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Integrating Bone Targeting Radiopharmaceuticals Into the Management of Patients With Castrate-Resistant Prostate Cancer With Symptomatic Bone Metastases

  • Genitourinary Cancers (W Oh and M Galsky, Section Editors)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Metastatic castrate-resistant prostate cancer (CRPC) refers to the disease state in which metastatic prostate cancer fails to respond to androgen deprivation therapy (ADT). This can be manifest as a rising PSA, increase in radiographically measurable disease, or progression of clinical disease. Roughly 90 % of men with metastatic prostate cancer have bone metastases, which is a predictor of both morbidity and mortality. Historically, treatment has been palliative, consisting of external beam radiation therapy (EBRT) and pharmacological analgesics for pain control and osteoclast inhibitors, such as bisphosphonates and denosumab to mitigate skeletal-related events. Older radiopharmaceuticals, such as Strontium-89 and Samarium-153, are Beta-emitting agents that were found to provide palliation but were without survival benefit and carried high risks of myelosuppression. Radium-223 is an Alpha-emitting radiopharmaceutical that has demonstrated a significant overall survival benefit in men with metastatic CRPC, delay to symptomatic skeletal events (SSEs), and improvement in pain control, with a favorable toxicity profile compared with placebo. Unlike EBRT, Radium-223 has systemic uptake, with the potential to address several bone metastases concurrently and provides overall survival benefit. It is a simple administration with minimal complexity and shielding requirements in experienced hands. EBRT appears to provide a more rapid and dramatic palliative benefit to any given lesion. Because Radium-223 has limited myelosuppression, the two can be thoughtfully integrated, along with multiple agents, for the treatment of men with CRPC with symptomatic bone metastases. Given its excellent safety profile, there is interest and anecdotal safety combining Radium-223 with therapies, such as abiraterone and enzalutamide. Formal recommendations regarding combination therapies will require clinical trials. The use of Alpha-emitting radiopharmaceuticals in castrate-sensitive disease, in metastatic asymptomatic CRPC, the categorical sequencing amongst other treatments for CRPC, as well as the application to other primary pathologies, such as metastatic breast cancer, is currently evolving.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. American Cancer Society. Prostate Cancer. 2013.

  2. Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res. 2006;12(20 Pt 2):6243s–9s.

    Article  PubMed  Google Scholar 

  3. Nørgaard M, et al. Skeletal related events, bone metastasis and survival of prostate cancer: a population based cohort study in Denmark (1999 to 2007). J Urol. 184(1):162-167.

  4. Hess KR et al. Metastatic patterns in adenocarcinoma. Cancer. 2006;106(7):1624–33.

    Article  PubMed  Google Scholar 

  5. Fizazi K et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377(9768):813–22. Osteoclast inhibitors represent an important class of pharmaceutical in this patient population. This randomized study was seminal in establishing the superiority of Denosumab to the only bisphosphonate that has consistently demonstrated benefit, Zoledronic acid.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Lage MJ et al. The cost of treating skeletal-related events in patients with prostate cancer. Am J Manage Care. 2008;14(5):317–22.

    Google Scholar 

  7. Zustovich F, Fabiani F. Therapeutic opportunities for castration-resistant prostate cancer patients with bone metastases. Crit Rev Oncol Hematol. 2014;91(2):197–209.

    Article  PubMed  Google Scholar 

  8. From ASCO-prostate cancer: Chemohormonal therapy leads the way in prostate cancer. Nat Rev Clin Oncol. 2014;11(7):380. The E3805 trial was presented at ASCO 2014 and is practice changing. Although the subject of this study is beyond the scope of this review, the change in practice has future implications on the use of many of the CRPC modalities and sequencing.

  9. Tannock IF et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351(15):1502–12.

    Article  CAS  PubMed  Google Scholar 

  10. Hartsell WF et al. Randomized trial of short- versus long-course radiotherapy for palliation of painful bone metastases. J Natl Cancer Inst. 2005;97(11):798–804.

    Article  PubMed  Google Scholar 

  11. Steenland E et al. The effect of a single fraction compared to multiple fractions on painful bone metastases: a global analysis of the Dutch bone metastasis study. Radiother Oncol. 1999;52(2):101–9.

    Article  CAS  PubMed  Google Scholar 

  12. van der Linden YM et al. Single fraction radiotherapy is efficacious: a further analysis of the Dutch bone metastasis study controlling for the influence of retreatment. Int J Radiat Oncol Biol Phys. 2004;59(2):528–37.

    Article  PubMed  Google Scholar 

  13. 8 Gy single fraction radiotherapy for the treatment of metastatic skeletal pain: randomised comparison with a multifraction schedule over 12 months of patient follow-up. Bone pain trial working party. Radiother Oncol. 1999;52(2):111-21.

  14. Lutz S et al. Palliative radiotherapy for bone metastases: an ASTRO evidence-based guideline. Int J Radiat Oncol Biol Phys. 2011;79(4):965–76.

    Article  PubMed  Google Scholar 

  15. Roach 3rd M. Radium-223 vs EBRT for multiple painful bone metastases: is less more? Oncology (Williston Park). 2014;28(4):297–8.

    Google Scholar 

  16. Salazar OM et al. Fractionated half-body irradiation (HBI) for the rapid palliation of widespread, symptomatic, metastatic bone disease: a randomized phase III trial of the International Atomic Energy Agency (IAEA). Int J Radiat Oncol Biol Phys. 2001;50(3):765–75.

    Article  CAS  PubMed  Google Scholar 

  17. Ki Y et al. Fractionated wide-field radiation therapy followed by fractionated local-field irradiation for treating widespread painful bone metastasis. Int J Radiat Oncol Biol Phys. 2011;79(1):220–5.

    Article  PubMed  Google Scholar 

  18. Yamada Y et al. High-dose, single-fraction image-guided intensity-modulated radiotherapy for metastatic spinal lesions. Int J Radiat Oncol Biol Phys. 2008;71(2):484–90.

    Article  PubMed  Google Scholar 

  19. Gerszten PC et al. Radiosurgery for spinal metastases: clinical experience in 500 cases from a single institution. Spine (Phila Pa 1976). 2007;32(2):193–9.

    Article  Google Scholar 

  20. Rades D, Schild SE. Is stereotactic radiosurgery the best treatment option for patients with spinal metastases? Nat Clin Pract Oncol. 2007;4(7):400–1.

    Article  PubMed  Google Scholar 

  21. Gagnon GJ et al. Cyberknife radiosurgery for breast cancer spine metastases: a matched-pair analysis. Cancer. 2007;110(8):1796–802.

    Article  PubMed  Google Scholar 

  22. Sahgal A et al. Stereotactic body radiotherapy is effective salvage therapy for patients with prior radiation of spinal metastases. Int J Radiat Oncol Biol Phys. 2009;74(3):723–31.

    Article  PubMed  Google Scholar 

  23. Sahgal A et al. Vertebral compression fracture after spine stereotactic body radiotherapy: a multi-institutional analysis with a focus on radiation dose and the spinal instability neoplastic score. J Clin Oncol. 2013;31(27):3426–31.

    Article  PubMed  Google Scholar 

  24. Sahgal A et al. Vertebral compression fracture after stereotactic body radiotherapy for spinal metastases. Lancet Oncol. 2013;14(8):e310–20.

    Article  PubMed  Google Scholar 

  25. Rose PS et al. Risk of fracture after single fraction image-guided intensity-modulated radiation therapy to spinal metastases. J Clin Oncol. 2009;27(30):5075–9.

    Article  PubMed Central  PubMed  Google Scholar 

  26. Ryu S et al. RTOG 0631 phase 2/3 study of image guided stereotactic radiosurgery for localized (1-3) spine metastases: phase 2 results. Pract Radiat Oncol. 2014;4(2):76–81.

    Article  PubMed Central  PubMed  Google Scholar 

  27. Roque M et al. Radioisotopes for metastatic bone pain. Cochrane Database Syst Rev. 2003;4, CD003347.

    PubMed  Google Scholar 

  28. Vapiwala N, Glatstein E. Fighting prostate cancer with radium-223–not your Madame's isotope. N Engl J Med. 2013;369(3):276–8.

    Article  PubMed  Google Scholar 

  29. Janjan N et al. Therapeutic guidelines for the treatment of bone metastasis: a report from the American College of radiology appropriateness criteria expert panel on radiation oncology. J Palliat Med. 2009;12(5):417–26.

    Article  PubMed  Google Scholar 

  30. Pandit-Taskar N, Batraki M, Divgi CR. Radiopharmaceutical therapy for palliation of bone pain from osseous metastases. J Nucl Med. 2004;45(8):1358–65.

    CAS  PubMed  Google Scholar 

  31. Porter AT et al. Results of a randomized phase-III trial to evaluate the efficacy of strontium-89 adjuvant to local field external beam irradiation in the management of endocrine resistant metastatic prostate cancer. Int J Radiat Oncol Biol Phys. 1993;25(5):805–13.

    Article  CAS  PubMed  Google Scholar 

  32. Quilty PM et al. A comparison of the palliative effects of strontium-89 and external beam radiotherapy in metastatic prostate cancer. Radiother Oncol. 1994;31(1):33–40.

    Article  CAS  PubMed  Google Scholar 

  33. Zorga P et al. Effectiveness of strontium-89 palliative therapy in patients with painful bone metastases. Ann Acad Med Stetin. 2011;57(1):49–53. discussion 53.

    CAS  PubMed  Google Scholar 

  34. James N, et al. Clinical outcomes in patients with castrate-refractory prostate cancer (CRPC) metastatic to bone randomized in the factorial trapeze trial to docetaxel (D) with strontium-89 (Sr89), zoledronic acid (ZA), neither, or both. J Clin Oncol, 2013;31 no. 15_suppl LBA5000.

  35. Serafini AN et al. Palliation of pain associated with metastatic bone cancer using samarium-153 lexidronam: a double-blind placebo-controlled clinical trial. J Clin Oncol. 1998;16(4):1574–81.

    CAS  PubMed  Google Scholar 

  36. Sartor O et al. Samarium-153-Lexidronam complex for treatment of painful bone metastases in hormone-refractory prostate cancer. Urology. 2004;63(5):940–5.

    Article  PubMed  Google Scholar 

  37. Bruland OS et al. High-linear energy transfer irradiation targeted to skeletal metastases by the alpha-emitter 223Ra: adjuvant or alternative to conventional modalities? Clin Cancer Res. 2006;12(20 Pt 2):6250s–7s.

    Article  CAS  PubMed  Google Scholar 

  38. Xofigo® (radium Ra 223 dichloride) injection [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; May 2013.

  39. Parker C et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213–23. The ALSYMPCA trial is the first Phase III study to demonstrate and overall survival benefit with the use of a radiopharmaceutical and validated the use of an alpha emitter into the therapeutic armamentarium against CRPC. This is a seminal paper, which is essential for understanding the new landscape of radiopharmaceutical use in this patient population.

    Article  CAS  PubMed  Google Scholar 

  40. Sartor O 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. This analysis of the SSEs from ALSYMPCA provide a validation of which SSEs were improved most with Radium-223.

    Article  CAS  PubMed  Google Scholar 

  41. Nilsson S, et al. Patient-reported quality of life (QOL) analysis of radium-223 dichloride (Ra-223) evaluating pain relief from the phase 3 ALSYMPCA study. J Clin Oncol. 2014;32:5s, 2014 (suppl; abstr 5069).

  42. Nilsson S, Vogelzang N, Sartor AO, et al. 1.5-Year post-treatment follow-up of radium-223 dichloride (Ra-223) in patients with castration-resistant prostate cancer (CRPC) and bone metastases from the phase 3 ALSYMPCA study 9. Clin Adv Hematol Oncol. 2014;12(4 Suppl 11):9–10.

    Google Scholar 

  43. D'Amico AV. US Food and Drug Administration approval of drugs for the treatment of prostate cancer: a new era has begun. J Clin Oncol. 2014;32(4):362–4.

    Article  PubMed  Google Scholar 

  44. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines)®. Prostate Cancer. Version 4. 2013.

  45. Radium-223 Dichloride and Abiraterone Acetate Compared to Placebo and Abiraterone Acetate for Men With Cancer of the Prostate When Medical or Surgical Castration Does Not Work and When the Cancer Has Spread to the Bone, Has Not Been Treated With Chemotherapy and is Causing no or Only Mild Symptoms; NCT02043678. ClinicalTrials.gov, 2014.

  46. Saad F et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst. 2004;96(11):879–82.

    Article  CAS  PubMed  Google Scholar 

  47. Tran C et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324(5928):787–90.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Scher HI et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187–97. The AFFIRM study provided a practice-changing therapeutic modality in the spectrum of CRPC treatment in the post-docetaxel grouping.

    Article  CAS  PubMed  Google Scholar 

  49. de Bono JS et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364(21):1995–2005. The COU-AA-301 trial is a seminal publication in the CRPC treatment landscape. It introduced abiraterone as a first line potential treatment modality in the post-docetaxel space.

    Article  PubMed Central  PubMed  Google Scholar 

  50. Fizazi K et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012;13(10):983–92. The COU-AA-301 trial is a seminal publication in the CRPC treatment landscape. It introduced abiraterone as a first line potential treatment modality in the post-docetaxel space.

    Article  CAS  PubMed  Google Scholar 

  51. Logothetis CJ et al. Effect of abiraterone acetate and prednisone compared with placebo and prednisone on pain control and skeletal-related events in patients with metastatic castration-resistant prostate cancer: exploratory analysis of data from the COU-AA-301 randomised trial. Lancet Oncol. 2012;13(12):1210–7. Significant to this topic, this publication highlighted the ability of abiraterone to decrease skeletal events.

    Article  CAS  PubMed  Google Scholar 

  52. Ryan CJ et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368(2):138–48. This paper also is practice changing, introducing abiraterone as a viable treatment option for CRPC in the predocetaxel space, also demonstrated an improvement in skeletal events.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Conflict of Interest

Seth R. Blacksburg is on the Speaker’s Bureau for Bayer Pharmaceuticals. Matthew R. Witten and Jonathan A. Haas have received speaker’s honoraria from Accuray.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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  1. Winthrop-University Hospital, 259 First Street, Mineola, NY, 11501, USA

    Seth R. Blacksburg MD, MBA, Matthew R. Witten PhD & Jonathan A. Haas MD

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  1. Seth R. Blacksburg MD, MBA
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  3. Jonathan A. Haas MD
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Correspondence to Seth R. Blacksburg MD, MBA.

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This article is part of the Topical Collection on Genitourinary Cancers

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Blacksburg, S.R., Witten, M.R. & Haas, J.A. Integrating Bone Targeting Radiopharmaceuticals Into the Management of Patients With Castrate-Resistant Prostate Cancer With Symptomatic Bone Metastases. Curr. Treat. Options in Oncol. 16, 11 (2015). https://doi.org/10.1007/s11864-014-0325-1

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