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Der Nuklearmediziner 2015; 38(02): 131-137
DOI: 10.1055/s-0035-1548770
Diagnostik und Therapie des Prostatakarzinoms – Neue Entwicklungen
© Georg Thieme Verlag KG Stuttgart · New York

Radium-223 Chlorid zur Schmerztherapie bei ossärer Metastasierung des Prostatakarzinoms

K. Liepe
1   Klinik für Nuklearmedizin, Klinikum Frankfurt (Oder)
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Publication History

Publication Date:
09 June 2015 (online)

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Zusammenfassung

Die palliative Schmerztherapie mit Betastrahlern wird erst relativ spät und im fortgeschrittenem Tumorstadium eingesetzt, obwohl eine frühzeitige Therapie einen signifikant besseren Effekt in der Schmerzreduktion zeigt [7]. In einer randomisierten Phase-III-Studie (ALSYMPCA) mit dem Alphastrahler Radium-223 (Xofigo®) konnte erstmalig ein verlängertes Überleben der Patienten von 3,6 Monaten und somit wahrscheinlich ein tumorreduktiver Effekt der Therapie nachgewiesen werden [11] [29] [32]. Die Zeit bis zu einem skelettassoziierten Ereignis (SRE) wird dabei durch das Radium-223 um 5,5 Monate verlängert [29]. Die Nebenwirkungsrate der Therapie ist gering, wobei die Knochenmarktoxizität aufgrund der geringen Reichweite der Alphapartikel deutlich niedriger ausfällt als bei der Therapie mit Betapartikeln. Die Ausscheidung erfolgt vorwiegend über den Darm (13% der applizierten Aktivität) und weniger über die Nieren (2%) [5].

Zugelassen ist Xofigo® nur für das hormonrefraktäre Prostatakarzinom. Die Applikation erfolgt alle 4 Wochen 6-mal i. v. in einer Dosierung von 50 kBq/kg Körpergewicht Radium-223.

Unter Berücksichtigung des lebensverlängernden Effekts bei der palliativen Therapie mit Radium-223 sollte diese möglicherweise frühzeitiger in das Therapiemanagement eingebunden werden. In weiteren Studien sollte die Option einer Kombination mit einer Chemotherapie untersucht werden. Hier ist Radium-223 aufgrund seiner geringen Knochenmarktoxizität besonders interessant. Auch ein Cocktail mit Betastrahlern ist denkbar, um die Tumorzellen, die weiter von den ossären Strukturen entfernt liegen, zu erreichen.

Abstract

The palliative treatment in bone pain using beta-emitters are used often relative late in the therapeutic management, although an early treatment have a significant better pain palliation [7]. In a randomized phase III trial (ALSYMPCA) using radium-223 (Xofigo®) for the first-time, a longer overall survival of 3.6 months was observed in treated patients, as a sign for an anti-tumor effect [11] [29] [32]. The time to first skeletal-related events was significant longer in the therapy group compared to placebo. The rate of side effects is low; especially the bone marrow toxicity is lower in comparison to beta-emitters, due to the low range of alpha-particles. Elimination is mainly through the gastrointestinal tract (13% of applied activity) and only limited via renal excretion (2%) [5].

Xofigo® is only approved for castrate-resistant prostate cancer. Administration is six times with an interval of 4 weeks using 50 kBq/kg body weight intravenous.

An earlier treatment with Xofigo® should be discussed due the possible antitumor effects. Further studies should evaluate a combination with chemotherapy with respect to the low bone marrow toxicity of this agent. Also a cocktail with beta-emitters would be thinkable to get an effect on tumor cells which are located deeper in the osseous structures.

Schlüsselwörter

Radium-223 - Xofigo® - Radionuklidtherapie - Überlebensvorteil - Nebenwirkungen

Key words

radium-223 - Xofigo® - radionuclide therapy - overall survival benefit - side effects
 

  • Literatur

  • 1 Berthold DR, Pond GR, Soban F et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol 2008; 10: 242-245
    PubMedGoogle Scholar
  • 2 Biersack HJ, Palmedo H, Andris A et al. Palliation and survival after repeated (188)Re-HEDP therapy of hormone-refractory bone metastases of prostate cancer: a retrospective analysis. J Nucl Med 2011; 52: 1721-1726
    CrossrefPubMedGoogle Scholar
  • 3 Body JJ. Metastatic bone disease: clinical and therapeutic aspects. Bone 1992; 13 (Suppl. 01) S57-S62
    CrossrefPubMedGoogle Scholar
  • 4 Chiang PH, Wang HC, Lai YL et al. Zoledronic acid treatment for cancerous bone metastases: a phase IV study in Taiwan. J Cancer Res Ther 2013; 9: 653-659
    CrossrefPubMedGoogle Scholar
  • 5 Chittenden S, Hindorf C, Aksnes AK et al. Dosimetry and Pharmacoconetics of 223Ra Chloride in Patients with Bone Metastases due to Hormone Refractory Prostate Cancer. Eur J Nucl Med 2012; 39 (Suppl. 02) S308
    PubMedGoogle Scholar
  • 6 Coleman R, Aksnes AK, Naume B et al. A phase IIa, nonrandomized study of radium-223 dichloride in advanced breast cancer patients with bone-dominant disease. Breast Cancer Res Treat 2014; 145: 411-418
    CrossrefPubMedGoogle Scholar
  • 7 Dafermou AF, Colamussi PF, Giganti MF et al. A multicentre observational study of radionuclide therapy in patients with painful bone metastases of prostate cancer. Eur J Nucl Med 2001; 28: 788-798
    CrossrefPubMedGoogle Scholar
  • 8 de Bono JS, Logothetis CJ, Molina A et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011; 26: 1995-2005
    PubMedGoogle Scholar
  • 9 Ernst DS, Tannock IF, Winquist EW et al. Randomized, double-blind, controlled trial of mitoxantrone/prednisone and clodronate versus mitoxantrone/prednisone and placebo in patients with hormone-refractory prostate cancer and pain. J Clin Oncol 2003; 21: 3335-3342
    CrossrefPubMedGoogle Scholar
  • 10 Hindorf C, Chittenden S, Aksnes AK et al. Quantitative imaging of 223Ra-chloride (Alpharadin) for targeted alpha-emitting radionuclide therapy of bone metastases. Nucl Med Commun. 2012; 33: 726-732
    CrossrefPubMedGoogle Scholar
  • 11 Hoskin P, Sartor O, O'Sullivan JM 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, double-blind, phase 3 ALSYMPCA trial. Lancet Oncol 2014; 15: 1397-1406
    CrossrefPubMedGoogle Scholar
  • 12 http://www.ema.europa.eu/docs/de_DE/document_library/EPAR_-_Product_Information/human/002653/WC500156172.pdf
    PubMed
  • 13 Liepe K, Geidel HH, Bergmann R et al. Autoradiographic studies of rhenium-188-hydroxyethylidine diphosphonate in normal skeleton and osteoblastic bone metastases in a rat model of metastatic prostate cancer. Nucl Med Commun 2009; 30: 693-699
    CrossrefPubMedGoogle Scholar
  • 14 Liepe K, Kotzerke J. Internal radiotherapy of painful bone metastases. Methods 2011; 55: 258-270
    CrossrefPubMedGoogle Scholar
  • 15 Liepe K, Runge R, Kotzerke J. Systemic radionuclide therapy in pain palliation. Am J Hosp Palliat Care 2005; 22: 457-464
    CrossrefPubMedGoogle Scholar
  • 16 Liepe K. Alpharadin, a 223Ra-based alpha-particle-emitting pharmaceutical for the treatment of bone metastases in patients with cancer. Curr Opin Investig Drugs 2009; 10: 1346-1358
    PubMedGoogle Scholar
  • 17 Lin A, Ray ME. Targeted and systemic radiotherapy in the treatment of bone metastasis. Cancer Metastasis Rev 2006; 25: 669-675
    PubMedGoogle Scholar
  • 18 Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002; 2: 584-593
    CrossrefPubMedGoogle Scholar
  • 19 Nekolla EA, Walsh L, Spiess H. Incidence of malignant diseases in humans injected with radium-224. Radiat Res 2010; 174: 377-386
    CrossrefPubMedGoogle Scholar
  • 20 Nielsen OS, Munro AJ, Tannock IF. Bone metastases: pathophysiology and management policy. J Clin Oncol 1991; 9: 509-524
    PubMedGoogle Scholar
  • 21 Nielsen OS, Parker C, Haugen I et al. Radium-223 chloride, a first-in-class alpha-pharmaceutical with a benign safety profile for patients with castration-resistant prostate cancer (CRPC) and bone metastases: Combined analysis of phase I and II clinical trials. J Clin Oncol 2010; 28 absre 4678
    PubMedGoogle Scholar
  • 22 Nilsson S, Balteskard L, Fosså SD. Phase I study of Alpharadin2 (223Ra), and a-emitting bone-seeking agent in cancer patients with skeletal metastases. Eur J Nucl Med 2004; 31 (S2)(S290):Abstract 370
    PubMedGoogle Scholar
  • 23 Nilsson S, Franzén L, Parker C et al. Two-year survival follow-up of the randomized, double-blind, placebo-controlled phase II study of radium-223 chloride in patients with castration-resistant prostate cancer and bone metastases. Clin Genitourin Cancer 2013; 11: 20-23
    CrossrefPubMedGoogle Scholar
  • 24 Nilsson S, Larsen RH, Fossa SD et al. First clinical experience with alpha-emitting radium-223 in the treatment of skeletal metastases. Clin Cancer Res 2005; 11: 4451-4459
    CrossrefPubMedGoogle Scholar
  • 25 Nilsson S, Larsen RH, Fosså SD et al. First clinical experience with alpha-emitting radium-223 in the treatment of skeletal metastases. Clin Cancer Res 2005; 15: 4451-4459
    PubMedGoogle Scholar
  • 26 Nilsson S, Strang P, Aksnes AK 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; 48: 678-686
    CrossrefPubMedGoogle Scholar
  • 27 Nilsson S, Tomblyn M, Cislo P 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 abstr 5069
    PubMedGoogle Scholar
  • 28 Oefelein MG, Ricchiuti V, Conrad W et al. Skeletal fractures negatively correlate with overall survival in men with prostate cancer. J Urol 2002; 168: 1005-1007
    CrossrefPubMedGoogle Scholar
  • 29 Parker C, Nilsson S, Heinrich D et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369: 231-223
    PubMedGoogle Scholar
  • 30 Parker C, Pascoe S, Chodacki A 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; 63: 189-197
    CrossrefPubMedGoogle Scholar
  • 31 Portenoy RK. Cancer pain: pathophysiology and syndromes. Lancet 1992; 339: 1026-1031
    CrossrefPubMedGoogle Scholar
  • 32 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: 738-746
    CrossrefPubMedGoogle Scholar
  • 33 Serafini AN. Current status of systemic intravenous radiopharmaceuticals for the treatment of painful metastatic bone disease. Int J Radiat Oncol Biol Phys 1994; 30: 1187-1194
    CrossrefPubMedGoogle Scholar
  • 34 Shipman CM, Rogers MJ, Apperley JF et al. Bisphosphonates induce apoptosis in human myeloma cell lines: a novel anti-tumour activity. Br J Haematol 1997; 98: 665-672
    CrossrefPubMedGoogle Scholar
  • 35 Tu SM, Millikan RE, Mengistu B et al. Bone-targeted therapy for advanced androgen-independent carcinoma of the prostate: a randomised phase II trial. Lancet 2001; 357: 336-341
    CrossrefPubMedGoogle Scholar
  • 36 von Moos R, Sternberg C, Body JJ et al. Reducing the burden of bone metastases: current concepts and treatment options. Support Care Cancer 2013; 24: 1773-1783
    PubMedGoogle Scholar
  • 37 Wanke C, Pinkert P, Szermerski B et al. Design and preliminary results from RAPSODY – a study to estimate the effective dose to relatives of patients treated with Ra-223 dichloride in Germany. Eur J Nucl Med 2014; 41 (Suppl. 01) S271
    PubMedGoogle Scholar
  • 38 Weinfurt KP, Anstrom KJ, Castel LD et al. Effect of zoledronic acid on pain associated with bone metastasis in patients with prostate cancer. Ann Oncol 2006; 17: 986-989
    CrossrefPubMedGoogle Scholar
  • 39 Wick RR, Chmelevsky D, Gössner W. 224Ra: risk to bone and haematopoietic tissue in ankylosing spondylitis patients. Strahlentherapie Sonderb 1985; 80: 38-44
    PubMedGoogle Scholar
  • 40 World Health Organization . Cancer Pain Relief and Palliative Care: Report of a WHO Expert Committee. Geneva, Switzerland: World Health Organization; 1990
    Google Scholar