BLADDER CANCER: CURRENT CHALLENGES AND PROSPECTS FOR PERSONALIZED THERAPY

Bladder cancer (BC) is one of the most common tumors of the urinary tract, ranking sixth among malignancies in developed countries. According to GLOBOCAN 2020, 573,000 new cases and 213,000 deaths connected with BC were reported globally. In the Russian Federation, 11,000-15,000 new cases are diagnosed annually, accounting for 3-4% of all cancer cases, with men being 4.5 times more likely to develop BC than women.

The majority of cases are non-muscle-invasive bladder cancer (NMIBC), with a five-year survival rate of approximately 90%, but a recurrence rate of 50-70%. Muscle-invasive bladder cancer (MIBC) has a five-year survival rate of 50-60% following radical cystectomy, which decreases to 5–10% in metastatic stages. Major risk factors include smoking (50-65% of cases), occupational exposure to carcinogens, and chronic inflammatory conditions.

Current treatments include transurethral resection (TUR), BCG therapy, chemotherapy, and immunotherapy. Targeted agents such as enfortumab vedotin and erdafitinib improve overall survival, reaching 26.1 months in combination with pembrolizumab. Future research focuses on advancing molecular profiling, improving organ-preserving strategies, and developing combined immunotherapy approaches.

1. Saginala, K., Barsouk, A., Aluru, J., Rawla, P., Padala, S., & Barsouk, A. Epidemiology of Bladder Cancer. Medical Sciences. 2020; 8(1): 15. https://doi.org/10.3390/medsci8010015. (In Engl).

2. Timofeev I.V., Alekseeva G.N., Petkau V.V., Zukov R.A., Mazhbich M.S., Semenov A.V., Statsenko G.B., Novikova O.Yu., Zaitsev I.V., Popova I.L., Gurina L.I., Mukhina M.A., Vladimirova L.Yu. Life expectancy of patients with metastatic bladder cancer the bubble in the Russian Federation: the results of the URRU multicenter registry study. Oncourology. 2021;17(3):102-109. https://doi.org/10.17650/1726-9776-2021-17-3-102-109. (In Russ).

3. Cumberbatch, M., & Noon, A. Epidemiology, aetiology and screening of bladder cancer. Translational Andrology and Urology. 2019; 8: 5-11. https://doi.org/10.21037/tau.2018.09.11. (In Engl).

4. Sanli, O., Dobruch, J., Knowles, M., Burger, M., Alemozaffar, M., Nielsen, M., & Lotan, Y. Bladder cancer. Nature Reviews Disease Primers. 2017; 3: 17022. https://doi.org/10.1038/nrdp.2017.22. (In Engl).

5. Dobruch, J., & Oszczudłowski, M. Bladder Cancer: Current Challenges and Future Directions. Medicina. 2021; 57(8): 749. https://doi.org/10.3390/medicina57080749. (In Engl).

6. Pane K, Mirabelli P, Coppola L, Illiano E, Salvatore M and Franzese M. New Roadmaps for Non-muscle-invasive Bladder Cancer With Unfavorable Prognosis. Front. Chem. 2020; 8:600. doi: 10.3389/fchem.2020.00600. (In Engl).

7. Hayashi, T., Fujita, K., Hayashi, Y., Hatano, K., Kawashima, A., McConkey, D. J., & Nonomura, N. Mutational Landscape and Environmental Effects in Bladder Cancer. International Journal of Molecular Sciences. 2020; 21(17): 6072. https://doi.org/10.3390/ijms21176072. (In Engl).

8. Kim, H., Kim, K., Lee, S., Swan, H., Kazmi, S., Kim, Y., Kim, K., Kim, M., Cha, J., Kang, T., Hann, H., & Ahn, H. Familial Risk and Interaction With Smoking and Alcohol Consumption in Bladder Cancer: A Population-Based Cohort Study. World Journal of Oncology. 2023:14: 382 391. https://doi.org/10.14740/wjon1639. (In Engl).

9. Chou, W., McGregor, B., Schmidt, A., Carvalho, F., Hirsch, M., Chang, S., Kibel, A., & Mossanen, M. (2021). Cyclophosphamideassociated bladder cancers and considerations for survivorship care: A systematic review.. Urologic oncology. 2021; 39(10): 678-685. https://doi.org/10.1016/j.urolonc.2021.05.017. (In Engl).

10. Babjuk, M., Burger, M., Compérat, E., Gontero, P., Mostafid, A., Palou, J., Van Rhijn, B., Rouprêt, M., Shariat, S., Sylvester, R., Zigeuner, R., Čapoun, O., Cohen, D., Escrig, J., Hernández, V., Peyronnet, B., Seisen, T., & Soukup, V. European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (TaT1 and Carcinoma In Situ) 2019 Update.. European urology. 2019; 76(5): 639-657. https://doi.org/10.1016/j.eururo.2019.08.016. (In Engl).

11. Babjuk, M., Burger, M., Čapoun, O., Cohen, D., Compérat, E., Escrig, J., Gontero, P., Liedberg, F., Masson-Lecomte, A., Mostafid, A., Palou, J., Van Rhijn, B., Rouprêt, M., Shariat, S., Seisen, T., Soukup, V., & Sylvester, R. European Association of Urology Guidelines on Non-muscle-invasive Bladder Cancer (Ta, T1, and Carcinoma in Situ).. European urology. 2021; 81(1): 75-94. https://doi.org/10.1016/j.eururo.2021.08.010. (In Engl).

12. Flaig, T. W., Spiess, P. E., Abern, M., Agarwal, N., Bangs, R., Buyyounouski, M. K., Chan, K., Chang, S. S., Chang, P., Friedlander, T., Greenberg, R. E., Guru, K. A., Herr, H. W., Hoffman-Censits, J., Kaimakliotis, H., Kishan, A. U., Kundu, S., Lele, S. M., Mamtani, R., Mian, O. Y., Michalski, J., Montgomery, J. S., Parikh, M., Patterson, A., Peyton, C., Plimack, E. R., Preston, M. A., Richards, K., Sexton, W. J., Siefker-Radtke, A. O., Stewart, T., Sundi, D., Tollefson, M., Tward, J., Wright, J. L., Cassara, C. J., & Gurski, L. A. NCCN Guidelines® Insights: Bladder Cancer, Version 3.2024: Featured Updates to the NCCN Guidelines. Journal of the National Comprehensive Cancer Network. 2024; 22(4): 216-225. Retrieved Nov 24, 2024, from https://doi.org/10.6004/jnccn.2024.0024. (In Engl).

13. Gurung, P., Barnett, A., Wilson, J., Hudson, J., Ward, D., Messing, E., & Bryan, R. Prognostic DNA Methylation Biomarkers in Highrisk Non-muscle-invasive Bladder Cancer: A Systematic Review to Identify Loci for Prospective Validation.. European urology focus. 2020; 6(4): 683 697. https://doi.org/10.1016/j.euf.2019.02.012. (In Engl).

14. Morgan, R., Yann, N., Aurelie, B. [et all.] ALBAN: An open label, randomized, phase III trial, evaluating efficacy of atezolizumab in addition to one year BCG (bacillus Calmette-Guerin) bladder instillation in BCG-naive patients with high-risk nonmuscle invasive bladder cancer (AFU-GETUG 37).. JCO 37, TPS4589-TPS4589. 2019; 37:15_suppl. DOI:10.1200/JCO.2019.37.15_suppl.TPS4589. (In Engl)

15. Chatterjee, A., Bakshi, G., Pal, M., Kapoor, A., Joshi, A., & Prakash, G. Perioperative therapy in muscle invasive bladder cancer. Indian Journal of Urology : IJU : Journal of the Urological Society of India. 2021; 37: 226-233. https://doi.org/10.4103/iju.IJU_540_20. (In Engl).

16. Joshua, M., & Black, P. Current Perioperative Therapy for Muscle Invasive Bladder Cancer.. Hematology/oncology clinics of North America. 2021; 35(3): 495-511. https://doi.org/10.1016/j.hoc.2021.02.002. (In Engl).

17. Kim, I., & Lee, H. Perioperative Systemic Treatment for Muscle-Invasive Bladder Cancer: Current Evidence and Future Perspectives. International Journal of Molecular Sciences. 2021; 22(13): 7201. https://doi.org/10.3390/ijms22137201. (In Engl).

18. Pederzoli, F., Bandini, M., Marandino, L., Raggi, D., Giannatempo, P., Salonia, A., Gallina, A., Briganti, A., Montorsi, F., & Necchi, A. Neoadjuvant Chemotherapy or Immunotherapy for Clinical T2N0 Muscle-invasive Bladder Cancer: Time to Change the Paradigm?. European urology oncology. 2021; 4(6): 1006-1010. https://doi.org/10.1016/j.euo.2020.07.006. (In Engl).

19. Matthew D. Galsky et al., Adjuvant Nivolumab in High-Risk Muscle-Invasive Urothelial Carcinoma: Expanded Efficacy From CheckMate 274. JCO 0, JCO. 2024; 24.00340. DOI:10.1200/JCO.24.00340. (In Engl).

20. Rosenberg, J. E., Powles, T., Sonpavde, G. P., Loriot, Y., Duran, I., Lee, J. L., Matsubara, N., Vulsteke, C., Castellano, D., Mamtani, R., Wu, C., Matsangou, M., Campbell, M., & Petrylak, D. P. EV-301 long-term outcomes: 24-month findings from the phase III trial of enfortumab vedotin versus chemotherapy in patients with previously treated advanced urothelial carcinoma. Annals of oncology : official journal of the European Society for Medical Oncology. 2023; 34(11): 1047–1054. https://doi.org/10.1016/j.annonc.2023.08.016. (In Engl).

21. O'Donnell, P. H., Milowsky, M. I., Petrylak, D. P., Hoimes, C. J., Flaig, T. W., Mar, N., Moon, H. H., Friedlander, T. W., McKay, R. R., Bilen, M. A., Srinivas, S., Burgess, E. F., Ramamurthy, C., George, S., Geynisman, D. M., Bracarda, S., Borchiellini, D., Geoffrois, L., Maroto Rey, J. P., Ferrario, C., … Rosenberg, J. E. Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2023; 41(25): 4107–4117. https://doi.org/10.1200/JCO.22.02887 (In Engl).

22. Kimura, T., Ishikawa, H., Kojima, T., Kandori, S., Kawahara, T., Sekino, Y., Sakurai, H., & Nishiyama, H. Bladder preservation therapy for muscle invasive bladder cancer: the past, present and future.. Japanese journal of clinical oncology. 2020; 50(10): 1097–1107. https://doi.org/10.1093/jjco/hyaa155. (In Engl).

23. Wettstein MS, Rooprai JK, Pazhepurackel C, Wallis CJD, Klaassen Z, [et al.] Systematic review and meta-analysis on trimodal therapy versus radical cystectomy for muscle-invasive bladder cancer: Does the current quality of evidence justify definitive conclusions?. PLOS ONE 2019; 14(4): e0216255. https://doi.org/10.1371/journal.pone.0216255. (In Engl).

24. Pingping Zhu. Neo Two-cancer Screening Benefits Both Nation and the People–A Response to Fight for Men’s Health: Call of Bladder Cancer and Prostate Cancer Screening. Cancer Plus. 2021; 3(1): 40–41. https://doi.org/10.18063/cp.v3i1.247. (In Engl).

25. Alifrangis, C., McGovern, U., Freeman, A. [et al.] Molecular and histopathology directed therapy for advanced bladder cancer. Nat Rev Urol. 2019; 16: 465-483. https://doi.org/10.1038/s41585-019-0208-0.

26. Tran, L., Xiao, J., Agarwal, N., Duex, J., & Theodorescu, D. Advances in bladder cancer biology and therapy. Nature Reviews Cancer. 2020; 21: 104-121. https://doi.org/10.1038/s41568-020-00313-1. (In Engl).

27. Thomas, J., & Sonpavde, G. (2022). Molecularly Targeted Therapy towards Genetic Alterations in Advanced Bladder Cancer. Cancers, https://doi.org/10.3390/cancers14071795. (In Engl).

28. Malone, E.R., Oliva, M., Sabatini, P.J.B. [et al.] Molecular profiling for precision cancer therapies. Genome Med. 2020; 12: 8. https://doi.org/10.1186/s13073-019-0703-1. (In Engl).

29. Sicklick, J., Kato, S., Okamura, R., Schwaederlé, M., Hahn, M., Williams, C., De, P., Krie, A., Piccioni, D., Miller, V., Ross, J., Ross, J., Benson, A., Webster, J., Stephens, P., Lee, J., Fanta, P., Lippman, S., Leyland-Jones, B., & Kurzrock, R. Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study. Nature medicine. 2019; 25: 744-750. https://doi.org/10.1038/s41591-019-0407-5. (In Engl).

30. Sardana, R., Mishra, S., Williamson, S., Mohanty, A., & Mohanty, S. Immune checkpoints and their inhibitors: Reappraisal of a novel diagnostic and therapeutic dimension in the urologic malignancies. Seminars in oncology. 2020; 47(6): 367-379. (In Engl). https://doi.org/10.1053/j.seminoncol.2020.09.002.