RADIUM-223. PLACE IN THE TREATMENT OF METASTATIC CASTRATION-REFRACTORY PROSTATE CANCER

Patients with castration-refractory prostate cancer (PC) are a complicated group of patients for treatment. At the time of diagnosis, 85% of patients have a localized tumor process, however, in 40% of patients, generalization of the tumor process is observed. The most common localization of prostate cancer metastasis is the skeletal bone, which affects up to 90% of cases.

At the same time, taking into account the increase in the morbidity of prostate cancer pathology, it dictates the need to search for new, more effective methods of treatment for this group of patients. Currently, there are six effective methods of treatment of metastatic castration-refractory prostate cancer (mCRPC): effects on androgenic stimulation (abiraterone acetate, enzalutamide); chemotherapy with drugs from the taxane group (docetaxel, cabazitaxel); immunotherapy (Sipuleucel-T), radionuclide therapy with Radium-223 chloride (Ksofigo®). 223Ra is a tropic to bone tissue alpha emitter, which, due to its high linear energy transfer and short transmission distance, provides an enhanced localized antitumor effect due to higher energy delivery. The article presents a literature review highlighting the mechanisms of development of castration refractoriness, the characteristic and efficacy of Radium-223 in the treatment of patients with metastatic castration-refractory prostate cancer.

1. Kaprin AD, Starinskii VV, Petrova GV. Malignant neoplasms in Russia in 2016 (morbidity and mortality). Мoscow: P. Hertsen Moscow Oncology Research Institute — Branch of the National Medical Radiology Research Centre, 2018, 250 p. Available at: http://www.oncology.ru/service/statistics/malignant_tumors/2016.pdf (In Russian).

2. Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015 Mar 1;136 (5): E359–86. DOI: 10.1002/ijc.29210.

3. Gupta N, Devgan A, Bansal I, Olsavsky TD, Li S, Abdelbaki A, Kumar Y. Usefulness of radium-223 in patients with bone metastases. Proc (Bayl Univ Med Cent). 2017 Oct;30 (4):424–426. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5595381/

4. Bubendorf L, Schöpfer A, Wagner U, Sauter G, Moch H, Willi N, et al. Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol. 2000 May;31 (5):578–83.

5. Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 2008 Mar 1;26 (7):1148–59. DOI: 10.1200/JCO.2007.12.4487

6. Taylor CD, Elson P, Trump DL. Importance of continued testicular suppression in hormone-refractory prostate cancer. J Clin Oncol. 1993 Nov;11 (11):2167–72. DOI: 10.1200/JCO.1993.11.11.2167

7. Beer TM, Tombal B. Enzalutamide in Metastatic Prostate Cancer before Chemotherapy. N Engl J Med. 2014 Oct 30;371 (18):1755–6. DOI: 10.1056/NEJMc1410239.

8. Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, Jones RJ, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COUAA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012 Oct;13 (10):983–92. DOI: 10.1016/S1470–2045 (12)70379–0

9. Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive 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 Feb;16 (2):152–60. DOI: 10.1016/S1470–2045 (14)71205–7

10. Berthold DR, Pond GR, Soban F, de Wit R, Eisenberger M, Tannock IF. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol. 2008 Jan 10;26 (2):242–5. DOI: 10.1200/JCO.2007.12.4008

11. de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010 Oct 2;376 (9747):1147–54. DOI: 10.1016/S0140–6736(10)61389-X

12. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer. N Engl J Med. 2004 Oct 7;351 (15):1502–12. DOI: 10.1056/NEJMoa040720

13. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T Immunotherapy for Castration-Resistant Prostate Cancer. N Engl J Med. 2010 Jul 29;363 (5):411–22. DOI: 10.1056/NEJMoa1001294.

14. Ibrahim T, Flamini E, Mercatali L, Sacanna E, Serra P, Amadori D. Pathogenesis of osteoblastic bone metastases from prostate cancer. Cancer. 2010 Mar 15;116 (6):1406–18. DOI: 10.1002/cncr.24896

15. Logothetis CJ, Lin SH. Osteoblasts in prostate cancer metastasis to bone. Nat Rev Cancer. 2005 Jan;5 (1):21–8. DOI: 10.1038/nrc1528

16. Festuccia C, Giunciuglio D, Guerra F, Villanova I, Angelucci A, Manduca P, et al. Osteoblasts modulate secretion of urokinase-type plasminogen activator (uPA) and matrix metalloproteinase-9 (MMP-9) in human prostate cancer cells promoting migration and matrigel invasion. Oncol Res. 1999;11 (1):17–31.

17. Armstrong AP, Miller RE, Jones JC, Zhang J, Keller ET, Dougall WC. RANKL acts directly on RANK-expressing prostate tumor cells and mediates migration and expression of tumor metastasis genes. Prostate. 2008 Jan 1;68 (1):92–104. DOI: 10.1002/pros.20678

18. Suominen MI, Fagerlund KM, Rissanen JP, Konkol YM, Morko JP, Peng Z, et al. Radium-223 Inhibits Osseous Prostate Cancer Growth by Dual Targeting of Cancer Cells and Bone Microenvironment in Mouse Models. Clin Cancer Res. 2017 Aug 1;23 (15):4335–4346. DOI: 10.1158/1078–0432.CCR-16–2955

19. Dauer LT, Williamson MJ, Humm J, O’Donoghue J, Ghani R, Awadallah R, et al. Radiation safety considerations for the use of 223RaCl₂ DE in men with castration-resistant prostate cancer. Health Phys. 2014 Apr;106 (4):494–504. DOI: 10.1097/HP.0b013e3182a82b37.

20. Bruland OS, Nilsson S, Fisher DR, Larsen RH. High-Linear Energy Transfer Irradiation Targeted to Skeletal Metastases by the -Emitter 223Ra: Adjuvant or Alternative to Conventional Modalities? Clin Cancer Res. 2006 Oct 15;12 (20 Pt 2):6250s-6257s. DOI: 10.1158/1078–0432.CCR-06–0841

21. File: Alfa beta gamma radiation penetration-RUS.svg — Wikimedia Commons [Internet]. URL: https://commons.wikimedia.org/wiki/File: Alfa_beta_gamma_radiation_penetration-RUS.svg (accessed 18.09.2017).

22. Nilsson S, Larsen RH, Fosså SD, Balteskard L, Borch KW, Westlin JE, et al. First Clinical Experience with -Emitting Radium-223 in the Treatment of Skeletal Metastases. Clin Cancer Res. 2005 Jun 15;11 (12):4451–9. DOI: 10.1158/1078–0432.CCR-04–2244

23. Nilsson S, Franzén L, Parker C, Tyrrell C, Blom R, Tennvall J, et al. Bone-targeted radium-223 in symptomatic, hormone-refractory prostate cancer: a randomised, multicentre, placebo-controlled phase II study. Lancet Oncol. 2007 Jul;8 (7):587–94. DOI: 10.1016/S1470–2045(07)70147-X

24. Nilsson S, Strang P, Aksnes AK, Franzèn L, Olivier P, Pecking A, et al. A randomized, dose-response, multicenter phase II study of radium-223 chloride for the palliation of painful bone metastases in patients with castration-resistant prostate cancer. Eur J Cancer. 2012 Mar;48 (5):678–86. DOI: 10.1016/j.ejca.2011.12.023

25. Parker CC, Pascoe S, Chodacki A, O’Sullivan JM, Germá JR, O’Bryan-Tear CG, et al. A randomized, double-blind, dose-finding, multicenter, phase 2 study of radium chloride (Ra 223) in patients with bone metastases and castration-resistant prostate cancer. Eur Urol. 2013 Feb;63 (2):189–97. DOI: 10.1016/j.eururo.2012.09.008

26. Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fosså SD, et al. Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer. N Engl J Med. 2013 Jul 18;369 (3):213–23. DOI: 10.1056/NEJMoa1213755

27. Sartor O, Hoskin P, Coleman RE, Nilsson S, Vogelzang NJ, Petrenciuc O, et al. Chemotherapy following radium-223 dichloride treatment in ALSYMPCA. Prostate. 2016 Jul;76 (10):905–16. DOI: 10.1002/pros.23180