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DOI: 10.1055/s-0029-1185804
© Georg Thieme Verlag KG Stuttgart · New York
Interdisziplinäres Konsensuspapier zum adjuvanten Einsatz von Bisphosphonaten bei Mammakarzinom-Patientinnen
Interdisciplinary Consensus on the Use of Adjuvant Bisphosphonate Therapy in Breast Cancer PatientsPublikationsverlauf
eingereicht 15.4.2009
revidiert 8.5.2009
akzeptiert 25.5.2009
Publikationsdatum:
02. Juli 2009 (online)
Zusammenfassung
Gynäkologen und Onkologen trafen sich im November 2008, um auf der Basis der derzeit vorliegenden Evidenzen eine Empfehlung zu erarbeiten, die künftig als Grundlage für die adjuvante Therapie und Prävention des Tumorprogresses durch Bisphosphonate bei hormonrezeptorpositiven Mammakarzinom-Patientinnen dienen könnte. Maligne epitheliale Tumoren disseminieren häufig in das Knochenmark. Dieses stellt durch seinen Reichtum an Zytokinen und Wachstumsfaktoren ein ideales Kompartiment für das Überleben und Wachstum der Tumorzellen dar. In der Knochenmatrix wird eine Reihe von Wachstumsfaktoren, wie Transforming Growth Factor β (TGF-β) oder Insulin-like Growth Factor (IGF), gespeichert, die durch die osteoklastäre Resorption der Knochenmatrix freigesetzt und so für die Tumorzellen verfügbar werden. Der Knochen und das ossäre Mikromilieu spielen eine zentrale Rolle in der Tumorprogression, da disseminierte Tumorzellen im Knochenmark überdauern, Metastasen entstehen bzw. die Tumorzellen ausgehend vom Knochen wieder in die Zirkulation eintreten können, mit der Folge einer möglichen Besiedlung von weiteren distanten Organen. Verschiedene Studien haben jüngst eine Verbesserung des krankheitsfreien Überlebens beim hormonrezeptorpositivem Mammakarzinom durch die zusätzliche adjuvante Therapie mit Bisphosphonaten gezeigt. Insgesamt 12 Experten erarbeiteten unter Berücksichtigung der aktuell verfügbaren Evidenzen eine Empfehlung zum adjuvanten Einsatz der Bisphosphonate, da eine therapeutische Notwendigkeit für diese Intervention besteht, detaillierte Handlungsanweisungen zur Therapiegestaltung derzeit jedoch fehlen. Diese kritische Expertenmeinung soll basierend auf den verfügbaren Evidenzen eine adäquate Bisphosphonat-Therapie in der Adjuvanz ermöglichen.
Abstract
Gynaecologists and oncologists (listed below) met in November 2008 to draw up recommendations to be used as guidelines for adjuvant treatment with bisphosphonates for the prevention of tumour progression in receptor positive breast cancer patients based on the currently available evidence. Malignant epithelial tumours usually disseminate into bone marrow. Because of the abundance of cytokines and the stimulating growth factors found there, this microenvironment is ideal for the survival and growth of cancer cells. A variety of growth factors such as transforming growth factor β (TGF-β) or insulin-like growth factor (IGF) are accumulated within the bone matrix and can be released by stimulated osteoclasts and become available for tumour cells. Therefore the bone and its microenvironment play an important role in tumour progression because cancer cells can survive in bone marrow and grow to become bone metastases. In addition, tumour cells can reenter in the circulation and form new metastases in more distant organs. Recently, various studies have shown that adjuvant bisphosphonate therapy can improve disease-free survival in hormone receptor positive breast cancer patients. Due to medical need and because detailed guidelines for this therapeutic intervention are still lacking, twelve experts have put together recommendations for adjuvant bisphosphonate therapy based on the currently available evidence. This critical consensus could help to encourage the use of appropriate adjuvant bisphosphonate therapy in these patients.
Schlüsselwörter
Metastasen - Hormonrezeptor - disseminierte Tumorzellen
Key words
metastases - hormone receptor - tumour cells
Literatur
- 1 Aparicio A, Gardner A, Tu Y. et al . In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates. Leukemia. 1998; 12 220-229
- 2 Corey E, Brown L G, Quinn J E. et al . Zoledronic acid exhibits inhibitory effects on osteoblastic and osteolytic metastases of prostate cancer. Clin Cancer Res. 2003; 9 295-306
- 3 Derenne S, Amiot M, Barille S. et al . Zoledronate is a potent inhibitor of myeloma cell growth and secretion of IL‐6 and MMP‐1 by the tumoral environment. J Bone Miner Res. 1999; 14 2048-2056
- 4 Senaratne S G, Pirianov G, Mansi J L. et al . Bisphosphonates induce apoptosis in human breast cancer cell lines. Br J Cancer. 2000; 82 1459-1468
- 5 Jagdev S P, Coleman R E, Shipman C M. et al . The bisphosphonate, zoledronic acid, induces apoptosis of breast cancer cells: evidence for synergy with paclitaxel. Br J Cancer. 2001; 84 1126-1134
- 6 Wood J, Schnell C, Green J R. Zoledronic acid (Zometa), a potent inhibitor of bone resorption, inhibits proliferation and induces apoptosis in human endothelial cells in vitro and is anti-angiogenic in a murine growth factor implant model. In: ASCO Annual Meeting 2000. Program/Proceedings Abstracts, Vol. 19. Pp. Abstr. 2620.
- 7 Scavelli C, Di Pietro G, Cirulli T. et al . Zoledronic acid affects over-angiogenic phenotype of endothelial cells in patients with multiple myeloma. Mol Cancer Ther. 2007; 6 3256-3262
- 8 Boissier S, Ferreras M, Peyruchaud O. et al . Bisphosphonates inhibit breast and prostate carcinoma cell invasion, an early event in the formation of bone metastases. Cancer Res. 2000; 60 2949-2954
- 9 Daubiné F, Le Gall C, Gasser J. et al . Antitumor effects of clinical dosing regimens of bisphosphonates in experimental breast cancer bone metastasis. J Natl Cancer Inst. 2007; 99 322-330
- 10 Neville-Webbe H L, Rostami-Hodjegan A, Evans C A. et al . Sequence- and schedule-dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells. Int J Cancer. 2005; 20: 113 364-371
- 11 Brubaker K D, Brown L G, Vessella R L. et al . Administration of zoledronic acid enhances the effects of docetaxel on growth of prostate cancer in the bone environment. BMC Cancer. 2006; 6 15
- 12 Neville-Webbe H L, Evans C A, Coleman R E. et al . Mechanisms of the synergistic interaction between the bisphosphonate zoledronic acid and the chemotherapy agent paclitaxel in breast cancer cells in vitro. Tumour Biol. 2006; 27 92-103
- 13 Santini D, Vincenzi B, Galluzzo S. et al . Repeated intermittent low-dose therapy with zoledronic acid induces an early, sustained, and long-lasting decrease of peripheral vascular endothelial growth factor levels in cancer patients. Clin Cancer Res. 2007; 13 4482-4486
- 14 Mystakidou K, Katsouda E, Parpa E. et al . Randomized, open label, prospective study on the effect of zoledronic acid on the prevention of bone metastases in patients with recurrent solid tumors that did not present with bone metastases at baseline. Med Oncol. 2005; 22 195-201
- 15 Aft R, Watson M, Ylagan L. et al . Effect of zoledronic acid on bone marrow micrometastases in women undergoing neoadjuvant chemotherapy for breast cancer. J Clin Oncol. 2008; ASCO Annual Meeting Proceedings, Vol 26, No 15S 1021
- 16 Lin Y, Park J W, 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; ASCO Annual Meeting Proceedings, Vol 26, No 15S 559
- 17 Rack B, Schindlbeck C, Strobl B. et al . Efficacy of zoledronate in treating persisting isolated tumor cells in bone marrow in patients with breast cancer. A phase II pilot study. Dtsch Med Wochenschr. 2008; 133 285-289
- 18 Solomayer E, Gebauer G, Hirnle. et al . Influence of zoledronic acid on disseminated tumor cells (DTC) in primary breast cancer patients. Cancer Research. 2009; 69 171S
- 19 Diel I J, Solomayer E F, Costa S D. et al . Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med. 1998; 339 357-363
- 20 Diel I J, Jaschke A, Solomayer E F. 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 2007-2011
- 21 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). Breast Cancer Res. 2006; 8 R13
- 22 Saarto T, Blomqvist C, Virkkunen P. et al . 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 10-17
- 23 Gnant M, Mlineritsch B, Schippinger W. et al . Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 2009; 360 679-691
- 24 Bria E, Nistico C, Cuppone F. et al . Benefit of taxanes as adjuvant chemotherapy for early breast cancer: pooled analysis of 15,500 patients. Cancer. 2006; 106 2337-2344
- 25 Eidtmann H, Bundred N J, De Boer R. et al . The effect of zoledronic acid on aromatase inhibitor associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole: 36 months follow-up of ZO-FAST. Cancer Res. 2009; 69 74S
- 26 Brufsky A, Harker G, Beck T. et al . The effect of zoledronic acid in the prevention of aromatase inhibitor-associated bone loss on postmenopausal women with early breast cancer receiving adjuvant letrozol: the Z-FAST study 36-months follow-up. Cancer Res. 2009; 69 176S
- 27 Winter M C, Thorpe H C, Burkinshaw R. et al . The addition of zoledronic acid to neoadjuvant chemotherapy may influence pathological response – exploratory evidence for direct anti-tumor activity in breast cancer. Cancer Res. 2009; 69 330S
- 28 Burkinshaw R. et al . Osteonecrosis of the jaw and dental related adverse events during adjuvant therapy for early breast cancer: Initial dental safety findings from the AZURE study. Cancer Treat Rev. 2008; 34 S75-S76
- 29 Empfehlungen der Arbeitsgemeinschaft gynäkologische Onkologie, Stand Februar 2009. www.ago-online.org/index.php?lang=de
Prof. Dr. Ingo Diel
P7, 16–17
68161 Mannheim
eMail: diel@cgg-mannheim.de