Clinical trial NCT00295646: Tamoxifen Versus Anastrozole, Alone or in Combination With Zoledronic Acid
Official title: Tamoxifen Versus Anastrozole, Alone or in Combination With Zoledronic Acid, in Premenopausal, Hormone Receptor-positive Breast Cancer Patients (Stage I, II)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Keywords: Austrian Breast & Colorectal Cancer Study Group (ABCSG)
12
Phase 3
breast cancer
anastrozole
tamoxifen
zoledronic acid
premenopausal
hormone receptor-positive
Stage I
Stage II
bone mineral density
BMD
bisphosphonate
zoledronate
Lead sponsor: Austrian Breast & Colorectal Cancer Study Group
Sponsor class: NETWORK
Collaborators: name: AstraZeneca
name: Novartis Pharmaceuticals
First posted: 2006-02-24
Enrollment: 1803
Sex: FEMALE
Minimum age (years): 19
Maximum age (years): 59
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective is, first, the comparison of tamoxifen and anastrozole and, second, the comparison of zoledronate added to standard adjuvant therapy with controls according to disease-free survival (DFS) in premenopausal patients with non-metastatic breast cancer treated with tamoxifen or anastrozole. To assess whether zoledronate added to standard adjuvant therapy can decrease or even prevent bone loss in patients treated with hormonal blockade combined with an antiestrogen or aromatase inhibitor.

Detailed description: The trial is conducted as an open multi-center phase III study, in a two-factorial study design and according to Good Clinical Practice (GCP) guidelines. Patients will be randomly assigned to a total of 4 study groups in a 1:1:1:1 assignment ratio. Several stratification criteria will be used in order to ensure balanced distribution of known risk factors.

A total of 1.803 patients will be enrolled in 4 arms. Patients will either be treated with anastrozole (1mg daily for 3 years) or tamoxifen (20mg daily for 3 years), and will additionally receive either zoledronate (8mg q4 weeks for 3 years) or no zoledronate (arm A: Nolvadex alone; arm B: Nolvadex plus zoledronate; arm C: Arimidex alone; arm D: Arimidex plus zoledronate).

Zoledronate will be administered by i.v. injection at a dose of 4 mg/month for the treatment period of 3 years. Five Bone Mineral Density (BMD) measurements will be performed in a subgroup of patients (404 patients, enrolled in 3 centres).

Eligibility criteria: Inclusion Criteria:

* Premenopausal, hormone receptor-positive patient
* Histologically verified (minimally) invasive breast cancer, local radical treatment
* 0-9 involved axillary lymph nodes (≥ 10 histologically examined nodes)
* Tumor stage: pT1b-3, yT0 or yT1a

Exclusion Criteria:

* T1a, T4d, yT4; M1
* Previous breast tumor irradiation
* Previous or concurrent chemotherapy (except for preoperative chemotherapy)
* Serum creatinine \> 1.5 x UNL or creatinine clearance \< 60 ml/min

Primary outcomes:
measure: Comparison of Anastrozole vs Tamoxifen in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Disease-free Survival (DFS)
timeFrame: Time from randomization to the analysis data cut-off date when 124 DFS events had occurred. On the analysis data cut-off date, maximum time on study per patient was 102 months.
measure: Comparison of Zoledronate vs no Zoledronate in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Disease-free Survival (DFS)
timeFrame: Time from randomization to the analysis data cut-off date when 124 DFS events had occurred. On the analysis data cut-off date, maximum time on study per patient was 102 months.
Secondary outcomes:
measure: Comparison of Anastrozole vs Tamoxifen in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Recurrence-free Survival (RFS)
timeFrame: Time from randomization to the analysis data cut-off date when 124 DFS events had occurred. On the analysis data cut-off date, maximum time on study per patient was 102 months.
measure: Comparison of Zoledronate vs no Zoledronate in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Recurrence-free Survival (RFS)
timeFrame: Time from randomization to the analysis data cut-off date when 124 DFS events had occurred. On the analysis data cut-off date, maximum time on study per patient was 102 months.
measure: Comparison of Anastrozole vs Tamoxifen in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Overall Survival (OS)
timeFrame: Time from randomization to the analysis data cut-off date when 124 DFS events had occurred. On the analysis data cut-off date, maximum time on study per patient was 102 months.
measure: Comparison of Zoledronate vs no Zoledronate in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Overall Survival (OS)
timeFrame: Time from randomization to the analysis data cut-off date when 124 DFS events had occurred. On the analysis data cut-off date, maximum time on study per patient was 102 months.
Other outcomes:
Locations:
city: Guessing
country: Austria
facility: Hospital of Guessing
state: Burgenland
city: Oberpullendorf
country: Austria
facility: Hospital Oberpullendorf
state: Burgenland
city: Oberwart
country: Austria
facility: Hospital Oberwart
state: Burgenland
city: Klagenfurt
country: Austria
facility: State Hospital Klagenfurt, Surgery
state: Carinthia
city: Klagenfurt
country: Austria
facility: State Hospital Klagenfurt
state: Carinthia
city: St. Veit a. d. Glan
country: Austria
facility: Hospital BHB St. Veit
state: Carinthia
city: St. Veit a. d. Glan
country: Austria
facility: Ordination Dr. Wette
state: Carinthia
city: Villach
country: Austria
facility: State Hospital Villach
state: Carinthia
city: Villach
country: Austria
facility: Privat Hospital Villach
state: Carinthia
city: Wolfsberg
country: Austria
facility: State Hospital Wolfsberg
state: Carinthia
city: Hainburg An Der Donau
country: Austria
facility: Hospital Hainburg
state: Lower Austria
city: Klosterneuburg
country: Austria
facility: Hospital Klosterneuburg, Internal Medicine
state: Lower Austria
city: Krems
country: Austria
facility: Hospital Krems
state: Lower Austria
city: Melk
country: Austria
facility: Hospital Melk
state: Lower Austria
city: Mistelbach
country: Austria
facility: Hospital Mistelbach
state: Lower Austria
city: Mödling
country: Austria
facility: Hospital Mödling
state: Lower Austria
city: Neunkirchen
country: Austria
facility: Hospital Neunkirchen
state: Lower Austria
city: Scheibbs
country: Austria
facility: Hospital Scheibbs
state: Lower Austria
city: St. Poelten
country: Austria
facility: Hospital St. Poelten
state: Lower Austria
city: Tulln
country: Austria
facility: Hospital Tulln
state: Lower Austria
city: Waidhofen An Der Thaya
country: Austria
facility: Hospital Waidhofen/Thaya
state: Lower Austria
city: Wiener Neustadt
country: Austria
facility: Hospital of Wiener Neustadt
state: Lower Austria
city: Schwarzach
country: Austria
facility: Kardinal Schwarzenberg'sches Hospital
state: Salzburg
city: Feldbach
country: Austria
facility: State Hospital Feldbach
state: Styria
city: Graz
country: Austria
facility: Gynaegological Medical University of Graz
state: Styria
city: Graz
country: Austria
facility: Medical University of Graz, Oncology
state: Styria
city: Leoben
country: Austria
facility: State Hospital Leoben
state: Styria
city: Rottenmann
country: Austria
facility: State Hospital Rottenmann
state: Styria
city: Weiz
country: Austria
facility: Brustgesundheitszentrum-Süd Institut / Dr. Thiel
state: Styria
city: Hall in Tirol
country: Austria
facility: District Hospital Hall in Tirol
state: Tyrol
city: Innsbruck
country: Austria
facility: Gynaegological Medical University Innsbruck
state: Tyrol
city: Kufstein
country: Austria
facility: District Hospital Kufstein
state: Tyrol
city: Lienz
country: Austria
facility: District Hospital Lienz
state: Tyrol
city: Zams
country: Austria
facility: Hospital St. Vinzenz
state: Tyrol
city: Bad Ischl
country: Austria
facility: State Hospital Bad Ischl
state: Upper Austria
city: Freistadt
country: Austria
facility: State Hospital Freistadt
state: Upper Austria
city: Gmunden
country: Austria
facility: State Hospital Gmunden
state: Upper Austria
city: Kirchdorf
country: Austria
facility: State Hospital Kirchdorf
state: Upper Austria
city: Linz
country: Austria
facility: Hospital BHS Linz
state: Upper Austria
city: Linz
country: Austria
facility: Hospital Elisabethinen Linz
state: Upper Austria
city: Linz
country: Austria
facility: General Hospital Linz
state: Upper Austria
city: Linz
country: Austria
facility: Hospital BHB Linz
state: Upper Austria
city: Linz
country: Austria
facility: Ordination Dr. Pöstlberger
state: Upper Austria
city: Ried
country: Austria
facility: Hospital BHS Ried
state: Upper Austria
city: Rohrbach
country: Austria
facility: State Hospital Rohrbach
state: Upper Austria
city: Schärding
country: Austria
facility: State Hospital Schärding
state: Upper Austria
city: Steyr
country: Austria
facility: State Hospital Steyr
state: Upper Austria
city: Voecklabruck
country: Austria
facility: State Hospital Voecklabruck, Internal Medicine
state: Upper Austria
city: Voecklabruck
country: Austria
facility: State Hospital Voecklabruck, Surgery Dept.
state: Upper Austria
city: Wels
country: Austria
facility: Klinikum Wels-Grieskirchen
state: Upper Austria
city: Bregenz
country: Austria
facility: State Hospital Bregenz
state: Vorarlberg
city: Dornbirn
country: Austria
facility: State Hospital of Dornbirn
state: Vorarlberg
city: Feldkirch
country: Austria
facility: State Hospital Feldkirch
state: Vorarlberg
city: Salzburg
country: Austria
facility: Paracelsus Medical University Salzburg - Oncology
city: Vienna
country: Austria
facility: Hospital BHB Vienna, Surgery
city: Vienna
country: Austria
facility: Hospital Sanatorium Hera
city: Vienna
country: Austria
facility: Medical University of Vienna, General Hospital, Gynaecology and Obstetrics
city: Vienna
country: Austria
facility: Medical University of Vienna, General Hospital
city: Vienna
country: Austria
facility: Medical University Vienna, General Hospital
city: Vienna
country: Austria
facility: State Hospital Vienna-Hietzing
city: Vienna
country: Austria
facility: Hanusch Hospital
city: Vienna
country: Austria
facility: Wilheminenspital, Internal Medicin I
city: Freiburg
country: Germany
facility: Practice Dr. Marschner
state: Baden-Wuerttemberg
city: Ulm
country: Germany
facility: Medical Care Center
state: Baden-Wuerttemberg
city: Amberg
country: Germany
facility: Klinikum St. Marien
state: Bavaria
city: Muenchen
country: Germany
facility: Frauenklinik vom Roten Kreuz
state: Bavaria
city: Munich
country: Germany
facility: Med. University of Munich
state: Bavaria
city: Kassel
country: Germany
facility: Elisabeth-Hospital
state: Hesse
city: Oldenburg
country: Germany
facility: Internal-haematological Practice Oldenburg
state: Lower Saxony
city: Gifhorn
country: Germany
facility: General Hospital Gifhorn
state: Saxony
city: Kiel
country: Germany
facility: Medical University Kiel
state: Schleswig-Holstein
city: Berlin
country: Germany
facility: Vivantes-Klinikum Friedrichshain
Study officials:
affiliation: Austrian Breast & Colorectal Cancer Study Group
name: Raimund Jakesz, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gnant M, Mlineritsch B, Luschin-Ebengreuth G, Kainberger F, Kassmann H, Piswanger-Solkner JC, Seifert M, Ploner F, Menzel C, Dubsky P, Fitzal F, Bjelic-Radisic V, Steger G, Greil R, Marth C, Kubista E, Samonigg H, Wohlmuth P, Mittlbock M, Jakesz R; Austrian Breast and Colorectal Cancer Study Group (ABCSG). Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 5-year follow-up of the ABCSG-12 bone-mineral density substudy. Lancet Oncol. 2008 Sep;9(9):840-9. doi: 10.1016/S1470-2045(08)70204-3. Epub 2008 Aug 19.
citation: Gnant MF, Mlineritsch B, Luschin-Ebengreuth G, Grampp S, Kaessmann H, Schmid M, Menzel C, Piswanger-Soelkner JC, Galid A, Mittlboeck M, Hausmaninger H, Jakesz R; Austrian Breast and Colorectal Cancer Study Group. Zoledronic acid prevents cancer treatment-induced bone loss in premenopausal women receiving adjuvant endocrine therapy for hormone-responsive breast cancer: a report from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol. 2007 Mar 1;25(7):820-8. doi: 10.1200/JCO.2005.02.7102. Epub 2006 Dec 11.
citation: Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Postlberger S, Menzel C, Jakesz R, Seifert M, Hubalek M, Bjelic-Radisic V, Samonigg H, Tausch C, Eidtmann H, Steger G, Kwasny W, Dubsky P, Fridrik M, Fitzal F, Stierer M, Rucklinger E, Greil R; ABCSG-12 Trial Investigators; Marth C. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 2009 Feb 12;360(7):679-91. doi: 10.1056/NEJMoa0806285.
citation: Gnant M, Dubsky P, Fitzal F, Blaha P, Schoppmann S, Steger G, Marth C, Samonigg H, Huttner K, Fohler H, Ruecklinger E, Jakesz R, Greil R; Austrian Breast and Colorectal Cancer Study Group. Maintaining bone density in patients undergoing treatment for breast cancer: is there an adjuvant benefit? Clin Breast Cancer. 2009 Jun;9 Suppl 1:S18-27. doi: 10.3816/CBC.2009.s.002.
citation: Gnant M. Can oral bisphosphonates really reduce the risk of breast cancer in healthy women? J Clin Oncol. 2010 Aug 1;28(22):3548-51. doi: 10.1200/JCO.2010.29.6327. Epub 2010 Jun 21. No abstract available.
citation: Gnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Heck D, Menzel C, Jakesz R, Seifert M, Hubalek M, Pristauz G, Bauernhofer T, Eidtmann H, Eiermann W, Steger G, Kwasny W, Dubsky P, Hochreiner G, Forsthuber EP, Fesl C, Greil R; Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol. 2011 Jul;12(7):631-41. doi: 10.1016/S1470-2045(11)70122-X. Epub 2011 Jun 5.
citation: Gnant M. Zoledronic acid in breast cancer: latest findings and interpretations. Ther Adv Med Oncol. 2011 Nov;3(6):293-301. doi: 10.1177/1758834011420599.
citation: Pfeiler G, Konigsberg R, Fesl C, Mlineritsch B, Stoeger H, Singer CF, Postlberger S, Steger GG, Seifert M, Dubsky P, Taucher S, Samonigg H, Bjelic-Radisic V, Greil R, Marth C, Gnant M. Impact of body mass index on the efficacy of endocrine therapy in premenopausal patients with breast cancer: an analysis of the prospective ABCSG-12 trial. J Clin Oncol. 2011 Jul 1;29(19):2653-9. doi: 10.1200/JCO.2010.33.2585. Epub 2011 May 9.
citation: Ressler S, Mlineritsch B, Greil R. Zoledronic acid for adjuvant use in patients with breast cancer. Expert Rev Anticancer Ther. 2011 Mar;11(3):333-49. doi: 10.1586/era.11.13.
citation: Hadji P, Coleman R, Gnant M, Green J. The impact of menopause on bone, zoledronic acid, and implications for breast cancer growth and metastasis. Ann Oncol. 2012 Nov;23(11):2782-2790. doi: 10.1093/annonc/mds169. Epub 2012 Jun 22.
citation: Rugani P, Luschin G, Jakse N, Kirnbauer B, Lang U, Acham S. Prevalence of bisphosphonate-associated osteonecrosis of the jaw after intravenous zoledronate infusions in patients with early breast cancer. Clin Oral Investig. 2014;18(2):401-7. doi: 10.1007/s00784-013-1012-5. Epub 2013 Jun 10.
citation: Gnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Knauer M, Moik M, Jakesz R, Seifert M, Taucher S, Bjelic-Radisic V, Balic M, Eidtmann H, Eiermann W, Steger G, Kwasny W, Dubsky P, Selim U, Fitzal F, Hochreiner G, Wette V, Sevelda P, Ploner F, Bartsch R, Fesl C, Greil R; Austrian Breast and Colorectal Cancer Study Group, Vienna, Austria. Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12. Ann Oncol. 2015 Feb;26(2):313-20. doi: 10.1093/annonc/mdu544. Epub 2014 Nov 17.
citation: Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet. 2015 Oct 3;386(10001):1353-1361. doi: 10.1016/S0140-6736(15)60908-4. Epub 2015 Jul 23.
citation: Lipton A, Gnant M, Aapro M. Managing aromatase inhibitor-associated bone loss in breast cancer. Womens Health (Lond). 2007 Jul;3(4):441-8. doi: 10.2217/17455057.3.4.441.