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Bisphosphonate in der adjuvanten Therapie des Mammakarzinoms

Bisphosphonates in Adjuvant Therapy of Breast Cancer

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Zusammenfassung

Seit über 10 Jahren wird, basierend auf Ergebnissen mit dem Bisphosphonat Clodronsäure, diskutiert, ob die Gabe von Bisphosphonaten das Auftreten von Metastasen beim Mammakarzinom verhindern oder zumindest verzögern kann. Die Ergebnisse neuerer Studien z.B. mit den Bisphosphonaten Zoledronsäure oder Ibandronsäure erscheinen auf den ersten Blick nicht zuletzt wegen des therapeutischen Bekanntheitsgrades der Bisphosphonate in der Therapie von Osteoporose und ossären Komplikationen von Malignomen sowie deren Nebenwirkungsspektrum und derzeit anerkannten Wirkungsmechanismus hoffnungsvoll. Vielfach wird schon davon ausgegangen, dass die jetzige Datenlage eindeutig einen Stellenwert der Bisphosphonate in der adjuvanten Therapie des Mammakarzinoms zeige. Signifikante relative Risikoreduktionen von z.B. 36% für das krankheitsfreie Überleben sind eindrucksvoll, die entsprechenden absoluten Werte von 3,2% werden erst in zweiter Linie kommuniziert. Werden die bisher publizierten Studien aber unter dem Aspekt der evidenzbasierten Medizin ausgewertet, ergeben sich noch viele ungeklärte Fragen, und methodische Schwächen der bisher publizierten Studien werden offenkundig. Für Wirksamkeit und Nutzen eines im adjuvanten Therapieansatz verabreichten Bisphosphonats bei Mammakarzinom liegen bisher noch keine evidenzbasierten Daten vor. Vor diesem Hintergrund hat als bisher einzige Fachgesellschaft die Arbeitsgemeinschaft Gynäkologische Onkologie (AGO) eine adjuvante Therapie mit Bisphosphonaten in Kombination mit der endokrinen Therapie im Rahmen von Studienteilnahmen empfohlen.

Abstract

For more than 10 years, based on the results with the bisphosphonate clodronic acid, it has been discussed, whether the occurence of breast cancer metastases can be avoided or at least delayed by administration of bisphosphonates. The published results of recent studies applying, e.g., the bisphosphonates zoledronic and ibandronic acid, respectively, seem promising at first glance, especially, if the therapeutic acceptance of bisphosphonates in the indications osteoporosis and bone-related complications of malignancies, respectively, as well as their spectrum of side effects are taken into account and their putative mechanism of action is considered. There is a broad consensus that the existing data basis suffices to demonstrate importance of bisphosphonates in an adjuvant therapeutic setting of breast cancer. Significant relative risk reductions of, e.g., 36% in disease-free survival are very impressing and the corresponding absolute values of 3.2% are second-line communications. However, evaluation of all studies published so far according to the criteria of evidence-based medicine demonstrates many open questions and several methodical insufficiencies. Therefore, effectiveness and benefit of an adjuvant therapeutic application of bisphosphonates in breast cancer patients cannot be drawn out of evidence-based data. A recommendation of this therapy is given only by the German Working Pool of Gynecologic Oncology (AGO), but limited to study participation.

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Literatur

  1. Bakewell SJ, Nestor P, Prasad S, et al. Platelet and osteoclast beta 3 integrins are critical for bone me-tastasis. Proc Natl Acad Sci U S A 2003;100:14205–10.

    Article  CAS  PubMed  Google Scholar 

  2. Barni S, Mandalà M, Cazzaniga M, et al. Bisphos-phonates and metastatic bone disease. Ann Oncol 2006;17:Suppl 2:ii91–5.

    Article  PubMed  Google Scholar 

  3. Coleman RE. Bisphosphonates: clinical experience. Oncologist 2004;9:Suppl 4:14–27.

    Article  CAS  PubMed  Google Scholar 

  4. Delmas PD, Balena R, Confravreux E. Bisphosphonate risedronate prevents bone loss in women with artificial menopause due to chemotherapy of breast cancer: a double-blind, placebo-controlled study. J Clin Oncol 1997;15:955–62.

    CAS  PubMed  Google Scholar 

  5. De Luca A, Gallo M, Maiello M, et al. Zoledronic acid affects the expression of VEGF in breast cancer cells and in bone marrow stromal cells through direct and indirect mechanisms. 99th Annual Meeting of the American Association for Cancer Research, Philadelphia, PA, April 12–16, 2008.

  6. Deuber HJ. Therapie der renalen Osteopathie mit-tels Ibandronat. Dialyse aktuell 2004;8:28–30.

    Google Scholar 

  7. Diel IJ, Jaschke A, Solomayer EF, et al. Adjuvant oral clodronate improves the overall survival of primary breast cancer patients with micrometastases to the bone marrow: a long-term follow-up. Ann Oncol 2008;19:2007–11.

    Article  CAS  PubMed  Google Scholar 

  8. Diel IJ, Solomayer EF, Bastert G. Bisphosphonates and the prevention of metastasis. Cancer 2000;88:3080–8.

    Article  CAS  PubMed  Google Scholar 

  9. Diel IJ, Solomayer EF, Costa SD, et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 1998;339:357–63.

    Article  CAS  PubMed  Google Scholar 

  10. Gnant M, Hausmaninger H, Samonigg H. Changes in bone mineral density caused by anastrozole or tamoxifen in combination with goserelin (± zole dronate) as adjuvant treatment for hormone receptor-positive premenopausal breast cancer: results of a randomized multicenter trial. 25th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 11–14, 2002.

  11. Gnant M, Mlineritsch B, Luschin-Ebengreuth G, et al. Zoledronic acid prevents cancer treatment-in-duced bone loss in premenopausal women receiving adjuvant endocrine therapy for hormone-respronsive breast cancer: a report from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol 2007;25:820–8.

    Article  CAS  PubMed  Google Scholar 

  12. Gnant M, Mlineritsch B, Schippinger W, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med 2009;360:679–91.

    Article  CAS  PubMed  Google Scholar 

  13. Green JR. Bisphosphonates: preclinical review. Oncologist 2004;9:Suppl:3–13.

    Article  CAS  PubMed  Google Scholar 

  14. Ha TC, Li H. Meta-analysis of clodronate and breast cancer survival. Br J Cancer 2007;96:1796–801.

    Article  CAS  PubMed  Google Scholar 

  15. Hadji R. Adjuvante Bisphosphonattherapie–quo vadis? Gynäkologie 2009;5:19–21.

    Google Scholar 

  16. Hillner BE, Ingle JN, Chlebowski RT. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer [Erratum in: J Clin Oncol 2004;22:1351]. J Clin Oncol 2003;21:4042–57.

    Article  CAS  PubMed  Google Scholar 

  17. Jaschke A, Bastert G, Solomayer EF, et al. Adjuvant clodronate treatment improves the overall survival of primary breast cancer patients with micrometastases to bone marrow — a longtime follow-up. J Clin Oncol 2004;22:Suppl 14:529.

    Google Scholar 

  18. Kristensen B, Ejlertsen B, Mouridsen HT, et al. Bisphosphonate treatment in primary breast cancer: results from a randomised comparison of oral pamidronate versus no pamidronate in patients with primary breast cancer. Acta Oncol 2008;47:740–6.

    Article  CAS  PubMed  Google Scholar 

  19. Lin AY, Park JW, Scott J, et al. Zoledronic acid as adjuvant therapy for women with early stage breast cancer and disseminated tumor cells in bone marrow. J Clin Oncol 2008;26:Suppl:20s.

  20. 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;88:1082–90.

    Article  CAS  PubMed  Google Scholar 

  21. Peters G, Voudsen KH, eds. Oncogenes and tumor suppressors. New York: Oxford University Press, 1997.

    Google Scholar 

  22. Pavlakis N, Schmidt R, Stockler M. Bisphosphonates for breast cancer. Cochrane Database Syst Rev 2005;3:CD003474.

    PubMed  Google Scholar 

  23. Powles T, Paterson S, Kanis JA. Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol 2002;20:3219–24.

    Article  CAS  PubMed  Google Scholar 

  24. Powles T, Paterson A, McCloskey E, et al. Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026] [Erratum in: Breast Cancer Res 2006 8:406]. Breast Cancer Res 2006;8:R13.

    Article  PubMed  Google Scholar 

  25. Saarto T, Blomqvist C, Valimaki M. Clodronate improves bone mineral density in post-menopausal breast cancer patients treated with adjuvant antiestrogens. Br J Cancer 1997;75:602–5.

    CAS  PubMed  Google Scholar 

  26. Saarto T, Blomqvist C, Valimaki M. Chemical castration induced by adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy causes rapid bone loss that is reduced by clodronate: a randomized study in premenopausal breast cancer patients. J Clin Oncol 1997;15:1341–7.

    CAS  PubMed  Google Scholar 

  27. Saarto T, Blomqvist C, Virkkunen P, Elomaa I. Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-year results of a randomized controlled trial. J Clin Oncol 2001;19:10–7.

    CAS  PubMed  Google Scholar 

  28. Saarto T, Vehmanen L, Blomqvist C, Elomaa I. Ten-year follow-up of a randomized controlled trial of adjuvant clodronate treatment in node-positive breast cancer patients. J Clin Oncol 2004;22:Suppl 14:abstract 527.

  29. Saarto T, Vehmanen L, Blomqvist C, Elomaa I. Ten-year follow-up of 3 years of oral adjuvant clodronate therapy shows significant prevention of osteoporosis in early-stage breast cancer. J Clin Oncol 2008;26:4289–95.

    Article  CAS  PubMed  Google Scholar 

  30. Santini D, Martini F, Fratto ME, et al. In vivo effects of zoledronic acid on peripheral gammadelta T lymphocytes in early breast cancer patients. Cancer Immunol Immunother 2009;58:31–8.

    Article  CAS  PubMed  Google Scholar 

  31. Van Beek E, Pieterman E, Cohen L, et al. Farnesyl pyrophosphate synthase is the molecular target of nitrogen-containing bisphosphonates. Biophys Biochem Res Commun 1999;264:108–11.

    Article  Google Scholar 

  32. Zoledronat (Zometa): Prophylaxe von Knochen-metastasen bei Brustkrebs? arznei-telegramm 2009;40:38–9.

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Deuber, H.J., Theiss, F. Bisphosphonate in der adjuvanten Therapie des Mammakarzinoms. Med Klin 105, 635–646 (2010). https://doi.org/10.1007/s00063-010-1103-x

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  • DOI: https://doi.org/10.1007/s00063-010-1103-x

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