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Therapie von Knochenmetastasen

Stellenwert der Osteoklastenhemmung durch Bisphosphonate oder RANK-Ligand-Inhibition

Therapy of bone metastases

Importance of osteoclast inhibition by bisphosphonates or RANK ligand inhibition

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Der Onkologe Aims and scope

Zusammenfassung

Hintergrund

Knochenmetastasen kommen häufig beim fortgeschrittenen Mamma- und Prostatakarzinomen vor, Osteolysen sind wiederum typisch beim multiplen Myelom. Knochenerkrankungen durch Metastasen sind bedeutende Ursachen der Morbidität bei Krebs. Tumorzellen können sich in den Nischen der hämatopoetischen Stammzellen absiedeln und dort lange Zeit ruhen, bevor sie sich zu erkennbaren Metastasen weiterentwickeln. Die zellulären Interaktionen im Knochenmark sind von großer Bedeutung bei ruhenden Tumorzellen und Metastasierung. Die osteolytische Knochenzerstörung entsteht durch Osteoklasten, die durch tumorassoziierte Zytokine stimuliert werden.

Methode

Recherche und Analyse der aktuellen Literatur.

Diagnostik

Differenzialdiagnostisch kommen Osteoporose, degenerative Erkrankungen und Paget-Erkrankung des Knochens in Frage. Ein Knochenszintigramm ist eine sensitive Untersuchung für pathologische Skelettveränderungen (außer beim multiplen Myelom), jedoch ohne Hinweise auf die Ursache. Veränderungen der Knochen können am besten mit Computertomographie (CT)und Kernspintomographie (MRT) erfasst werden. Eine Positronenemissionstomographie (PET) gibt zusätzliche funktionelle Hinweise bei der Diagnostik. Der Patient muss klinisch untersucht und sein Aktivitätsstatus immer beurteilt werden. Zur Beurteilung der Wirksamkeit können radiologische Untersuchungen erfolgen, allerdings sind die Methoden wenig sensitiv und mit verzögertem Nachweis. Nuklearmedizinische Untersuchungen des Knochens sind zur Beurteilung nicht geeignet. Biochemische Marker des Knochenstoffwechsels können Informationen zu Prognose und Ansprechen auf die knochenspezifische Therapie geben, werden aber zur Routineanwendung nicht empfohlen.

Therapie

Patienten mit Knochenmetastasen sollten interdisziplinär therapiert werden. Die Behandlung sollte systemische, radiologische, orthopädische und neurochirurgische sowie supportive und palliative Therapien integrieren. Bei lokalisiertem Schmerz ist die Bestrahlung die Therapie der Wahl. Dabei ist eine Einzeldosistherapie genauso effektiv wie fraktionierte Bestrahlungen. Bisphosphonate und der RANK-Ligand-Inhibitor Denosumab hemmen die Osteoklastenaktivität und sind daher essenziell zur Therapie der Knochenerkrankung durch Metastasen. Denosumab war in 3 prospektiven Vergleichsstudien bei soliden Tumoren signifikant effektiver als Zolendonat.

Abstract

Context

Bone metastases often occur with advanced breast and prostate cancer and osteolysis is typical for multiple myeloma. Bone diseases caused by metastases are important causes of morbidity in cancer. Tumor cells can colonize the niches of the hemopoietic stem cells and can lay dormant there for a long time before developing into recognizable metastases. The cellular interactions in the bone marrow are of great importance for latent tumor cells and metastasization. The osteolytic destruction of bone originates from osteoclasts which are stimulated by tumor-associated cytokines.

Method

Research and Analysis of the current literature

Diagnostics

The differential diagnosis includes osteoporosis, degenerative diseases and Paget’s disease of bone. A bone scintigram is a sensitive method for pathological skeletal alterations (with the exception of multiple myeloma) but does not provide evidence of the cause. Alterations of bone can best be detected by computed tomography and magnetic resonance imaging. Positron emission tomography can supply additional functional information for the diagnostics. Patients must always be clinically examined and the activity status must be assessed. Radiological investigations can be carried out to assess the effectiveness but the methods are not very sensitive and with delayed detection. Nuclear medical investigations of bone are not suitable for assessment. Biochemical markers of bone metabolism can give information on the prognosis and response to bone-specific therapy but are not recommended for routine use.

Therapy

Patients with bone metastases should receive interdisciplinary treatment and integrate systemic, radiological, orthopedic and neurosurgical as well as supportive and palliative therapy. Radiation therapy is the method of choice for localized pain and single dose therapy is just as effective as fractionated irradiation. Bisphosphonates and the receptor activator of nuclear factor kappa-B (RANK) ligand (RANKL) inhibitor denosumab inhibit osteoclast activity. Denosumab was more effective than zoledronic acid as shown in three prospective trials in solid tumors. These substances are therefore essential for therapy of bone diseases due to metastases in that they can delay the occurrence of bone complications, relieve symptoms and improve the quality of life.

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Literatur

  1. Coleman R, Body JJ, Aapro M et al (2014) Bone health in cancer patients: ESMO clinical practice guidelines. Ann Oncol

  2. Kaplan RN, Rafii S, Lyden D (2006) Preparing the „Soil“: the premetastatic niche. Cancer Res 66(23):11089–11093

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Chiang AC, Massagué J (2008) Molecular basis of metastasis. N Engl J Med 359(26):2814–2823

    Article  CAS  PubMed  Google Scholar 

  4. Weilbaecher KN, Guise TA, McCauley LK (2011) Cancer to bone: a fatal attraction. Nat Rev Cancer 11(6):411–425

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Costelloe CM, Chuang HH, Madewell JE, Ueno NT (2010) Cancer response criteria and bone metastases: RECIST 1.1, MDA and PERCIST. J Cancer 1:80–92

    Article  PubMed Central  PubMed  Google Scholar 

  6. Stewart AF (2005) Hypercalcemia associated with cancer. N Engl J Med 352(4):373–379

    Article  CAS  PubMed  Google Scholar 

  7. Lutz S, Chow E (2012) A review of recently published radiotherapy treatment guidelines for bone metastases: Contrasts or convergence? J Bone Oncol 1(1):18–23

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  9. Papapoulos SE (2008) Bisphosphonates: how do they work? Best Pract Res Clin Endocrinol Metab 22(5):831–847

    Article  CAS  PubMed  Google Scholar 

  10. Whyte MP (2006) The long and the short of bone therapy. N Engl J Med 354(8):860–863

    Article  CAS  PubMed  Google Scholar 

  11. Brown JE, Coleman RE (2012) Denosumab in patients with cancer – a surgical strike against the osteoclast. Nat Rev Clin Oncol 9(2):110–118

    Article  CAS  PubMed  Google Scholar 

  12. Fizazi K, Lipton A, Mariette X et al (2009) Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol 27:1564–1571

    Article  CAS  PubMed  Google Scholar 

  13. Rosen LS, Gordon D, Kaminski M et al (2003) Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer 98(8):1735–1744

    Article  CAS  PubMed  Google Scholar 

  14. Rosen LS, Gordon D, Kaminski M et al (2001) Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase III, double-blind, comparative trial. Cancer J (Sudbury, Mass) 7(5):377–387

  15. Barrett-Lee P, Casbard A, Abraham J et al (2014) Oral ibandronic acid versus intravenous zoledronic acid in treatment of bone metastases from breast cancer: a randomised, open label, non-inferiority phase 3 trial. Lancet Oncol 15(1):114–122

    Article  CAS  PubMed  Google Scholar 

  16. Stopeck AT, Lipton A, Body JJ et al (2010) Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 28(35):5132–5139

    Article  CAS  PubMed  Google Scholar 

  17. Martin M, Bell R, Bourgeois H et al (2012) Bone-related complications and quality of life in advanced breast cancer: results from a randomized phase III trial of denosumab versus zoledronic acid. Clin Cancer Res 18(17):4841–4849

    Article  CAS  PubMed  Google Scholar 

  18. Saad F, Gleason DM, Murray R et al (2004) Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 96(11):879–882

    Article  CAS  PubMed  Google Scholar 

  19. Fizazi K, Carducci M, Smith M et al (2011) Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet 377(9768):813–822

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Rosen LS, Gordon D, Tchekmedyian NS et al (2004) Long-term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with nonsmall cell lung carcinoma and other solid tumors: a randomized, Phase III, double-blind, placebo-controlled trial. Cancer 100(12):2613–2621

    Article  CAS  PubMed  Google Scholar 

  21. Henry DH, Costa L, Goldwasser F et al (2011) Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 29(9):1125–1132

    Article  CAS  PubMed  Google Scholar 

  22. Henry D, Vadhan-Raj S, Hirsh V et al (2014) Delaying skeletal-related events in a randomized phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer: an analysis of data from patients with solid tumors. Support Care Cancer 22(3):679–687

    Article  PubMed  Google Scholar 

  23. Scagliotti GV, Hirsh V, Siena S et al (2012) Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study. J Thorac Oncol 7(12):1823–1829

    Article  CAS  PubMed  Google Scholar 

  24. Mhaskar R, Redzepovic J, Wheatley K et al (2012) Bisphosphonates in multiple myeloma: a network meta-analysis. Cochrane Database Syst Rev 5:Cd003188

    PubMed  Google Scholar 

  25. Gimsing P, Carlson K, Turesson I et al (2010) Effect of pamidronate 30 mg versus 90 mg on physical function in patients with newly diagnosed multiple myeloma (Nordic Myeloma Study Group): a double-blind, randomised controlled trial. Lancet Oncol 11(10):973–982

    Article  CAS  PubMed  Google Scholar 

  26. Morgan GJ, Child JA, Gregory WM et al (2011) Effects of zoledronic acid versus clodronic acid on skeletal morbidity in patients with newly diagnosed multiple myeloma (MRC Myeloma IX): secondary outcomes from a randomised controlled trial. Lancet Oncol 12(8):743–752

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Morgan GJ, Davies FE, Gregory WM et al (2010) First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet 376(9757):1989–1999

    Article  CAS  PubMed  Google Scholar 

  28. Terpos E, Morgan G, Dimopoulos MA et al (2013) International Myeloma Working Group recommendations for the treatment of multiple myeloma-related bone disease. J Clin Oncol 31(18):2347–2357

    Article  CAS  PubMed  Google Scholar 

  29. Van Poznak CH, Von Roenn JH, Temin S (2011) American society of clinical oncology clinical practice guideline update: recommendations on the role of bone-modifying agents in metastatic breast cancer. J Oncol Pract 7:117–121

    Article  Google Scholar 

  30. Amadori D, Aglietta M, Alessi B et al (2013) Efficacy and safety of 12-weekly versus 4-weekly zoledronic acid for prolonged treatment of patients with bone metastases from breast cancer (ZOOM): a phase 3, open-label, randomised, non-inferiority trial. Lancet Oncol 14(7):663–670

    Article  CAS  PubMed  Google Scholar 

  31. Saad F, Brown JE, Van Poznak C et al (2012) Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol 23(5):1341–1347

    Article  CAS  PubMed  Google Scholar 

  32. Bisphosphonat-assoziierte Kiefernekrose (BP-ONJ) und andere Medikamenten-assoziierte Kiefernekrosen. Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V. (AWMF). 2012 [cited 31.5.2014]. http://www.awmf.org/leitlinien/detail/ll/007-091.html.

  33. Zometa: EPAR – Product Information. EMA. 2014 [cited 31.5.2014]. http://www.ema.europa.eu/docs/de_DE/document_library/EPAR_-_Product_Information/human/000336/WC500051730.pdf.

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Einhaltung ethischer Richtlinien

Interessenkonflikt. H. Link weist auf folgenden Interessenkonflikt hin: Vorträge und Projekte mit der Fa. Amgen München. Der Beitrag enthält keine Studien an Menschen und Tieren.

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  1. Klinik für Innere Medizin I, Hämatologie, Onkologie, Stammzelltransplantation, Diabetologie, Westpfalz-Klinikum, Hellmut Hartertstraße 1, 67653, Kaiserslautern, Deutschland

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Link, H. Therapie von Knochenmetastasen. Onkologe 20, 766–771 (2014). https://doi.org/10.1007/s00761-014-2671-9

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  • DOI: https://doi.org/10.1007/s00761-014-2671-9

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