Tamoxifen Versus Anastrozole, Alone or in Combination With Zoledronic Acid

Breast Cancer Clinical Trial

Official title:

Tamoxifen Versus Anastrozole, Alone or in Combination With Zoledronic Acid, in Premenopausal, Hormone Receptor-positive Breast Cancer Patients (Stage I, II)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00295646
• Other study ID #: ABCSG-12
• Secondary ID: CZOL 446 1B 01Zo
• Status: Completed
• Phase: Phase 3
• Start date: June 1999
• Est. completion date: June 26, 2018

Study information

• Verified date: March 2024
• Source: Austrian Breast & Colorectal Cancer Study Group
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1803
• Est. completion date: June 26, 2018
• Est. primary completion date: March 27, 2008
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 19 Years to 59 Years

Eligibility

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

Related Conditions & MeSH terms

• Breast Cancer
• Breast Neoplasms

Intervention

Drug:
• tamoxifen
20 mg/d
• anastrozole
1 mg/d
• zoledronic acid
4 mg q6m

Other:
• goserelin
3.6 mg goserelin subcutaneously every 28 days

Locations

Country	Name	City	State
Austria	State Hospital Bad Ischl	Bad Ischl	Upper Austria
Austria	State Hospital Bregenz	Bregenz	Vorarlberg
Austria	State Hospital of Dornbirn	Dornbirn	Vorarlberg
Austria	State Hospital Feldbach	Feldbach	Styria
Austria	State Hospital Feldkirch	Feldkirch	Vorarlberg
Austria	State Hospital Freistadt	Freistadt	Upper Austria
Austria	State Hospital Gmunden	Gmunden	Upper Austria
Austria	Gynaegological Medical University of Graz	Graz	Styria
Austria	Medical University of Graz, Oncology	Graz	Styria
Austria	Hospital of Guessing	Guessing	Burgenland
Austria	Hospital Hainburg	Hainburg An Der Donau	Lower Austria
Austria	District Hospital Hall in Tirol	Hall in Tirol	Tyrol
Austria	Gynaegological Medical University Innsbruck	Innsbruck	Tyrol
Austria	State Hospital Kirchdorf	Kirchdorf	Upper Austria
Austria	State Hospital Klagenfurt	Klagenfurt	Carinthia
Austria	State Hospital Klagenfurt, Surgery	Klagenfurt	Carinthia
Austria	Hospital Klosterneuburg, Internal Medicine	Klosterneuburg	Lower Austria
Austria	Hospital Krems	Krems	Lower Austria
Austria	District Hospital Kufstein	Kufstein	Tyrol
Austria	State Hospital Leoben	Leoben	Styria
Austria	District Hospital Lienz	Lienz	Tyrol
Austria	General Hospital Linz	Linz	Upper Austria
Austria	Hospital BHB Linz	Linz	Upper Austria
Austria	Hospital BHS Linz	Linz	Upper Austria
Austria	Hospital Elisabethinen Linz	Linz	Upper Austria
Austria	Ordination Dr. Pöstlberger	Linz	Upper Austria
Austria	Hospital Melk	Melk	Lower Austria
Austria	Hospital Mistelbach	Mistelbach	Lower Austria
Austria	Hospital Mödling	Mödling	Lower Austria
Austria	Hospital Neunkirchen	Neunkirchen	Lower Austria
Austria	Hospital Oberpullendorf	Oberpullendorf	Burgenland
Austria	Hospital Oberwart	Oberwart	Burgenland
Austria	Hospital BHS Ried	Ried	Upper Austria
Austria	State Hospital Rohrbach	Rohrbach	Upper Austria
Austria	State Hospital Rottenmann	Rottenmann	Styria
Austria	Paracelsus Medical University Salzburg - Oncology	Salzburg
Austria	State Hospital Schärding	Schärding	Upper Austria
Austria	Hospital Scheibbs	Scheibbs	Lower Austria
Austria	Kardinal Schwarzenberg'sches Hospital	Schwarzach	Salzburg
Austria	Hospital St. Poelten	St. Poelten	Lower Austria
Austria	Hospital BHB St. Veit	St. Veit a. d. Glan	Carinthia
Austria	Ordination Dr. Wette	St. Veit a. d. Glan	Carinthia
Austria	State Hospital Steyr	Steyr	Upper Austria
Austria	Hospital Tulln	Tulln	Lower Austria
Austria	Hanusch Hospital	Vienna
Austria	Hospital BHB Vienna, Surgery	Vienna
Austria	Hospital Sanatorium Hera	Vienna
Austria	Medical University of Vienna, General Hospital	Vienna
Austria	Medical University of Vienna, General Hospital, Gynaecology and Obstetrics	Vienna
Austria	Medical University Vienna, General Hospital	Vienna
Austria	State Hospital Vienna-Hietzing	Vienna
Austria	Wilheminenspital, Internal Medicin I	Vienna
Austria	Privat Hospital Villach	Villach	Carinthia
Austria	State Hospital Villach	Villach	Carinthia
Austria	State Hospital Voecklabruck, Internal Medicine	Voecklabruck	Upper Austria
Austria	State Hospital Voecklabruck, Surgery Dept.	Voecklabruck	Upper Austria
Austria	Hospital Waidhofen/Thaya	Waidhofen An Der Thaya	Lower Austria
Austria	Brustgesundheitszentrum-Süd Institut / Dr. Thiel	Weiz	Styria
Austria	Klinikum Wels-Grieskirchen	Wels	Upper Austria
Austria	Hospital of Wiener Neustadt	Wiener Neustadt	Lower Austria
Austria	State Hospital Wolfsberg	Wolfsberg	Carinthia
Austria	Hospital St. Vinzenz	Zams	Tyrol
Germany	Klinikum St. Marien	Amberg	Bavaria
Germany	Vivantes-Klinikum Friedrichshain	Berlin
Germany	Practice Dr. Marschner	Freiburg	Baden-Wuerttemberg
Germany	General Hospital Gifhorn	Gifhorn	Saxony
Germany	Elisabeth-Hospital	Kassel	Hesse
Germany	Medical University Kiel	Kiel	Schleswig-Holstein
Germany	Frauenklinik vom Roten Kreuz	Muenchen	Bavaria
Germany	Med. University of Munich	Munich	Bavaria
Germany	Internal-haematological Practice Oldenburg	Oldenburg	Lower Saxony
Germany	Medical Care Center	Ulm	Baden-Wuerttemberg

Sponsors (3)

Lead Sponsor	Collaborator
Austrian Breast & Colorectal Cancer Study Group	AstraZeneca, Novartis Pharmaceuticals

Countries where clinical trial is conducted

Austria,  Germany, 

References & Publications (14)

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. Erratum In: Lancet. 2016 Jan 2;387(10013):30. Lancet. 2017 Jun 24;389(10088):2472. — View 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. — View 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. — View 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. Erratum In: N Engl J Med. 2009 May 28;360(22):2379. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Comparison of Anastrozole vs Tamoxifen in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Disease-free Survival (DFS)	DFS is defined as time from randomization to first occurrence of a local, regional, or distant recurrence, second primary carcinoma (including contralateral breast cancer), or death from any cause	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.
Primary	Comparison of Zoledronate vs no Zoledronate in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Disease-free Survival (DFS)	DFS is defined as time from randomization to first occurrence of a local, regional, or distant recurrence, second primary carcinoma (including contralateral breast cancer), or death from any cause	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	Comparison of Anastrozole vs Tamoxifen in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Recurrence-free Survival (RFS)	RFS is defined as time from randomization to first occurrence of a local, regional, or distant recurrence, second primary carcinoma (including contralateral breast cancer), or death from breast cancer	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	Comparison of Zoledronate vs no Zoledronate in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Recurrence-free Survival (RFS)	RFS is defined as time from randomization to first occurrence of a local, regional, or distant recurrence, second primary carcinoma (including contralateral breast cancer), or death from breast cancer	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	Comparison of Anastrozole vs Tamoxifen in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Overall Survival (OS)	OS is defined as time from randomization to death from any cause	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	Comparison of Zoledronate vs no Zoledronate in Premenopausal Patients With Non-metastatic Breast Cancer With Respect to Overall Survival (OS)	OS is defined as time from randomization to death from any cause	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.