Brust- und gynäkologische Tumoren – medikamentöse Therapie ossärer Metastasen

Der Knochen stellt einen häufigen Metastasierungsort solider Tumoren dar. Knochenmetastasen können starke Schmerzen sowie skelettbezogene Komplikationen verursachen, die zu einer erhöhten Mortalität und Morbidität sowie einer erheblichen Beeinträchtigung der Lebensqualität führen.

Kernaussagen

• Zur Prävention von SREs können bei soliden Tumoren Zoledronat und Denosumab angewendet werden, während beim Mammakarzinom zudem die Bisphosphonate Clodronat, Ibandronat und Pamidronat zur Auswahl stehen.

• Vor Anwendung einer osteoprotektiven Therapie muss im Falle von Denosumab ein Kalziummangel ausgeglichen werden, im Falle von Bisphosphonaten wird ein Ausgleich ebenfalls empfohlen.

• Insbesondere bei Anwendung von Denosumab sowie im Falle einer Niereninsuffizienz besteht ein erhöhtes Risiko für eine Hypokalzämie, sodass unter osteoprotektiver Therapie – sofern nicht kontraindiziert – eine Kalzium- und Vitamin-D-Substitution erfolgen sollte.

• Die Kieferosteonekrose stellt eine gefürchtete Nebenwirkung dar, sodass eine Prävention durch eine vorherige und im Verlauf regelmäßige zahnärztliche Vorstellung sowie eine gute Mundhygiene essenziell sind.

• Denosumab konnte im Vergleich zu Zoledronat in einigen Studien eine Überlegenheit hinsichtlich der SRE-Prävention aufzeigen, hinsichtlich des Überlebens konnte bisher kein Unterschied festgestellt werden.

• Bei der Auswahl des Präparates sind insbesondere renale Vorerkrankungen und gastrointestinale Erkrankungen zu beachten. Im Falle einer Niereninsuffizienz müssen die potenzielle Nierentoxizität insbesondere von Zoledronat und Pamidronat und entsprechende Dosis- sowie Laufzeitanpassungen beachtet werden, bei Gabe von Denosumab ist keine Anpassung notwendig.

• Die oral verfügbaren Bisphosphonate gehen häufiger mit gastrointestinalen Nebenwirkungen einher.

• Das Dosisintervall für die intravenös verfügbaren Bisphosphonate sowie Denosumab liegt bei 4 Wochen, bei Zoledronat ist eine Ausweitung auf 12 Wochen möglich.

Schlüsselwörter

ossäre Metastasierung - skelettale Komplikationen - osteoprotektive Therapie - Bisphosphonate - Denosumab - Therapiedauer

Publication History

Article published online:
13 February 2023

• Literatur

• 1 Cremers S, Drake MT, Ebetino FH. et al. Pharmacology of bisphosphonates. Br J Clin Pharmacol 2019; 85: 1052-1062 DOI: 10.1111/bcp.13867. (PMID: 30650219)
• 2 Lacey DL, Boyle WJ, Simonet WS. et al. Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab. Nat Rev Drug Discov 2012; 11: 401-419 DOI: 10.1038/nrd3705. (PMID: 22543469)
• 3 Himmelstein AL, Foster JC, Khatcheressian JL. et al. Effect of longer-interval vs standard dosing of zoledronic acid on skeletal events in patients with bone metastases: A randomized clinical trial. JAMA 2017; 317: 48-58 DOI: 10.1001/jama.2016.19425.
• 4 Ng TL, Tu MM, Ibrahim MFK. et al. Long-term impact of bone-modifying agents for the treatment of bone metastases: a systematic review. Support Care Cancer 2021; 29: 925-943 DOI: 10.1007/s00520-020-05556-0. (PMID: 32535678)
• 5 Leitlinienprogramm Onkologie, Deutsche Krebsgesellschaft, Deutsche Krebshilfe, AWMF. Supportive Therapie bei onkologischen PatientInnen – Langversion 1.3, AWMF Registernummer: 032/054OL. 2020 Accessed December 02, 2022 at: https://register.awmf.org/de/leitlinien/detail/032–054OL
• 6 Wang-Gillam A, Miles DA, Hutchins LF. Evaluation of vitamin D deficiency in breast cancer patients on bisphosphonates. Oncologist 2008; 13: 821-827 DOI: 10.1634/theoncologist.2008-0013. (PMID: 18614589)
• 7 Body JJ, Bone HG, de Boer RH. et al. Hypocalcaemia in patients with metastatic bone disease treated with denosumab. Eur J Cancer 2015; 51: 1812-1821 DOI: 10.1016/j.ejca.2015.05.016.
• 8 Coleman RE, Hadji P, Body JJ. et al. Bone health in cancer: ESMO Clinical Practice Guidelines. Ann Oncol 2020; 31: 1650-1663 DOI: 10.1016/j.annonc.2020.07.019. (PMID: 32801018)
• 9 Henry DH, Costa L, Goldwasser F. et al. 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 2011; 29: 1125-1132 DOI: 10.1200/JCO.2010.31.3304. (PMID: 21343556)
• 10 Stopeck AT, Lipton A, Body JJ. et al. 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 2010; 28: 5132-5139 DOI: 10.1200/JCO.2010.29.7101.
• 11 Van Poznak CH, Unger JM, Darke AK. et al. Association of osteonecrosis of the jaw with zoledronic acid treatment for bone metastases in patients with cancer. JAMA Oncol 2021; 7: 246-254 DOI: 10.1001/jamaoncol.2020.6353.
• 12 Yarom N, Shapiro CL, Peterson DE. et al. Medication-related osteonecrosis of the jaw: MASCC/ISOO/ASCO Clinical Practice Guideline. J Clin Oncol 2019; 37: 2270-2290 DOI: 10.1200/JCO.19.01186. (PMID: 31329513)
• 13 O’Carrigan B, Wong MHF, Willson ML. et al. Bisphosphonates and other bone agents for breast cancer. Cochrane Database Syst Rev 2017; (10) CD003474 DOI: 10.1002/14651858.CD003474.pub4.
• 14 Reimer T, Solomayer E-F. AGO e. V.. Osteoonkologie und Knochengesundheit. 2022 Accessed November 30, 2022 at: https://www.ago-online.de/fileadmin/ago-online/downloads/_leitlinien/kommission_mamma/2022/Einzeldateien/AGO_2022D_20_Osteoonkologie_und_Knochengesundheit.pdf
• 15 Paterson AH, Powles TJ, Kanis JA. et al. Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 1993; 11: 59-65 DOI: 10.1200/JCO.1993.11.1.59.
• 16 Kristensen B, Ejlertsen B, Groenvold M. et al. Oral clodronate in breast cancer patients with bone metastases: a randomized study. J Intern Med 1999; 246: 67-74 DOI: 10.1046/j.1365-2796.1999.00507.x.
• 17 Lipton A, Theriault RL, Hortobagyi GN. et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long term follow-up of two randomized, placebo-controlled trials. Cancer 2000; 88: 1082-1090 DOI: 10.1002/(sici)1097-0142(20000301)88:5<1082::aid-cncr20>3.0.co;2-z.
• 18 Awan AA, Hutton B, Hilton J. et al. De-escalation of bone-modifying agents in patients with bone metastases from breast cancer: a systematic review and meta-analysis. Breast Cancer Res Treat 2019; 176: 507-517 DOI: 10.1007/s10549-019-05265-1.
• 19 Kohno N, Aogi K, Minami H. et al. Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: a randomized, placebo-controlled trial. J Clin Oncol 2005; 23: 3314-3321 DOI: 10.1200/JCO.2005.05.116.
• 20 Amadori D, Aglietta M, Alessi B. et al. 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 2013; 14: 663-670 DOI: 10.1016/S1470-2045(13)70174-8.
• 21 Hortobagyi GN, Van Poznak C, Harker WG. et al. Continued treatment effect of zoledronic acid dosing every 12 vs 4 weeks in women with breast cancer metastatic to bone: The OPTIMIZE-2 randomized clinical trial. JAMA Oncol 2017; 3: 906-912 DOI: 10.1001/jamaoncol.2016.6316.
• 22 Heras P, Kritikos K, Hatzopoulos A. et al. Efficacy of ibandronate for the treatment of skeletal events in patients with metastatic breast cancer. Eur J Cancer Care 2009; 18: 653-656 DOI: 10.1111/j.1365-2354.2008.00980.x.
• 23 Body JJ, Diel IJ, Lichinitzer M. et al. Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: results from two randomised, placebo-controlled phase III studies. Br J Cancer 2004; 90: 1133-1137 DOI: 10.1038/sj.bjc.6601663.
• 24 von Au A, Milloth E, Diel I. et al. Intravenous pamidronate versus oral and intravenous clodronate in bone metastatic breast cancer: a randomized, open-label, non-inferiority Phase III trial. Onco Targets Ther 2016; 9: 4173-4180 DOI: 10.2147/OTT.S103130. (PMID: 27468239)
• 25 Barrett-Lee P, Casbard A, Abraham J. et al. 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 2014; 15: 114-122 DOI: 10.1016/S1470-2045(13)70539-4.
• 26 Rosen LS, Gordon DH, Dugan jr W. et al. Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 2004; 100: 36-43 DOI: 10.1002/cncr.11892.
• 27 Rosen LS, Gordon D, Kaminski M. et al. 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 2003; 98: 1735-1744 DOI: 10.1002/cncr.11701. (PMID: 14534891)
• 28 Stopeck A, Brufsky A, Kennedy L. et al. Cost-effectiveness of denosumab for the prevention of skeletal-related events in patients with solid tumors and bone metastases in the United States. J Med Econ 2020; 23: 37-47 DOI: 10.1080/13696998.2019.1651122.
• 29 Rosen LS, Gordon D, Tchekmedyian N. et al. Long term efficacy and safety of zoledronic acid in the treatment of skeletal metastases in patients with non small cell lung carcinoma and other solid tumors: a randomized, phase III, double blind, placebo-controlled trial. Cancer 2004; 100: 2613-2621 DOI: 10.1002/cncr.20308.
• 30 Henry D, Vadhan-Raj S, Hirsh V. et al. 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 2014; 22: 679-687 DOI: 10.1007/s00520-013-2022-1.
• 31 Black DM, Abrahamsen B, Bouxsein ML. et al. Atypical femur fractures: review of epidemiology, relationship to bisphosphonates, prevention, and clinical management. Endoc Rev 2019; 40: 333-368 DOI: 10.1210/er.2018-00001. (PMID: 30169557)
• 32 Perazella MA, Markowitz GS. Bisphosphonate nephrotoxicity. Kidney Int 2008; 74: 1385-1393 DOI: 10.1038/ki.2008.356. (PMID: 18685574)
• 33 Tanvetyanon T, Stiff PJ. Management of the adverse effects associated with intravenous bisphosphonates. Ann Oncol 2006; 17: 897-907 DOI: 10.1093/annonc/mdj105. (PMID: 16547070)
• 34 Wilkinson GS, Baillargeon J, Kuo YF. et al. Atrial fibrillation and stroke associated with intravenous bisphosphonate therapy in older patients with cancer. J Clin Oncol 2010; 28: 4898-4905 DOI: 10.1200/JCO.2010.28.7524.
• 35 Deligiorgi MV, Trafalis DT. The safety profile of denosumab in oncology beyond the safety of denosumab as an anti-osteoporotic agent: still more to learn. Expert Opin Drug Saf 2021; 20: 191-213 DOI: 10.1080/14740338.2021.1861246. (PMID: 33287586)
• 36 Tovazzi V, Dalla Volta A, Pedersini R. et al. Excess of second tumors in denosumab-treated patients: a metabolic hypothesis. Future Oncol 2019; 15: 2319-2321 DOI: 10.2217/fon-2019-0170.
• 37 Gnant M, Pfeiler G, Steger GG. et al. Adjuvant denosumab in postmenopausal patients with hormone receptor-positive breast cancer (ABCSG-18): disease-free survival results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2019; 20: 339-351 DOI: 10.1016/S0140-6736(15)60995-3.
• 38 Cheng ML, Fong L. Effects of RANKL-targeted therapy in immunity and cancer. Front Oncol 2014; 3: 329 DOI: 10.3389/fonc.2013.00329. (PMID: 24432249)
• 39 Srivastava A, Nogueras Gonzalez GM, Gen Y. et al. Prevalence of medication related osteonecrosis of the jaw in patients treated with sequential antiresorptive drugs: systematic review and meta-analysis. Support Care Cancer 2021; 5: 2305-2317 DOI: 10.1007/s00520-020-05882-3.