Clinical trial NCT00512993: Postoperative Use of Zoledronic Acid in Breast Cancer Patients After Neoadjuvant Chemotherapy
Official title: A Randomized, Multicenter, Open Phase III Study Comparing the Postoperative Use of Zoledronic Acid Versus no Treatment in Patients With Histological Tumor Residuals After Preoperative Anthracycline and Taxane Containing Chemotherapy for Primary Breast Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Breast Cancer
Keywords: Postoperative treatment with zoledronic acid
Preoperative anthracycline/taxane containing chemotherapy
Lead sponsor: GBG Forschungs GmbH
Sponsor class: OTHER
Collaborators: name: Austrian Breast & Colorectal Cancer Study Group
name: Novartis Pharmaceuticals
First posted: 2007-08-08
Enrollment: 654
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine the event-free survival (EFS) after zoledronic acid for 5 years versus no postoperative treatment in patients with "chemo-insensitive" breast cancer (ypT1-4 and/or ypN1-3) after preoperative anthracycline/taxane containing chemotherapy

Detailed description: The study is restricted to patients having had primary systemic chemotherapy for stage II and III breast cancer. Participation in a preoperative chemotherapy trial investigating anthracycline and taxane based regimen is allowed, but not mandatory for all patients. Patients must have significant remaining tumor tissue in the breast and/or axillary lymph node. This implies resistance to further chemotherapy and a clinically relevant risk for relapse. Bisphosphonates have a distinct mechanism of action and have demonstrated efficacy in the treatment of breast cancer with metastasis to the bone as well as adjuvant treatment after surgery of primary breast cancer. The 3rd generation bisphosphonate zoledronic acid has a favorable toxicity profile and can be conveniently given to patients over a long term period.

Eligibility criteria: Inclusion Criteria:

* Written informed consent must be obtained and documented according to the local regulatory requirements prior to beginning specific protocol procedures;
* Complete baseline documentation sent to GBG;
* Prior preoperative chemotherapy for at least 4 cycles, of which at least two must contain a taxane and an anthracycline;
* Completely resected unilateral or bilateral primary carcinoma of the breast with histologically detectable tumor residuals (ypT1-4) and/or histology confirmed involvement of axillary nodes (ypN1-3). Sentinel node biopsy is allowed, but complete axillary clearance is mandatory in node positive cases;
* A maximum interval of 3 years from date of axillary surgery to entering this trial;
* Age 18 years or older;
* Karnofsky index \>= 70%;
* Life expectancy of at least 10 years, disregarding the diagnosis of cancer;
* No clinical evidence of local recurrence or distant metastases. Complete staging work-up: All patients must have breast ultrasound, chest X-ray, ultrasound or CT scan of the liver within 3 months prior to registration, as well as (bilateral) mammography or breast MRI and bone scan within 8 months prior to registration. In case of a positive bone scan, bone X-ray is mandatory. Other tests may be performed as clinically indicated;
* Adequate renal and hepatic function (serum creatinine, bilirubin, and transaminases within 1.5 × upper normal range);
* Patients must be available and compliant for treatment and follow-up. Patients registered on this trial must be treated and followed up at the participating center.

Exclusion Criteria:

* Known hypersensitivity reaction to the investigational compound;
* Prior postoperative chemotherapy;
* Prior treatment with bisphosphonates since breast cancer surgery;
* Pregnant or lactating patients. Patients of childbearing potential must have a negative pregnancy test (urine or serum) within 14 days prior to registration and must implement adequate non-hormonal contraceptive measures (barrier methods, intra uterine contraceptive devices, sterilization) during study treatment;
* History of diseases with influence on bone metabolism, such as Paget's disease of bone and primary hyperparathyroidism or osteoporosis requiring treatment at the time of study entry or considered likely to become necessary within the six months
* Other serious illness or medical condition that may interfere with the understanding and giving of informed consent and the conduct of the study
* Prior or concomitant secondary malignancy (except non-melanomatous skin cancer or carcinoma in situ of the uterine cervix)
* Concurrent treatment with other experimental drugs or any other anti-cancer therapy;
* Abnormal renal function as evidenced by a calculated creatinine clearance \< 30 ml/minute;
* Serum calcium concentration \< 8.0 mg/dl (2.00 mmol/L) or \> 12.0 mg/dl (3.00 mmol/L)
* Concurrent treatment with sex hormones. Prior treatment must be stopped before study entry;
* Current active dental problems including infection of the teeth or jawbone (maxilla or mandibular); dental or fixture trauma, or a current or prior diagnosis of osteonecrosis of the jaw, of exposed bone in the mouth, or of slow healing after dental procedures.
* Recent (within 6 weeks) or planned dental or jaw surgery (e.g.. extraction, implants)
* Male patients.

Primary outcomes:
measure: The event-free survival (EFS) after zoledronic acid for 5 years versus no postoperative treatment in patients with "chemo-insensitive" breast cancer (ypT1-4 and/or ypN1-3) after preoperative anthracycline/taxane containing chemotherapy.
timeFrame: 5 years
Secondary outcomes:
measure: The overall survival in both treatment arms.
timeFrame: 5 years
measure: The EFS with respect to the interval between surgery and randomization.
timeFrame: 5 years
measure: The bone-metastasis free-survival in both arms.
timeFrame: 5 years
measure: The toxicity of and compliance to zoledronic acid.
timeFrame: 5 years
measure: The predictive value of primary breast tumor response on the effect of postoperative treatment.
timeFrame: 5 years
measure: The prognostic impact of chemotherapy induced amenorrhea in premenopausal patients.
timeFrame: 5 years
Other outcomes:
Locations:
city: St. Veit a. d. Glan
country: Austria
facility: A. ö. Krankenhaus der Barmherzigen Brüder, Interne Abteilung
state: Carinthia
city: Wolfsberg
country: Austria
facility: Landeskrankenhaus Wolfsberg, Chirurgische Abteilung
state: Carinthia
city: Wien
country: Austria
facility: Medizinische Universität Wien
state: Lower Austria
city: Graz
country: Austria
facility: LKH-Univ. Klinikum Graz, Onkologie
state: Styria
city: Innsbruck
country: Austria
facility: Universitäts Klinikum Innsbruck
state: Tirol
city: Linz
country: Austria
facility: Allgemeines Krankenhaus der Stadt Linz, Innere Medizin 3/Zentrum f. Häm. u. Med. Onkologie
state: Upper Austria
city: Steyr
country: Austria
facility: Landeskrankenhaus Steyr, 2. Med. Abt. Onkologie
state: Upper Austria
city: Wels
country: Austria
facility: Klinikum Wels-Grieskirchen GmbH, Abt. f. Innere Medizin IV
state: Upper Austria
city: Rankweil
country: Austria
facility: Landeskrankenhaus Feldkirch
state: Vorarlberg
city: Salzburg
country: Austria
facility: LKH Salzburg, Uni.klinik f. Innere Med. III/Onkol. Amb.
city: Aalen
country: Germany
facility: Ostalb-Klinikum, ABC Brustzentrum, Frauenklinik
state: Baden-Württemberg
city: Böblingen
country: Germany
facility: Klinikum Sindelfingen-Böblingen / Kliniken Böblingen, Frauenklinik
state: Baden-Württemberg
city: Karlsruhe
country: Germany
facility: St. Vincentius Kliniken Karlsruhe
state: Baden-Württemberg
city: Lörrach
country: Germany
facility: Onkol. Schwerpunktpraxis Dr. Knoblich
state: Baden-Württemberg
city: Mannheim
country: Germany
facility: Universitätsklinikum Mannheim, Frauenklinik
state: Baden-Württemberg
city: Pforzheim
country: Germany
facility: Krankenhaus Siloah, Gynäkologie und Geburtshilfe
state: Baden-Württemberg
city: Reutlingen
country: Germany
facility: Klinikum am Steinenberg
state: Baden-Württemberg
city: Rheinfelden
country: Germany
facility: Frauenklinik Rheinfelden
state: Baden-Württemberg
city: Stuttgart
country: Germany
facility: Krankenhaus Bad Cannstatt, Frauenklinik
state: Baden-Württemberg
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen, Frauenklinik
state: Baden-Württemberg
city: Ebersberg
country: Germany
facility: Kreiskrankenhaus Ebersberg, Gynäkologisch-onkologische Abteilung
state: Bayern
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen, Frauenklinik mit Poliklinik
state: Bayern
city: Regensburg
country: Germany
facility: Caritas-Krankenhaus St. Josef, Klinik für Frauenheilkunde und Geburtshilfe
state: Bayern
city: Rosenheim
country: Germany
facility: Klinikum Rosenheim, Abt. Gynäkologie u. Geburtshilfe
state: Bayern
city: Berlin-Tempelhof
country: Germany
facility: Schwerpunktpraxis Gynäkologie, Onkologie, Naturheilverfahren
state: Berlin
city: Bernau
country: Germany
facility: Praxis Dr. Gottschalk, Fachärztin für Frauenheilkunde und Geburtshilfe
state: Brandenburg
city: Fuerstenwalde
country: Germany
facility: Schwerpunktpraxis der Gynäkologie und Onkologie
state: Brandenburg
city: Neuruppin
country: Germany
facility: Ruppiner Kliniken, Frauenklinik
state: Brandenburg
city: Frankfurt/Höchst
country: Germany
facility: Städt. Kliniken Frankfurt-Höchst, Frauenklinik
state: Hessen
city: Frankfurt
country: Germany
facility: Onkologie Bethanien, Onkologie / Tagesklinik
state: Hessen
city: Frankfurt
country: Germany
facility: St. Markus Krankenhaus, Frauenklinik
state: Hessen
city: Hanau
country: Germany
facility: Klinikum Stadt Hanau
state: Hessen
city: Kassel
country: Germany
facility: Klinikum Kassel GmbH, Gynäkologische Ambulanz
state: Hessen
city: Langen
country: Germany
facility: Asklepios Klinik, Frauenklinik
state: Hessen
city: Lich
country: Germany
facility: Asklepios-Klinik Lich, Frauenklinik
state: Hessen
city: Limburg
country: Germany
facility: St. Vincenz Krankenhaus, Frauenklinik
state: Hessen
city: Marburg
country: Germany
facility: Universitätsklinikum, Frauenklinik / Mutter-Kind-Zentrum
state: Hessen
city: Neu-Isenburg
country: Germany
facility: GBG Forschungs GmbH
state: Hessen
city: Wiesbaden
country: Germany
facility: St. Josefs-Hospital, Gynäkologie und Geburtshilfe
state: Hessen
city: Wiesbaden
country: Germany
facility: Asklepios Paulinen Klinik, Frauenklinik
state: Hessen
city: Wiesbaden
country: Germany
facility: Dr.-Horst-Schmidt-Kliniken GmbH, Klinik f. Gyn. und gyn. Onkologie
state: Hessen
city: Greifswald
country: Germany
facility: Universität Greifswald, Klinik für Frauenheilkunde und Geburtshilfe
state: Mecklenburg-Vorpommern
city: Neubrandenburg
country: Germany
facility: Dietrich-Bonhoeffer Klinikum, Frauenklinik
state: Mecklenburg-Vorpommern
city: Rostock
country: Germany
facility: Klinikum Südstadt, Universitätsfrauenklinik
state: Mecklenburg-Vorpommern
city: Lüneburg
country: Germany
facility: Schwerpunktpraxis, Internistisch-gynäkolog.-onkolog.
state: Niedersachsen.
city: Celle
country: Germany
facility: Allgm. Krankenhaus Celle, Frauenklinik
state: Niedersachsen
city: Cuxhaven
country: Germany
facility: Krankenhaus Cuxhaven, Frauenklinik
state: Niedersachsen
city: Gifhorn
country: Germany
facility: Kreiskrankenhaus Gifhorn, Interdisziplinäres Brustzentrum
state: Niedersachsen
city: Goslar
country: Germany
facility: Onkologische Schwerpunktpraxis Dr. Tessen
state: Niedersachsen
city: Hameln
country: Germany
facility: Kreiskrankenhaus Hameln, Brustzentrum
state: Niedersachsen
city: Hannover
country: Germany
facility: Henriettenstiftung
state: Niedersachsen
city: Hannover
country: Germany
facility: Vinzenzkrankenhaus, Gynäkologie
state: Niedersachsen
city: Hildesheim
country: Germany
facility: Gemeinschaftspraxis Gynäkologie
state: Niedersachsen
city: Ilsede
country: Germany
facility: Facharzt für Frauenheilkunde und Geburtshilfe
state: Niedersachsen
city: Stadhagen
country: Germany
facility: Klinikum Schaumburg, Kreiskrankenhaus Stadthagen, Gynäkologie und Geburtshilfe
state: Niedersachsen
city: Bielefeld
country: Germany
facility: Onkologische Schwerpunktpraxis, Dres. Schäfer / Just / Görner
state: Nordrhein-Westfalen
city: Bochum
country: Germany
facility: Praxis für Innere Medizin, Hämatologie, internistische Onkologie
state: Nordrhein-Westfalen
city: Coesfeld
country: Germany
facility: Onkologische Schwerpunktpraxis Dr. Glados, Hämatologie / Internistische Onkologie
state: Nordrhein-Westfalen
city: Düsseldorf
country: Germany
facility: Luisenkrankenhaus, Senologie, Brustzentrum
state: Nordrhein-Westfalen
city: Erkelenz
country: Germany
facility: Hermann-Josef Krankenhaus, Frauenklinik
state: Nordrhein-Westfalen
city: Eschweiler
country: Germany
facility: St. Antonius Hospital, Klinik für Hämatologie u. Onkologie
state: Nordrhein-Westfalen
city: Essen
country: Germany
facility: Universitätsklinikum Essen, Klinik für Frauenheilkunde und Geburtshilfe
state: Nordrhein-Westfalen
city: Essen
country: Germany
facility: Gynäkologische Praxis Dr. Deertz
state: Nordrhein-Westfalen
city: Essen
country: Germany
facility: Alfried-Krupp-Krankenhaus, Frauenklinik
state: Nordrhein-Westfalen
city: Essen
country: Germany
facility: Marienhospital Altenessen
state: Nordrhein-Westfalen
city: Herne
country: Germany
facility: Marienhospital Herne, Onkologische / Hämatologische Ambulanz
state: Nordrhein-Westfalen
city: Ibbenbüren
country: Germany
facility: Elisabeth-Hospital, Frauenklinik
state: Nordrhein-Westfalen
city: Köln
country: Germany
facility: Klinikum der Universität zu Köln, Klinik und Poliklinik für Gyn. und Geburtshilfe
state: Nordrhein-Westfalen
city: Köln
country: Germany
facility: Klinikum der Universität zu Köln
state: Nordrhein-Westfalen
city: Köln
country: Germany
facility: St. Elisabeth-KKH, Brustzentrum Koeln-Hohenlind
state: Nordrhein-Westfalen
city: Witten
country: Germany
facility: Marienhospital Witten, Brustzentrum
state: Nordrhein-Westfalen
city: Mainz
country: Germany
facility: St. Vincenz und Elisabeth-Hospital
state: Rheinland-Pfalz
city: Mainz
country: Germany
facility: Uniklinikum, Klinik für Geburtshilfe und Gynäkologie
state: Rheinland-Pfalz
city: Neunkirchen
country: Germany
facility: Krankenhaus Neunkirchen gGmbH, Frauenklinik
state: Saarland
city: Halle / Saale
country: Germany
facility: Krankenhaus St. Elisabeth und St. Barbara Halle, Klinik für Gynäkologie und Geburtshilfe
state: Sachsen-Anhalt
city: Magdeburg
country: Germany
facility: Klinikum der Otto-v.-Guericke-Universität, Frauenklinik
state: Sachsen-Anhalt
city: Quedlinburg
country: Germany
facility: Klinikum Quedlinburg, Frauenklinik
state: Sachsen-Anhalt
city: Stendal
country: Germany
facility: Johanniter-Krankenhaus Genthin-Stendal GmbH, Frauenheilkunde und Geburtshilfe
state: Sachsen-Anhalt
city: Chemnitz
country: Germany
facility: Klinikum Chemnitz gGmbH, Frauenklinik
state: Sachsen
city: Dresden
country: Germany
facility: Gemeinschaftspraxis, Fachärzte für Innere Medizin, Hämatologie und Internistische Onkologie
state: Sachsen
city: Dresden
country: Germany
facility: Technische Universität Dresden
state: Sachsen
city: Kiel
country: Germany
facility: Universitätsklinikum Schleswig-Holstein Campus Kiel
state: Schleswig-Holstein
city: Lübeck
country: Germany
facility: Universitätsklinikum Schleswig-Holstein
state: Schleswig-Holstein
city: Oldenburg
country: Germany
facility: Ostholstein Kliniken GmbH Klinik Oldenburg, Zentrum für Gynäkologie und Geburtshilfe Sana Kliniken Ostholstein
state: Schleswig-Holstein
city: Gera
country: Germany
facility: SRH Wald-Klinikum Gera gGmbH, Brustzentrum Ostthüringen
state: Thüringen
city: Jena
country: Germany
facility: Universitätsklinikum, Klinik für Frauenheilkunde und Geburtshilfe
state: Thüringen
city: Berlin
country: Germany
facility: Praxisklinik, Krebsheilkunde für Frauen / Brustzentrum
city: Berlin
country: Germany
facility: DRK Kliniken Köpenick, Frauenklinik
city: Bremen
country: Germany
facility: Onkologische Schwerpunktpraxis
city: Bremen
country: Germany
facility: Evangelisches Diakonie-Krankenhaus, Frauenklinik
city: Friedrichshafen
country: Germany
facility: Intern. Gemeinschaftspraxis
city: Hamburg
country: Germany
facility: Facharzt für Frauenheilkunde und Geburtshilfe
city: Salzwedel
country: Germany
facility: Krankenhaus Salzwedel
Study officials:
affiliation: GBG Forschungs GmbH, Hessen, Germany
name: Gunter von Minckwitz, Prof. MD
role: STUDY_CHAIR
affiliation: Austrian Breast & Colorectal Cancer Study Group
name: Peter Dubsky, MD
role: STUDY_CHAIR
References: