Рекомендации по проведению тримодальной терапии рака мочевого пузыря (Невский консенсус 2021)

Цель работы – уточнение и дополнение клинических рекомендаций по органосохраняющему лечению мышечноинвазивного рака мочевого пузыря. Стандартный протокол радикального консервативного лечения мышечно-инвазивного рака мочевого пузыря включает трансуретральную резекцию мочевого пузыря, дистанционную лучевую терапию с одновременной химиотерапией (радиосенсибилизацию) и называется тримодальной терапией. Широкое внедрение тримодальной терапии в отечественную практику ограничено отсутствием четких критериев для каждого из этапов. Участие в протоколе хирургов, радиационных онкологов и химиотерапевтов, с одной стороны, обеспечивает необходимый мультидисциплинарный характер лечения онкологического больного, с другой – затрудняет реализацию всего алгоритма. Для осуществления поставленной задачи отделениями радиотерапии (модераторы проекта) и онкоурологии, а также отделением химиотерапии и инновационных технологий НМИЦ онкологии им. Н.Н. Петрова под эгидой Петербургского онкологического научного общества сформирована группа экспертов, включающая радиационных онкологов, онкоурологов и химиотерапевтов федеральных и городских онкологических (образовательных) учреждений (г. Санкт-Петербург), имеющих опыт лечения мышечно-инвазивного рака мочевого пузыря. Разработка рекомендаций велась с учетом имеющихся рекомендаций ведущих профессиональных радиотерапевтических и онкологических (урологических) ассоциаций, опубликованных статей и собственного опыта.

1. Злокачественные новообразования в России в 2019 году (заболеваемость и смертность). Под ред. А.Д. Каприна, В.В. Старинского, А.О. Шахзадовой. М.: МНИОИ им. П.А. Герцена – филиал ФГБУ «НМИЦ радиологии» Минздрава России, 2020. 252 с.

2. Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2020. CA Cancer J Clin 2020;70(1):7–30. DOI: 10.3322/caac.21590

3. Cumberbatch M.G.K., Jubber I., Black P.C. et al. Epidemiology of bladder cancer: a systematic review and contemporary update of risk factors in 2018. Eur Urol 2018;74(6):784–95. DOI: 10.1016/j.eururo.2018.09.001

4. Rodrigues Pessoa R., Mueller A.C., Boxley P. et al. Systematic review and meta‑analysis of radiation therapy for high‑risk non‑muscle invasive bladder cancer. Urol Oncol 2021;39(11):786.e1–8. DOI: 10.1016/j.urolonc.2021.03.009

5. Witjes J.A., Bruins H.M., Cathomas R. et al. European Association of Urology guidelines on muscle‑invasive and metastatic bladder cancer: summary of the 2020 guidelines. Eur Urol 2021;79(1):82–104. DOI: 10.1016/j.eururo.2020.03.055

6. Chang S.S., Bochner B.H., Chou R. et al. Treatment of non‑metastatic muscle‑invasive bladder cancer: AUA/ASCO/ASTRO/ SUO Guideline. J Urol 2017;198(3):552–9. DOI: 10.1016/j.juro.2017.04.086

7. Flaig T.W., Spiess P.E., Agarwal N. et al. Bladder cancer, version 3.2020, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw 2020;18(3):329–54. DOI: 10.6004/jnccn.2020.0011

8. Witjes J.A., Babjuk M., Bellmunt J. et al. EAU‑ESMO consensus statements on the management of advanced and variant bladder cancer – an international collaborative multistakeholder effort: under the auspices of the EAU‑ESMO guidelines committees. Eur Urol 2020;77(2):223–50. DOI: 10.1016/j.eururo.2019.09.035

9. Choi H., Park J.Y., Bae J.H., Tae B.S. Health‑related quality of life after radical cystectomy. Transl Androl Urol 2020;9(6):2997–3006. DOI: 10.21037/tau.2020.02.01

10. Hautmann R.E., de Petriconi R.C., Volkmer В.G. Lessons learned from 1,000 neobladders: the 90‑day complication rate. J Urol 2010;184(3):990–4. DOI: 10.1016/j.juro.2010.05.037

11. Nielsen M.E., Mallin K., Weaver M.A. et al. Association of hospital volume with conditional 90‑day mortality after cystectomy: an analysis of the National Cancer Data Base. BJU Int 2014;114(1):46–55. DOI: 10.1111/bju.12566

12. Maffezzini M., Fontana V., Pacchetti A. et al. Age above 70 years and Charlson Comorbidity Index higher than 3 are associated with reduced survival probabilities after radical cystectomy for bladder cancer. Data from a contemporary series of 334 consecutive patients. Arch Ital Urol Androl 2021;93(1):15–20. DOI: 10.4081/aiua.2021.1.15

13. Novotny V., Froehner M., Koch R. et al. Age, American Society of Anesthesiologists physical status classification and Charlson score are independent predictors of 90‑day mortality after radical cystectomy. World J Urol 2016;34(8):1123–9. DOI: 10.1007/s00345‑015‑1744‑8

14. Howlader N., Noone A.M., Krapcho M. et al. (2017) SEER cancer statistics review, 1975–2014. National Cancer Institute, Bethesda, MD. Available at: https://seer.cancer.gov/csr/1975_2014.

15. Kimura T., Ishikawa H., Kojima T. et al. Bladder preservation therapy for muscle invasive bladder cancer: the past, present and future. Jpn J Clin Oncol 2020;50(10):1097–107. DOI: 10.1093/jjco/hyaa155

16. Varughese M., Treece S., Drinkwater K.J. Radiotherapy management of muscle invasive bladder cancer: evaluation of a national cohort. Clin Oncol (R Coll Radiol) 2019;31(9):637–45. DOI: 10.1016/j.clon.2019.04.009

17. Giacalone N.J., Shipley W.U., Clayman R.H. et al. Long‑term outcomes after bladderpreserving tri‑modality therapy for patients with muscle‑invasive bladder cancer: an updated analysis of the Massachusetts General Hospital experience. Eur Urol 2017;71(6):952–60. DOI: 10.1016/j.eururo.2016.12.020

18. Francolini G., Borghesi S., Fersino S. et al. Treatment of muscle‑invasive bladder cancer in patients without comorbidities and fit for surgery: trimodality therapy vs radical cystectomy. Development of GRADE (Grades of Recommendation, Assessment, Development and Evaluation) recommendation by the Italian Association of Radiotherapy and Clinical Oncology (AIRO). Crit Rev Oncol Hematol 2021;159:103235. DOI: 10.1016/j.critrevonc.2021.103235

19. Kulkarni G.S., Hermanns T., Wei Y. et al. Propensity score analysis of radical cystectomy versus bladder‑sparing trimodal therapy in the setting of a multidisciplinary bladder cancer clinic. J Clin Oncol 2017;35(20):2299–305. DOI: 10.1200/JCO.2016.69.2327

20. Ding H., Fan N., Ning Z., Ma D. Trimodal therapy vs. radical cystectomy for muscleinvasive bladder cancer: a meta‑analysis. Front Oncol 2020;10:564779. DOI: 10.3389/fonc.2020.564779

21. Deuker M., Krimphove M.J., Stolzenbach L.F. et al. Radical cystectomy vs. multimodality treatment in T2N0M0 bladder cancer: a population‑based, agematched analysis. Clin Genitourin Cancer 2021;19(4):e264–71. DOI: 10.1016/j.clgc.2021.03.010

22. Pieretti A., Krasnow R., Drumm M. et al. Complications and outcomes of salvage cystectomy after trimodality therapy. J Urol 2021;206(1):29–36. DOI: 10.1097/JU.0000000000001696

23. Клинические рекомендации. Рак мочевого пузыря. Министерство здравоохранения Российской Федерации, 2020. Доступно по: https://cr.minzdrav.gov.ru.

24. Pieters B.R., van der Steen‑Banasik E., Smits G.A. et al. GEC‑ESTRO/ACROP recommendations for performing bladdersparing treatment with brachytherapy for muscle‑invasive bladder carcinoma. Radiother Oncol 2017;122(3):340–6. DOI: 10.1016/j.radonc.2016.12.022

25. Der Steen‑Banasik E.V., Oosterveld B., Smits G. et al. Perpetual role of brachytherapy in organ‑sparing treatment for bladder cancer: a historical review. J Contemp Brachytherapy 2020;12(6): 618–28. DOI: 10.5114/jcb.2020.101697

26. Heidegger I., Oberaigner W., Horninger W., Pichler R. High incidence of clinically significant concomitant prostate cancer in patients undergoing radical cystectomy for bladder cancer: a 10‑year single‑center experience. Urol Oncol 2017;35(4):152.e1–5. DOI: 10.1016/j.urolonc.2016.11.004

27. Kumar A., Cherry D.R., Courtney P.T. et al. Outcomes for muscle‑invasive bladder cancer with radical cystectomy or trimodal therapy in US veterans. Eur Urol Open Sci 2021;30:1–10. DOI: 10.1016/j.euros.2021.05.009

28. Zhu Z., Zhao J., Li Y. et al. Prognostic value of preoperative hydronephrosis in patients with bladder cancer undergoing radical cystectomy: a meta‑analysis. PLoS One 2019;14(9):e0222223. DOI: 10.1371/journal.pone.0222223

29. Krasnow R.E., Drumm M., Roberts H.J. et al. Clinical outcomes of patients with histologic variants of urothelial cancer treated with trimodality bladder‑sparing therapy. Eur Urol 2017;72(1):54–60. DOI: 10.1016/j.eururo.2016.12.002

30. Bertz S., Wach S., Taubert H. et al. Micropapillary morphology is an indicator of poor prognosis in patients with urothelial carcinoma treated with transurethral resection and radiochemotherapy. Virchows Arch 2016;469(3):339–44. DOI: 10.1007/s00428‑016‑1986‑x

31. Nagumo Y., Kojima T., Shiga M. et al. A single‑institute experience of trimodal bladder‑preserving therapy for histologic variants of urothelial carcinoma. Int J Clin Oncol 2020;25(2):354–61. DOI: 10.1007/s10147‑019‑01553‑4

32. Khalifa J., Supiot S., Pignot G. et al. Recommendations for planning and delivery of radical radiotherapy for localized urothelial carcinoma of the bladder. Radiother Oncol 2021;161:95–114. DOI: 10.1016/j.radonc.2021.06.011

33. Premo C., Apolo A.B., Agarwal P.K., Citrin D.E. Trimodality therapy in bladder cancer: who, what, and when? Urol Clin North Am 2015;42(2):169–80. DOI: 10.1016/j.ucl.2015.02.002

34. Hindson B.R., Turner S.L., Millar J.L. et al. RANZCR Faculty of Radiation Oncology Genito‑Urinary Group (FROGG). Australian & New Zealand Faculty of Radia‑tion Oncology Genito‑Urinary Group: 2011 consensus guidelines for curative radiotherapy for urothelial carcinoma of the bladder. J Med Imaging Radiat Oncol 2012;56(1):18–30. DOI: 10.1111/j.1754‑9485.2011.02336.x

35. Gofrit O.N., Meirovitz A., Frank S. et al. Trimodal therapy in T2–4aN0M0 bladder cancer – how to select the best candidate? Cancer Med 2020;9(22):8491–7. DOI: 10.1002/cam4.3478

36. Huddart R.A., Birtle A., Maynard L. et al. Clinical and patient‑reported outcomes of SPARE – a randomised feasibility study of selective bladder preservation versus radical cystectomy. BJU Int 2017; 120(5): 639–50. DOI: 10.1111/bju.13900

37. Freeman R.M. How urgent is urgency? A review of current methods of assessment. Int Urogynecol J Pelvic Floor Dysfunct 2005;16(2):93–5. DOI: 10.1007/s00192‑004‑1253‑6

38. Feldman A.S., Kulkarni G.S., Bivalacqua T.J. et al. Surgical challenges and considerations in tri‑modal therapy for muscle invasive bladder cancer. Urol Oncol 2021:S1078–1439(21)00012–0. DOI: 10.1016/j.urolonc.2021.01.013

39. Nguyen E.K., Yu H., Pond G. et al. Outcomes of trimodality bladder‑sparing therapy for muscle‑invasive bladder cancer. Can Urol Assoc J 2020;14(4):122–9. DOI: 10.5489/cuaj.5945

40. Russell C.M., Lebastchi A.H., Borza T. et al. The Role of transurethral resection in trimodal therapy for muscle‑invasive bladder cancer. Bladder Cancer 2016;2(4):381–94. DOI: 10.3233/BLC‑160076

41. Ouzaid I., Panthier F., Hermieu J.F., Xylinas E. Contemporary surgical and technical aspects of transurethral resection of bladder tumor. Transl Androl Urol 2019;8(1):21–4. DOI: 10.21037/tau.2019.01.04

42. Russo G.I., Sholklapper T.N., Cocci A. et al. Performance of narrow band imaging (NBI) and photodynamic diagnosis (PDD) fluorescence imaging compared to white light cystoscopy (WLC) in detecting non‑muscle invasive bladder cancer: a systematic review and lesion‑level diagnostic meta‑analysis. Cancers (Basel) 2021;13(17):4378. DOI: 10.3390/cancers13174378

43. Babjuk M., Burger M., Capoun O. et al. European Association of Urology guidelines on non‑muscle‑invasive bladder cancer (Ta, T1, and carcinoma in situ). Eur Urol 2021;81(1):75–94. DOI: 10.1016/j.eururo.2021.08.010

44. Новиков А.И., Леоненков Р.В., Темкин Д.Б. и др. Трансуретральная резекция карциномы мочевого пузыря, распространяющейся на устье мочеточника. Онкоурология 2021;17(2):104–11. DOI: 10.17650/1726‑9776‑2021‑17‑2104‑111

45. Hafeez S., Lewis R., Hall E., Huddart R. RAIDER trial management group. Advancing radiotherapy for bladder cancer: randomised phase II trial of adaptive image‑guided standard or dose‑escalated tumour boost radiotherapy (RAIDER). Clin Oncol (R Coll Radiol) 2021;33(6):e251–6. DOI: 10.1016/j.clon.2021.02.012

46. Nolan C.P., Forde E.J. A review of the use of fiducial markers for image‑guided bladder radiotherapy. Acta Oncol 2016;55(5):533–8. DOI: 10.3109/0284186X.2015.1110250

47. De Ridder M., Gerbrandy L.C., de Reijke T.M. et al. BioXmark® liquid fiducial markers for image‑guided radiotherapy in muscle invasive bladder cancer: a safety and performance trial. Br J Radiol 2020;93(1111):20200241. DOI: 10.1259/bjr.20200241

48. Russell B., Liedberg F., Khan М.S. et al. Systematic review and meta‑analysis of delay in radical cystectomy and the effect on survival in bladder cancer patients. Eur Urol Oncol 2020;3(2):239–49. DOI: 10.1016/j.euo.2019.09.008

49. Yin M., Joshi M., Meijer R.P. et al. Chemotherapy for muscle‑invasive bladder cancer: a systematic review and two‑step meta‑analysis. Oncologist 2016;21(6):708–15. DOI: 10.1634/theoncologist.2015‑0440

50. Vale C.L. Advanced Bladder Cancer (ABC) Meta‑analysis Collaboration. Neoadjuvant chemotherapy in invasive bladder cancer: update of a systematic review and metaanalysis of individual patient data advanced bladder cancer (ABC) meta‑analysis collaboration. Eur Urol 2005;48(2):202–6; discussion 205–6. DOI: 10.1016/j.eururo.2005.04.006

51. Griffiths G., Hall R., Sylvester R. et al. International phase III trial assessing neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscleinvasive bladder cancer: long‑term results of the BA06 30894 trial. J Clin Oncol 2011;29(16):2171–7. DOI: 10.1200/JCO.2010.32.3139

52. Kragelj B., Zaletel‑Kragelj L., Sedmak B. et al. Phase II study of radiochemotherapy with vinblastine in invasive bladder cancer. Radiother Oncol 2005;75(1):44–7. DOI: 10.1016/j.radonc.2005.01.007

53. Tester W., Caplan R., Heaney J. et al. Neoadjuvant combined modality program with selective organ preservation for invasive bladder cancer: results of Radiation Therapy Oncology Group phase II trial 8802. J Clin Oncol 1996;14(1):119–26. DOI: 10.1200/JCO.1996.14.1.119

54. Lin C.C., Hsu C.H., Cheng J.C. et al. Induction cisplatin and fluorouracil‑based chemotherapy followed by concurrent chemoradiation for muscle‑invasive blad‑der cancer. Int J Radiat Oncol Biol Phys 2009;75(2):442–8. DOI: 10.1016/j.ijrobp.2008.11.030

55. Smith Z.L., Christodouleas J.P., Keefe S.M. et al. Bladder preservation in the treatment of muscle‑invasive bladder cancer (MIBC): a review of the literature and a practical approach to therapy. BJU Int 2013;112(1):13–25. DOI: 10.1111/j.1464‑410X.2012.11762.x

56. Efstathiou J.A., Spiegel D.Y., Shipley W.U. et al. Long‑term outcomes of selective bladder preservation by combined‑modality therapy for invasive bladder cancer: the MGH experience. Eur Urol 2012;61(4):705–11. DOI: 10.1016/j.eururo.2011.11.010

57. Ajib K., Tjong M.C., Tan G.H. et al. Canadian experience of neoadjuvant chemotherapy on bladder recurrences in patients managed with trimodal therapy for muscle‑invasive bladder cancer. Can Urol Assoc J 2020;14(12):404–10. DOI: 10.5489/cuaj.6459

58. Royce T.J., Liu Y., Milowsky M.I. et al. Trimodality therapy with or without neoadjuvant chemotherapy for muscle‑invasive bladder cancer. Clin Genitourin Cancer 2021;19(4):362–8. DOI: 10.1016/j.clgc.2021.03.007

59. Mitin T., Dengina N., Chernykh M. et al. Management of muscle invasive bladder cancer with bladder preservation in Russia: a survey‑based analysis of current practice and the impact of an educational workshop on clinical expertise. J Cancer Educ 2021;36(5):1005–13. DOI: 10.1007/s13187‑020‑01728‑y

60. Cowan R.A., McBain C.A., Ryder W.D. et al. Radiotherapy for muscle‑invasive carcinoma of the bladder: results of a randomized trial comparing conventional whole bladder with dose‑escalated partial bladder radiotherapy. Int J Radiat Oncol Biol Phys 2004;59(1):197–207. DOI: 10.1016/j.ijrobp.2003.10.018

61. Huddart R.A., Hall E., Hussain S.A. et al. Randomized noninferiority trial of reduced high‑dose volume versus standard volume radiation therapy for muscle‑invasive bladder cancer: results of the BC2001 trial (CRUK/01/004). Int J Radiat Oncol Biol Phys 2013;87(2):261–9. DOI: 10.1016/j.ijrobp.2013.06.2044

62. Nixon R.G., Chang S.S., Lafleur B.J. et al. Carcinoma in situ and tumor multifocality predict the risk of prostatic urethral involvement at radical cystectomy in men with transitional cell carcinoma of the bladder. J Urol 2002;167(2 Pt 1):502–5. DOI: 10.1097/00005392‑200202000‑00012

63. Kefer J.C., Voelzke B.B., Flanigan R.C. et al. Risk assessment for occult malignancy in the prostate before radical cystectomy. Urology 2005;66(6):1251–5. DOI: 10.1016/j.urology.2005.07.006

64. Stein J.P., Penson D.F., Wu S.D., Skinner D.G. Pathological guidelines for orthotopic urinary diversion in women with bladder cancer: a review of the litera‑ture. J Urol 2007;178(3 Pt 1):756–60. DOI: 10.1016/j.juro.2007.05.013

65. Rödel C., Grabenbauer G.G., Kühn R. et al. Combined‑modality treatment and selective organ preservation in invasive bladder cancer: long‑term results. J Clin Oncol 2002;20(14):3061–71. DOI: 10.1200/JCO.2002.11.027

66. Arcangeli G., Arcangeli S., Strigari L. A systematic review and meta‑analysis of clinical trials of bladder‑sparing trimodality treatment for muscle‑invasive bladder cancer (MIBC). Crit Rev Oncol Hematol 2015;94(1):105–15. DOI: 10.1016/j.critrevonc.2014.11.007

67. Van Leeuwen C.M., Oei A.L., Crezee J. et al. The alfa and beta of tumours: a review of parameters of the linear‑quadratic model, derived from clinical radiotherapy studies. Radiat Oncol 2018;13(1):96. DOI: 10.1186/s13014‑018‑1040‑z

68. Hoskin P.J., Rojas A.M., Bentzen S.M., Saunders M.I. Radiotherapy with concurrent carbogen and nicotinamide in bladder carcinoma. J Clin Oncol 2010;28(33):4912–8. DOI: 10.1200/JCO.2010.28.4950

69. James N.D., Hussain S.A., Hall E. et al. Radiotherapy with or without chemotherapy in muscle‑invasive bladder cancer. N Engl J Med 2012;366(16):1477–88. DOI: 10.1056/NEJMoa1106106

70. Choudhury A., Swindell R., Logue J.P. et al. Phase II study of conformal hypofractionated radiotherapy with concurrent gemcitabine in muscle‑invasive bladder cancer. J Clin Oncol 2011;29(6):733–8. DOI: 10.1200/JCO.2010.31.5721

71. Thompson C., Joseph N., Sanderson B. et al. Tolerability of concurrent chemoradiation therapy with gemcitabine (GemX), with and without prior neoadjuvant chemotherapy, in muscle invasive bladder cancer. Int J Radiat Oncol Biol Phys 2017;97(4):732–9. DOI: 10.1016/j.ijrobp.2016.11.040

72. Hussain S.A., Stocken D.D., Peake D.R. et al. Long‑term results of a phase II study of synchronous chemoradiotherapy in advanced muscle invasive bladder cancer. Br J Cancer 2004;90(11):2106–11. DOI: 10.1038/sj.bjc.6601852

73. Choudhury A., Porta N., Hall E. et al. Hypofractionated radiotherapy in locally advanced bladder cancer: an individual patient data meta‑analysis of the BC2001 and BCON trials. Lancet Oncol 2021;22(2):246–55. DOI: 10.1016/S1470‑2045(20)30607‑0

74. Zietman A.L., Grocela J., Zehr E. et al. Selective bladder conservation using transurethral resection, chemotherapy, and radiation: management and consequences of Ta, T1, and Tis recurrence within the retained bladder. Urology 2001;58(3):380–5. DOI: 10.1016/s0090‑4295(01)01219‑5

75. Pos F.J., Hart G., Schneider C., Sminia P. Radical radiotherapy for invasive bladder cancer: what dose and fractionation schedule to choose? Int J Radiat Oncol Biol Phys 2006;64(4):1168–73. DOI: 10.1016/j.ijrobp.2005.09.023

76. Whalley D., Caine H., McCloud P. et al. Promising results with image guided intensity modulated radiotherapy for muscle invasive bladder cancer. Radiat Oncol 2015;10:205. DOI: 10.1186/s13014‑015‑0499‑0

77. Murthy V., Gupta P., Baruah K. et al. Adaptive radiotherapy for carcinoma of the urinary bladder: long‑term outcomes with dose escalation. Clin Oncol (R Coll Radiol) 2019;31(9):646–52. DOI: 10.1016/j.clon.2019.06.005

78. Hafeez S., Warren‑Oseni K., McNair H.A. et al. Prospective study delivering simultaneous integrated high‑dose tumor boost (≤70 Gy) with image guided adaptive radiation therapy for radical treatment of localized muscle‑invasive bladder cancer. Int J Radiat Oncol Biol Phys 2016;94(5):1022–30. DOI: 10.1016/j.ijrobp.2015.12.379

79. Kibrom A.Z., Knight K.A. Adaptive radiation therapy for bladder cancer: a review of adaptive techniques used in clinical practice. J Med Radiat Sci 2015;62(4):277–85. DOI: 10.1002/jmrs.129

80. Stein J.P., Lieskovsky G., Cote R. et al. Radical cystectomy in the treatment of invasive bladder cancer: long‑term results in 1,054 patients. J Clin Oncol 2001;19(3):666–75. DOI: 10.1200/JCO.2001.19.3.666

81. Tunio M.A., Hashmi A., Qayyum A. et al. Whole‑pelvis or bladder‑only chemoradiation for lymph node‑negative invasive bladder cancer: single‑institution experience. Int J Radiat Oncol Biol Phys 2012;82(3):e457–62. DOI: 10.1016/j.ijrobp.2011.05.051

82. Mari A., Kimura S., Foerster B. et al. A systematic review and meta‑analysis of the impact of lymphovascular invasion in bladder cancer transurethral resection specimens. BJU Int 2019;123(1):11–21. DOI: 10.1111/bju.14417

83. Werntz R.P., Smith Z.L., Packiam V.T. et al. The impact of lymphovascular invasion on risk of upstaging and lymph node metastasis at the time of radical cystectomy. Eur Urol Focus 2020;6(2):292–7. DOI: 10.1016/j.euf.2018.09.019

84. Goldsmith B., Baumann B.C., He J. et al. Occult pelvic lymph node involvement in bladder cancer: implications for definitive radiation. Int J Radiat Oncol Biol Phys 2014;88(3):603–10. DOI: 10.1016/j.ijrobp.2013.11.211

85. Hall E., Hussain S.A., Porta N. et al. BC2001 long‑term outcomes: a phase III randomized trial of chemoradiotherapy versus radiotherapy (RT) alone and standard RT versus reduced high‑dose volume RT in muscle‑invasive bladder cancer. J Clin Oncol 2017;35:280. DOI: 10.1200/JCO.2017.35.6_suppl.280

86. Джойнер М.С., ван дер Когель О.Д. Основы клинической радиобиологии. Гл. 18. Совместное применение лучевой и химиотерапии. Пер. с англ. М.: БИНОМ. Лаборатория знаний, 2013. 600 с.

87. Coen J.J., Zhang P., Saylor P.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 – а randomized phase II trial. J Clin Oncol 2019;37(1):44–51. DOI: 10.1200/JCO.18.00537

88. Гладков О. А., Зуков Р.А., Матвеев В. Б. и др. Практические рекомендации по лекарственному лечению рака мочевого пузыря. Злокачественные опухоли: Практические рекомендации RUSSCO 2021;11(32). DOI: 10.18027/2224‑5057‑2021‑11‑3s2‑32

89. Portner R., Bajaj A., Elumalai T. et al. A practical approach to bladder preservation with hypofractionated radiotherapy for localised muscle‑invasive bladder cancer. Clin Transl Radiat Oncol 2021;31:1–7. DOI: 10.1016/j.ctro.2021.08.003

90. Caffo O., Thompson C., De Santis M. et al. Concurrent gemcitabine and radiotherapy for the treatment of muscle‑invasive bladder cancer: a pooled individual data analysis of eight phase I–II trials. Radiother Oncol 2016;121(2):193–8. DOI: 10.1016/j.radonc.2016.09.006

91. Wettstein M.S., Rooprai J.K., Pazhepurackel C. et al. Systematic review and meta‑analysis on trimodal therapy versus radical cystectomy for muscleinvasive bladder cancer: does the current quality of evidence justify definitive conclusions? PLoS One 2019;14(4):e0216255. DOI: 10.1371/journal.pone.0216255

92. Mak R.H., Hunt D., Shipley W.U. et al. Long‑term outcomes in patients with muscleinvasive 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 2014;32(34):3801–9. DOI: 10.1200/JCO.2014.57.5548

93. Bladder cancer: diagnosis and management of bladder cancer: ©NICE (2015) Bladder cancer: diagnosis and management of bladder cancer. BJU Int 2017;120(6):755–65. DOI: 10.1111/bju.14045

94. Payne H., Adamson A., Bahl A. et al. Chemicaland radiation‑induced haemorrhagic cystitis: current treatments and challenges. BJU Int 2013;112(7):885– 97. DOI: 10.1111/bju.12291

95. Kool R., Marcq G., El‑Achkar A. et al. Refining assessment of response to radiation‑based therapy for muscleinvasive bladder cancer: is post‑treatment tumor bed biopsy always necessary? Urol Oncol 2021;39(5):299.e7–14. DOI: 10.1016/j.urolonc.2020.10.001

96. Spencer K., Jones C.M., Girdler R. et al. The impact of the COVID‑19 pandemic on radiotherapy services in England UK: a population‑based study. Lancet Oncol 2021;22(3):309–20. DOI: 10.1016/S1470‑2045(20)30743‑9

97. Mitin T., Choudhury A. The role of biomarkers in bladder preservation management of muscle‑invasive bladder cancer. World J Urol 2019;37(9):1767–72. DOI: 10.1007/s00345‑018‑2480‑7

98. Wu C.T., Chen W.C., Chang Y.H. et al. The role of PD‑L1 in the radiation response and clinical outcome for bladder cancer. Sci Rep 2016;6:19740. DOI: 10.1038/srep19740