-metastatic breast cancer (mBC). Ann. Oncol. 33, S1386 (2022).

    Article  Google Scholar 

  295. Catto, J. W. F. et al. Quality of life after bladder cancer: a cross-sectional survey of patient-reported outcomes. Eur. Urol. 79, 621–632 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  296. Yoshimura, K. et al. Impact of superficial bladder cancer and transurethral resection on general health-related quality of life: an SF-36 survey. Urology 65, 290–294 (2005).

    Article  PubMed  Google Scholar 

  297. Siracusano, S. et al. Health-related quality of life after BCG or MMC induction for non-muscle invasive bladder cancer. Can. J. Urol. 25, 9480–9485 (2018).

    PubMed  Google Scholar 

  298. Wei, L., Li, Q., Liang, H. & Jianbo, L. The quality of life in patients during intravesical treatment and correlation with local symptoms. J. Chemother. 26, 165–168 (2014).

    Article  PubMed  Google Scholar 

  299. Yang, L. S. et al. A systematic review and meta-analysis of quality of life outcomes after radical cystectomy for bladder cancer. Surg. Oncol. 25, 281–297 (2016).

    Article  PubMed  Google Scholar 

  300. Khetrapal, P. et al. Robot-assisted radical cystectomy versus open radical cystectomy: a systematic review and meta-analysis of perioperative oncological and quality of life outcomes using randomized controlled trials. Eur. Urol. 84, 393–405 (2023).

    Article  PubMed  Google Scholar 

  301. Catto, J. W. F. et al. Effect of robot-assisted radical cystectomy with intracorporeal urinary diversion vs open radical cystectomy on 90-day morbidity and mortality among patients with bladder cancer: a randomized clinical trial. JAMA 327, 2092–2103 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  302. Efstathiou, J. A. et al. Late pelvic toxicity after bladder-sparing therapy in patients with invasive bladder cancer: RTOG 89-03, 95-06, 97-06, 99-06. J. Clin. Oncol. 27, 4055–4061 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  303. Huddart, R. A. et al. Patient-reported quality of life outcomes in patients treated for muscle-invasive bladder cancer with radiotherapy ± chemotherapy in the BC2001 phase III randomised controlled trial. Eur. Urol. 77, 260–268 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  304. Zietman, A. L. et al. Organ conservation in invasive bladder cancer by transurethral resection, chemotherapy and radiation: results of a urodynamic and quality of life study on long-term survivors. J. Urol. 170, 1772–1776 (2003).

    Article  PubMed  Google Scholar 

  305. Mak, K. S. et al. Quality of life in long-term survivors of muscle-invasive bladder cancer. Int. J. Radiat. Oncol. Biol. Phys. 96, 1028–1036 (2016).

    Article  PubMed  Google Scholar 

  306. Westergren, D.-O., Gårdmark, T., Lindhagen, L., Chau, A. & Malmström, P.-U. A nationwide, population based analysis of patients with organ confined, muscle invasive bladder cancer not receiving curative intent therapy in Sweden from 1997 to 2014. J. Urol. 202, 905–912 (2019).

    Article  PubMed  Google Scholar 

  307. Degboe, A., Ivanescu, C., Rohay, J. M., Turner, R. R. & Cella, D. Validity and performance of the Functional Assessment of Cancer Therapy-Bladder (FACT-Bl) among advanced urothelial cancer patients. Support. Care Cancer 27, 4189–4198 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  308. Kitamura, H. et al. Effect of neoadjuvant chemotherapy on health-related quality of life in patients with muscle-invasive bladder cancer: results from JCOG0209, a randomized phase III study. Jpn J. Clin. Oncol. 50, 1464–1469 (2020).

    Article  PubMed  Google Scholar 

  309. Witjes, J. A. et al. Health-related quality of life with adjuvant nivolumab after radical resection for high-risk muscle-invasive urothelial carcinoma: results from the phase 3 checkmate 274 trial. Eur. Urol. Oncol. 5, 553–563 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  310. Grivas, P. et al. Patient-reported outcomes from JAVELIN bladder 100: avelumab first-line maintenance plus best supportive care versus best supportive care alone for advanced urothelial carcinoma. Eur. Urol. 83, 320–328 (2023).

    Article  CAS  PubMed  Google Scholar 

  311. Vaughn, D. J. et al. Health-related quality-of-life analysis from KEYNOTE-045: a phase III study of pembrolizumab versus chemotherapy for previously treated advanced urothelial cancer. J. Clin. Oncol. 36, 1579–1587 (2018).

    Article  CAS  PubMed  Google Scholar 

  312. Mariotto, A. B., Enewold, L., Zhao, J., Zeruto, C. A. & Yabroff, K. R. Medical care costs associated with cancer survivorship in the United States. Cancer Epidemiol. Biomark. Prev. 29, 1304–1312 (2020).

    Article  Google Scholar 

  313. Leal, J., Luengo-Fernandez, R., Sullivan, R. & Witjes, J. A. Economic burden of bladder cancer across the European Union. Eur. Urol. 69, 438–447 (2016).

    Article  PubMed  Google Scholar 

  314. Botteman, M. F., Pashos, C. L., Redaelli, A., Laskin, B. & Hauser, R. The health economics of bladder cancer: a comprehensive review of the published literature. Pharmacoeconomics 21, 1315–1330 (2003).

    Article  PubMed  Google Scholar 

  315. Yeung, C., Dinh, T. & Lee, J. The health economics of bladder cancer: an updated review of the published literature. Pharmacoeconomics 32, 1093–1104 (2014).

    Article  PubMed  Google Scholar 

  316. 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 

  317. Kandoi, G., Acencio, M. L. & Lemke, N. Prediction of druggable proteins using machine learning and systems biology: a mini-review. Front. Physiol. 6, 366 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  318. Koprowski, R. & Foster, K. R. Machine learning and medicine: book review and commentary. Biomed. Eng. Online 17, 17 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  319. Sanli, O. et al. Bladder cancer. Nat. Rev. Dis. Primers 3, 17022 (2017).

    Article  PubMed  Google Scholar 

  320. Loriot, Y. et al. Erdafitinib in locally advanced or metastatic urothelial carcinoma. N. Engl. J. Med. 381, 338–348 (2019).

    Article  CAS  PubMed  Google Scholar 

  321. Powles, T. et al. Enfortumab vedotin in previously treated advanced urothelial carcinoma. N. Engl. J. Med. 384, 1125–1135 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  322. Hoimes, C. J. et al. Enfortumab vedotin plus pembrolizumab in previously untreated advanced urothelial cancer. J. Clin. Oncol. 41, 22–31 (2023).

    Article  CAS  PubMed  Google Scholar 

  323. Tagawa, S. T. et al. TROPHY-U-01: a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors. J. Clin. Oncol. 39, 2474–2485 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  324. Berglund, R. K. & Herr, H. W. in Campbell-Walsh Urology 10th edn (eds McDougal, W. et al.) Ch. 83, 2375 (Elsevier Health Sciences, 2011).

  325. Beer, N. Removal of neoplasms of the urinary bladder. A new method, employing high-frequency (oudin) currents through a catheterizing cystoscope. JAMA LIV, 1768–1769 (1910).

    Article  Google Scholar 

  326. Sternberg, C. N. et al. Preliminary results of M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for transitional cell carcinoma of the urothelium. J. Urol. 133, 403–407 (1985).

    Article  CAS  PubMed  Google Scholar 

  327. Sánchez de Badajoz, E. et al. Radical cystectomy and laparoscopic ileal conduit [Spanish]. Arch. Esp. Urol. 46, 621–624 (1993).

    PubMed  Google Scholar 

  328. Housset, M. et al. Combined radiation and chemotherapy for invasive transitional-cell carcinoma of the bladder: a prospective study. J. Clin. Oncol. 11, 2150–2157 (1993).

    Article  CAS  PubMed  Google Scholar 

  329. von der Maase, H. et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J. Clin. Oncol. 18, 3068–3077 (2000).

    Article  PubMed  Google Scholar 

  330. Menon, M. et al. Nerve-sparing robot-assisted radical cystoprostatectomy and urinary diversion. BJU Int. 92, 232–236 (2003).

    Article  CAS  PubMed  Google Scholar 

  331. Bellmunt, J. et al. Phase III trial of vinflunine plus best supportive care compared with best supportive care alone after a platinum-containing regimen in patients with advanced transitional cell carcinoma of the urothelial tract. J. Clin. Oncol. 27, 4454–4461 (2009).

    Article  CAS  PubMed  Google Scholar 

  332. Humphrey, P. et al. The 2016 WHO classification of tumours of the urinary system and male genital organs-part B: prostate and bladder tumours. Eur. Urol. 70, 106–119 (2016).

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark

    Lars Dyrskjøt

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

    Lars Dyrskjøt

  3. Division of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Donna E. Hansel

  4. Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Jason A. Efstathiou

  5. Division of Molecular Medicine, Leeds Institute of Medical Research at St James’s, St James’s University Hospital, Leeds, UK

    Margaret A. Knowles

  6. Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Matthew D. Galsky

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

    Jeremy Teoh

  8. Department of Urology, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Dan Theodorescu

  9. Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Dan Theodorescu

  10. Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA

    Dan Theodorescu

Authors
  1. Lars Dyrskjøt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Donna E. Hansel
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jason A. Efstathiou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Margaret A. Knowles
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Matthew D. Galsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jeremy Teoh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dan Theodorescu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Introduction (L.D. and D.T.); Epidemiology (D.E.H.); Mechanisms/pathophysiology (L.D., M.A.K. and D.T.); Diagnosis, screening and prevention (L.D., D.E.H., J.T. and J.A.E.); Management (J.T., J.A.E. and M.D.G.); Quality of life (J.T., J.A.E. and M.D.G.); Outlook (L.D. and D.T.); Overview of Primer (L.D. and D.T.).

Corresponding author

Correspondence to Dan Theodorescu.

Ethics declarations

Competing interests

L.D. has sponsored research agreements with Natera, C2i Genomics, AstraZeneca, Photocure and Ferring, has an advisory/consulting role at Ferring, MSD and UroGen, has received speaker honoraria from AstraZeneca, Pfizer and Roche, and is a board member for BioXpedia. D.E.H. is an advisory board member for AstraZeneca. M.D.G. receives or has received research funding from Bristol Myers Squibb, Novartis, Dendreon, AstraZeneca, Merck and Genentech. M.D.G. is or was a consultant for Bristol Myers Squibb, Merck, Genentech, AstraZeneca, Pfizer, EMD Serono, SeaGen, Janssen, Numab, Dragonfly, GlaxoSmithKline, Basilea, UroGen, Rappta Therapeutics, Alligator, Silverback, Fujifilm, Curis, Gilead, Bicycle, Asieris, Abbvie, Analogue Devices and Veracyte. J.A.E. is or was a consultant/advisory board member and receives or has received honoraria from Blue Earth Diagnostics, Boston Scientific, AstraZeneca, Lantheus, IBA, Astellas, Pfizer, Merck, Roivant Pharma, Myovant Sciences, Janssen, Bayer Healthcare, Progenics Pharmaceuticals, Genentech, Gilead, Angiodynamics and UptoDate. The other authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Disease Primers thanks A. Lopez-Beltran; Y. Lotan; P.-U. Malmström; A. Stenzl, who co-reviewed with A. Kielbik; and the other, anonymous, reviewer(s) 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.

Supplementary information

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

Dyrskjøt, L., Hansel, D.E., Efstathiou, J.A. et al. Bladder cancer. Nat Rev Dis Primers 9, 58 (2023). https://doi.org/10.1038/s41572-023-00468-9

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41572-023-00468-9

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