Системная альфа-радиотерапия радием-223: таргетное лечение больных кастрационно-резистентным раком предстательной железы с метастазами в кости

Спектр подходов к лечению кастрационно-резистентного рака предстательной железы в России включает химиотерапию (доцетаксел, кабазитаксел), ингибиторы андрогенного сигнала (абиратерон, энзалутамид) и системную альфа-радиотерапию (дихлорид радия-223). Радий-223 – радиоактивный кальциевый миметик, селективно кумулирующийся в метастатически пораженной костной ткани. В регистрационном исследовании доказано, что радий-223 достоверно увеличивает общую выживаемость и время до первого скелетного осложнения при кастрационно-резистентном раке предстательной железы с симптомными метастазами в кости у больных без висцеральных метастазов. Цель обзора – определение профиля пациентов, способных получить наибольший выигрыш от назначения системной радиотерапии, а также выделение оптимального места радия-223 в последовательности лекарственных агентов, применяемых при кастрационно-резистентном раке предстательной железы.

1. Tannock I.F., de Wit R., Berry W.R. et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351(15):1502–12. DOI: 10.1056/NEJMoa040720.

2. Freedland S.J., Richhariya A., Wang H. et al. Treatment patterns in patients with prostate cancer and bone metastasis among US community-based urology group practices. Urology 2012;80(2):293– 8. DOI: 10.1016/j.urology.2012.04.007.

3. Pezaro C.J., Omlin A., Lorente D. et al. Visceral disease in castration-resistant prostate cancer. Eur Urol 2014;65(2):270–3. DOI: 10.1016/j.eururo.2013.10.055.

4. Smith H.S. Painful osseous metastases. Pain Physician 2011;14:E373–403.

5. Coleman R.E. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res 2006;12:6243s–49s.

6. Som A., Tu S.M., Liu J. et al. Response in bone turnover markers during therapy predicts overall survival in patients with metastatic prostate cancer: analysis of three clinical trials. Br J Cancer 2012;107(9):1547–53. DOI: 10.1038/bjc.2012.436.

7. Tait C., Moore D., Hodgson C. et al. Quantification of skeletal metastases in castrate-resistant prostate cancer predicts progression-free and overall survival. BJU Int 2014;114(6b):E70–3. DOI: 10.1111/bju.12717.

8. Evans C.P., Higano C.S., Keane T. et al. The PREVAIL study: primary outcomes by site and extent of baseline disease for enzalutamide-treated men with chemotherapynaive metastatic castration-resistant prostate cancer. Eur Urol 2016;70(4):675–83. DOI: 10.1016/j.eururo.2016.03.017.

9. Asselah J., Sperlich C. Post-docetaxel options for further survival benefit in metastatic castration-resistant prostate cancer: questions of choice. Can Urol Assoc J 2013;7(1–2 Suppl 1):S11–7. DOI: 10.5489/cuaj.274.

10. Heidenreich A., Bastian P.J., Bellmunt J. et al. EAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol 2014;65(2):467–79. DOI: 10.1016/j.eururo.2013.11.002.

11. Носов Д. А., Гладков О. А., Королева И. А. и др. Практические рекомендации по лекарственному лечению рака предстательной железы. Злокачественные опухоли: практические рекомендации RUSSCO #3s2, 2018 (том 8). С. 458– 470.

12. Henriksen G., Breistol K., Bruland O.S. et al. Significant antitumor effect from boneseeking, alpha-particle-emitting Ra-223 demonstrated in an experimental skeletal metastases model. Cancer Res 2002;62:3120–5.

13. Brechbiel M.W. Targeted alpha-therapy: past, present, future? Dalton Trans 2007;21(43):4918–28. DOI: 10.1039/b704726f.

14. de Bono J.S., Oudard S., Ozguroglu M. et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet 2010;376(9747):1147–54. DOI: 10.1016/S0140-6736(10)61389-X.

15. Ryan C.J., Smith M.R., Fizazi K. et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapynaive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 2015;16(2):152–60. DOI: 10.1016/S1470-2045(14)71205-7.

16. Fizazi K., Scher H.I., Molina A. et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COUAA301 randomised, double-blind, placebocontrolled phase 3 study. Lancet Oncol 2012;13(10):983–92. DOI: 10.1016/S1470-2045(12)70379-0.

17. Beer T.M., Armstrong A.J., Rathkopf D. et al. Enzalutamide in men with chemotherapynaive metastatic castration-resistant prostate cancer: extended analysis of the phase 3 PREVAIL study. Eur Urol 2017;71(2):151–4. DOI: 10.1016/j.eururo.2016.07.032.

18. Scher H.I., Fizazi K., Saad F. et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 2012;367(13):1187–97. DOI: 10.1056/NEJMoa1207506.

19. Parker C., Nilsson S., Heinrich D. et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013;369(3):213–23. DOI: 10.1056/NEJMoa1213755.

20. Kantoff P.W., Higano C.S., Shore N.D. et al. Sipuleucel-T immunotherapy for castrationresistant prostate cancer. N Engl J Med 2010;363(5):411–22. DOI: 10.1056/NEJMoa1001294.

21. Kairemo K., Joensuu T., Rasulova N. et al. Evaluation of alpha – therapy with radium223-dichloride in castration resistant metastatic prostate cancer – the role of gamma scintigraphy in dosimetry and pharmacokinetics. Diagnostics (Basel) 2015;5(3):358– 68. DOI: 10.3390/diagnostics5030358.

22. Sartor O., Coleman R., Nilsson S. et al. Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial. Lancet Oncol 2014;15(7):738–46. DOI: 10.1016/S1470-2045(14)70183-4.

23. Hoskin P., Sartor O., O’Sullivan J.M. et al. Efficacy and safety of radium-223 dichloride in patients with castration-resistant prostate cancer and symptomatic bone metastases, with or without previous docetaxel use: a prespecified subgroup analysis from the randomised, doubleblind, phase 3 ALSYMPCA trial. Lancet Oncol 2014;15(12):1397–406. DOI: 10.1016/S1470-2045(14)70474-7.

24. Parker C., Finkelstein S.E., Michalski J.M. et al. Efficacy and safety of radium-223 dichloride in symptomatic castration-resistant prostate cancer patients with or without baseline opioid use from the phase 3 ALSYMPCA trial. Eur Urol 2016;70(5):875–83. DOI: 10.1016/j.eururo.2016.06.002.

25. Saad F. J Clin Oncol 2016;34(suppl; abstr 5082).

26. Sartor A.O., Amariglio R., Wilhelm S. et al. Correlation between baseline variables and survival in the radium-223 dichloride (Ra-223) phase III ALSYMPCA trial with attention to total ALP changes. J Clin Oncol 2013;31:5080.

27. Nilsson S., Cislo P., Sartor O. et al. Patient-reported quality-of-life analysis of radium-223 dichloride from the phase III ALSYMPCA study. Ann Oncol 2016;27(5):868–74. DOI: 10.1093/annonc/mdw065.

28. Parker C., Zhan L., Cislo P. et al. Effect of radium-223 dichloride (Ra-223) on hospitalisation: an analysis from the phase 3 randomised Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial. Eur J Cancer 2017;71:1–6. DOI: 10.1016/j.ejca.2016.10.020.

29. Saad F., Carles J., Gillessen S. et al. Radium-223 and concomitant therapies in patients with metastatic castration-resistant prostate cancer: an international, early access, open-label, single-arm phase 3b trial. Lancet Oncol 2016;17(9):1306–16. DOI: 10.1016/S1470-2045(16)30173-5.

30. Saad F. JCO, 2015;33:abst. 5034.

31. Cookson M.S., Roth B.J., Dahm P. et al. Castration-resistant prostate cancer: AUA guideline. American Urological Association. Available at: https://www.auanet.org/guidelines/castration-resistant-prostatecancer

32. Parker C., Gillessen S., Heidenreich A., Horwich A. Cancer of the prostate: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2015;26:v69–77. DOI: 10.1093/annonc/mdv222.

33. Saad F., Chi K.N., Finelli A. et al. The 2015 CUA-CUOG Guidelines for the management of castration-resistant prostate cancer (CRPC). Can Urol Assoc J 2015;9(3–4):90–6. DOI: 10.5489/cuaj.2526.

34. National Comprehensive Cancer Network. Clinical practice guidelines in oncology: prostate cancer version 2.2016. Fort Washington, PA: National Comprehensive Cancer Network, 2016.

35. Basch E., Loblaw D.A., Oliver T.K. et al. Systemic therapy in men with metastatic castration-resistant prostate cancer: American Society of Clinical Oncology and Cancer Care Ontario clinical practice guideline. J Clin Oncol 2014;32(30):3436–48. DOI: 10.1200/JCO.2013.54.8404.

36. Oh W.K., Tombal B.F., Delacruz A. et al. Recognizing symptom burden in advanced prostate cancer: a global patient and caregiver survey [abstract]. J Clin Oncol. 2016;34:abst 10124.

37. Men Who Speak Up. It’s time to speak up about advanced prostate cancer. Bayer. Available at: https://www.menwhospeakup.com/index.php

38. Sartor O., Hoskin P., Coleman R.E. et al. Chemotherapy following radium-223 dichloride treatment in ALSYMPCA. Prostate 2016;76(10):905–16. DOI: 10.1002/pros.23180.

39. Maughan B.L., Luber B., Nadal R., Antonarakis E.S. Comparing sequencing of abiraterone and enzalutamide in men with metastatic castration-resistant prostate cancer: a retrospective study. Prostate 2017;77(1):33–40. DOI: 10.1002/pros.23246.

40. Nordquist L.T., Shore N.D. Open-label phase II study evaluating the efficacy of concurrent administration of radium Ra 223 dichloride and abiraterone acetate in men with castration-resistant prostate cancer patients with symptomatic bone metastases. Presented at: 2016 ASCO Annual Meeting; June 3–7, 2016; Chicago, IL.

41. Smith M.R., Parker C., Tombal B.F. et al. ERA 223: a phase 3 trial of radium-223 dichloride (Ra-223) in combination with abiraterone acetate (abiraterone) and prednisone in the treatment of asymptomatic or mildly symptomatic chemotherapynaive patients (pts) with bone predominant metastatic castration-resistant prostate cancer (mCRPC) [abstract]. J Clin Oncol 2015;33:abstr TPS5082.

42. O’Sullivan J.M. ECC abstract 2561. Eur J Cancer 2015;51:S497–8.

43. Xofigo (radium-223 dichloride). Summary of Product Characteristics. Berlin, Germany: Bayer Pharma AG, 2016.

44. Xofigo (radium-223 dichloride). Full Prescribing Information, Bayer Health Care Pharmaceuticals Inc., Wayne, NJ, USA, 2013.

45. http://pharma.bayer.ru/scripts/pages/ru/catalog/xofigo.php

46. Morris M.J., Higano C.S., Scher H.I. et al. Effects of radium-223 dichloride (Ra-223) with docetaxel (D) vs D on prostatespecific antigen (PSA) and bone alkaline phosphatase (bALP) in patients (pts) with castration-resistant prostate cancer (CRPC) and bone metastases (mets): a phase 1/2a clinical trial [abstract]. J Clin Oncol 2015;33:abstr 5012.

47. Morris M.J., Loriot Y., Sweeney C. et al. Updated results: a phase I/IIa randomized trial of radium223 + docetaxel versus docetaxel in patients with castrationresistant prostate cancer and bone metastases. Presented at: 2016 ASCO Annual Meeting; June 3–7, 2016; Chicago, IL.

48. Nilsson S., Franzen L., Parker C. et al. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol 2007;8(7):587–94. DOI: 10.1016/S14702045(07)70147-X.

49. Finkelstein S.E., Michalski J.M., O’Sullivan J.M. et al. External beam radiation therapy (EBRT) use and safety with radium-223 dichloride (Ra-223) in patients (pts) with castration-resistant prostate cancer (CRPC) and symptomatic bone metastases (mets) from the ALSYMPCA trial. J Clin Oncol 2015;33:182.

50. Keizman D., Fosboel M.O., Reichegger H. et al. Imaging response during therapy with radium-223 for castration-resistant prostate cancer with bone metastasesanalysis of an international multicenter database. Prostate Cancer Prostatic Dis 2017;20(3):289–93. DOI: 10.1038/pcan.2017.6.

51. Blackledge M.D., Kohl D.M., Collins D.J. et al. Assessing response heterogeneity following radium 223 administration using whole body diffusion weighted MRI. Presented at: International Society for Magnetic Resonance in Medicine 25th Annual Meeting & Exhibition. April 22–27, 2017; Honolulu, HI.

52. Shore N.D. Radium-223 dichloride for metastatic castration-resistant prostate cancer: the urologist’s perspective. Urology. 2015;85(4):717–24. DOI: 10.1016/j.urology.2014.11.031.

53. Gillessen S., Omlin A., Attard G. et al. Management of patients with advanced prostate cancer: recommendations of the St Gallen Advanced Prostate Cancer Consensus Conference (APCCC) 2015. Ann Oncol 2015;26(8):1589–604. DOI: 10.1093/annonc/mdv257.

54. Morris M.J., Sartor A.O., Vogelzang N.J. et al. Effect of radium-223 dichloride (Ra-223) on pain from US EAP [abstract]. J Clin Oncol 2015;33:abstr 160.