Osteologie 2014; 23(04): 269-274
DOI: 10.1055/s-0037-1622026
Osteoonkologie
Schattauer GmbH

Radionuklidtherapie im Behandlungskonzept von Knochenmetastasen

Role of radiopharmaceuticals in the treatment of metastatic bone disease
T. Todenhöfer*
1   Klinik für Urologie, Eberhard-Karls-Universität Tübingen, Deutschland
2   Vancouver Prostate Centre, University of British Columbia, Vancouver, Kanada
,
M. Müller*
3   Klinik für Nuklearmedizin, Eberhard-Karls-Universität Tübingen, Deutschland
› Author Affiliations
Further Information

Publication History

eingereicht: 28 July 2014

angenommen: 07 October 2014

Publication Date:
02 January 2018 (online)

Zusammenfassung

Die durch Knochenmetastasen hervorgerufenen Komplikationen und Schmerzen führen zu einer erheblichen Beeinträchtigung der Lebensqualität. Im Rahmen eines multimodalen Therapiekonzeptes für die Behandlung von Knochenmetastasen ist eine effektive Analgesie unverzichtbar. β-Strahler wie Strontium-89-Chlorid und Samarium- 153-EDTMP können vor allem bei Patienten mit osteoblastisch metastasierten Tumoren eine signifikante Schmerzreduktion erzielen. Die mit der Substanzgruppe verbundene Hämatotoxizität hat jedoch bisher zu einem zurückhaltenden Einsatz der Substanzen geführt. Des Weiteren ist diese Zurückhaltung auch auf die geringe Anzahl an prospektiv randomisierten Studien zurückzuführen. Für den β-Strahler Radium-223-Chlorid konnte in einer großen randomisierten Studie neben einer Schmerzreduktion eine Verlängerung des medianen Gesamtüberlebens von Patienten mit kastrationsrefraktärem Prostatakarzinom um 2,8 Monate (14 vs. 11,2 Monate im Placeboarm) beobachtet werden. Diese Effekte waren mit einer im Vergleich zu β-Strahlern deutlich niedrigeren Hämatotoxizität assoziiert. Die vielversprechenden Ergebnisse von Radium-223-Chlorid lassen einen vermehrten Einsatz von Radionukliden bei Patienten mit Prostatakarzinom erwarten.

Summary

The presence of metastastic bone disease has a significant impact on mortality and morbidity of patients with advanced tumour disease. Skeletal related events and tumor-associated bone pain lead to a decrease of quality of life. A multimodal approach is of utmost importance in the management of symptomatic metastatic bone disease. Besides analgetic drugs and external radiotherapy, radiopharmaceuticals are effective tools in the treatment of bone pain. Beta-emitters such as Strontium-189-chloride and Samarium- 153-EDTMP have shown promising effects on tumour- associated pain mainly in patients with osteoblastic metastases from prostate cancer. However, the hematotoxicity of betaemitters has led to a relatively restrained use. In metastatic breast cancer, the low number of prospective randomized trials also causes the reluctance of using radiopharmaceuticals. The alpha-emitter Radium-223-chloride has been investigated in a large randomized phase III trial in patients with metastatic castration- resistant prostate cancer. Compared to placebo, the administration of Radium-223-chloride every four weeks led to a significant delay of symptomatic skeletal related events and a significant improvement of pain. Most importantly, median overall survival of patients receiving Radium- 223-chloride was significantly improved compared to placebo (14 vs. 11.2 months). The rate of hematologic side effects was relatively moderate compared to betaemitters. The substance is currently investigated in combination with several other antitumour drugs in prostate cancer. Moreover, a phase II trial in breast cancer shows promising effects on bone-turnover markers and metabolic activity of bone metastases.

* Beide Autoren haben den gleichen Anteil an der Publikation.


 
  • Literatur

  • 1 von Moos R, Body JJ, Egerdie B. et al. Pain and health-related quality of life in patients with advanced solid tumours and bone metastases: integrated results from three randomized, doubleblind studies of denosumab and zoledronic acid. Support Care Cancer 2013; 21: 3497-3507.
  • 2 Chow E, van der Linden YM, Roos D. et al. Single versus multiple fractions of repeat radiation for painful bone metastases: a randomised, controlled, noninferiority trial. Lancet Oncol 2014; 15: 164-171.
  • 3 Leitlinien der Deutschen Gesellschaft für Nuklearmedizin e. V. (DGN). Radionuklidtherapie bei schmerzhaften Knochenmetastasen. 2014
  • 4 Collins C, Eary JF, Donaldson G. et al. Samarium-153-EDTMP in bone metastases of hormone refractory prostate carcinoma: a phase I/II trial. J Nucl Med 1993; 34: 1839-1844.
  • 5 Palmedo H, Guhlke S, Bender H. et al. Dose escalation study with rhenium-188 hydroxyethylidene diphosphonate in prostate cancer patients with osseous metastases. Eur J Nucl Med 2000; 27: 123-130.
  • 6 Liepe K, Kotzerke J. A comparative study of 188Re-HEDP, 186Re-HEDP, 153Sm-EDTMP and 89Sr in the treatment of painful skeletal metastases. Nucl Med Commun 2007; 28: 623-630.
  • 7 Liepe K, Franke WG, Kropp J. et al. [Comparison of rhenium-188, rhenium-186-HEDP and strontium-89 in palliation of painful bone metastases]. Nuklearmedizin 2000; 39: 146-151.
  • 8 Dafermou A, Colamussi P, Giganti M. 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.
  • 9 Sinzinger H, Palumbo B, Ozker K. The Vienna protocol and perspectives in radionuclide therapy. Q J Nucl Med Mol Imaging 2011; 55: 420-430.
  • 10 Dickie GJ, Macfarlane D. Strontium and samarium therapy for bone metastases from prostate carcinoma. Australas Radiol 1999; 43: 476-479.
  • 11 Nair N. Relative efficacy of 32P and 89Sr in palliation in skeletal metastases. J Nucl Med 1999; 40: 256-261.
  • 12 Parker C, Nilsson S, Heinrich D. et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med 2013; 369: 213-223.
  • 13 Ritter MA, Cleaver JE, Tobias CA. High-LET radiations induce a large proportion of non-rejoining DNA breaks. Nature 1977; 266 (5603): 653-655.
  • 14 Bruland ØS, Nilsson S, Fisher DR, Larsen RH. 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-6257s.
  • 15 Sgouros G, Roeske JC, McDevitt MR. et al. MIRD Pamphlet No. 22 (abridged): radiobiology and dosimetry of alpha-particle emitters for targeted radionuclide therapy. J Nucl Med 2010; 51: 311-328.
  • 16 Brahme A. Accurate description of the cell survival and biological effect at low and high doses and LET’s. J Radiat Res 2011; 52: 389-407.
  • 17 Wenzl T, Wilkens JJ. Theoretical analysis of the dose dependence of the oxygen enhancement ratio and its relevance for clinical applications. Radiat Oncol 2011; 06: 171.
  • 18 Silberstein EB. The treatment of painful osseous metastases with phosphorus-32-labeled phosphates. Semin Oncol 1993; 20: 10-21.
  • 19 Mathe D, Balogh L, Polyak A. et al. Multispecies animal investigation on biodistribution, pharmacokinetics and toxicity of 177Lu-EDTMP, a potential bone pain palliation agent. Nucl Med Biol 2010; 37: 215-226.
  • 20 Bryan JN, Bommarito D, Kim DY. et al. Comparison of systemic toxicities of 177Lu-DOTMP and 153Sm-EDTMP administered intravenously at equivalent skeletal doses to normal dogs. J Nucl Med Technol 2009; 37: 45-52.
  • 21 Yuan J, Liu C, Liu X. et al. Efficacy and safety of 177Lu-EDTMP in bone metastatic pain palliation in breast cancer and hormone refractory prostate cancer: a phase II study. Clin Nucl Med 2013; 38: 88-92.
  • 22 Shinto AS, Shibu D, Kamaleshwaran KK. et al. 177Lu-EDTMP for treatment of bone pain in patients with disseminated skeletal metastases. J Nucl Med Technol 2014; 42: 55-61.
  • 23 Mottet N, Bellmunt J, Bolla M. et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol 2011; 59: 572-583.
  • 24 Serafini AN. Samarium Sm-153 lexidronam for the palliation of bone pain associated with metastases. Cancer 2000; 88: 2934-2939.
  • 25 Serafini AN, Houston SJ, Resche I. 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: 1574-1581.
  • 26 Bubendorf L, Schopfer A, Wagner U. et al. Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol 2000; 31: 578-583.
  • 27 Schoeneich G, Muller SC, Palmedo H. [Indications for nuclear medicine therapy in advanced prostate carcinoma]. Urologe A 1998; 37: 162-166.
  • 28 Kraeber-Bodere F, Campion L, Rousseau C. et al. Treatment of bone metastases of prostate cancer with strontium-89 chloride: efficacy in relation to the degree of bone involvement. Eur J Nucl Med 2000; 27: 1487-1493.
  • 29 Morris MJ, Pandit-Taskar N, Carrasquillo J. et al. Phase I study of samarium-153 lexidronam with docetaxel in castration-resistant metastatic prostate cancer. J Clin Oncol 2009; 27: 2436-2442.
  • 30 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.
  • 31 Ricci S, Boni G, Pastina I. et al. Clinical benefit of bone-targeted radiometabolic therapy with 153Sm-EDTMP combined with chemotherapy in patients with metastatic hormone-refractory prostate cancer. Eur J Nucl Med Mol Imaging 2007; 34: 1023-1030.
  • 32 Fizazi K, Beuzeboc P, Lumbroso J. et al. Phase II trial of consolidation docetaxel and samarium-153 in patients with bone metastases from castrationresistant prostate cancer. J Clin Oncol 2009; 27: 2429-2435.
  • 33 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.
  • 34 Christensen MH, Petersen LJ. Radionuclide treatment of painful bone metastases in patients with breast cancer: a systematic review. Cancer Treat Rev 2012; 38: 164-171.
  • 35 Sciuto R, Festa A, Pasqualoni R. et al. Metastatic bone pain palliation with 89-Sr and 186-Re-HEDP in breast cancer patients. Breast Cancer Res Treat 2001; 66: 101-109.
  • 36 Baczyk M, Czepczynski R, Milecki P. et al. 89Sr versus 153Sm-EDTMP: comparison of treatment efficacy of painful bone metastases in prostate and breast carcinoma. Nucl Med Commun 2007; 28: 245-250.
  • 37 Resche I, Chatal JF, Pecking A. et al. A dose-controlled study of 153Sm-ethylenediaminetetramethylenephosphonate (EDTMP) in the treatment of patients with painful bone metastases. Eur J Cancer 1997; 33: 1583-1591.
  • 38 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.
  • 39 Coleman R, Aksnes AK, Naume B. et al. A phase IIa, nonrandomized study of radium-223 dichloride in advanced breast cancer patients with bonedominant disease. Breast Cancer Res Treat 2014; 145: 411-418.
  • 40 Cardoso F, Harbeck N, Fallowfield L. et al. Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2012; 23 (Suppl. 07) vii11-vii19.