Postoperative Use of Zoledronic Acid in Breast Cancer Patients After Neoadjuvant Chemotherapy (NATAN)

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

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

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Zoledronic acid

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.

• Study Type: Interventional
• Enrollment (Anticipated): 654
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Salzburg, Austria, A-5020
    • LKH Salzburg, Uni.klinik f. Innere Med. III/Onkol. Amb.
  • Carinthia
    • St. Veit a. d. Glan, Carinthia, Austria, A-9300
      • A. ö. Krankenhaus der Barmherzigen Brüder, Interne Abteilung
    • Wolfsberg, Carinthia, Austria, A-9400
      • Landeskrankenhaus Wolfsberg, Chirurgische Abteilung
  • Lower Austria
    • Wien, Lower Austria, Austria
      • Medizinische Universität Wien
  • Styria
    • Graz, Styria, Austria, A-8036
      • LKH-Univ. Klinikum Graz, Onkologie
  • Tirol
    • Innsbruck, Tirol, Austria, 6020
      • Universitäts Klinikum Innsbruck
  • Upper Austria
    • Linz, Upper Austria, Austria, A-4020
      • Allgemeines Krankenhaus der Stadt Linz, Innere Medizin 3/Zentrum f. Häm. u. Med. Onkologie
    • Steyr, Upper Austria, Austria, A-4400
      • Landeskrankenhaus Steyr, 2. Med. Abt. Onkologie
    • Wels, Upper Austria, Austria, A-4600
      • Klinikum Wels-Grieskirchen GmbH, Abt. f. Innere Medizin IV
  • Vorarlberg
    • Rankweil, Vorarlberg, Austria, 6830
      • Landeskrankenhaus Feldkirch
• Germany
  • Berlin, Germany, 10367
    • Praxisklinik, Krebsheilkunde für Frauen / Brustzentrum
  • Berlin, Germany, 12559
    • DRK Kliniken Köpenick, Frauenklinik
  • Bremen, Germany, 28205
    • Onkologische Schwerpunktpraxis
  • Bremen, Germany, 28239
    • Evangelisches Diakonie-Krankenhaus, Frauenklinik
  • Friedrichshafen, Germany, 88045
    • Intern. Gemeinschaftspraxis
  • Hamburg, Germany, 22041
    • Facharzt für Frauenheilkunde und Geburtshilfe
  • Salzwedel, Germany, 29410
    • Krankenhaus Salzwedel
  • Baden-Württemberg
    • Aalen, Baden-Württemberg, Germany, 73430
      • Ostalb-Klinikum, ABC Brustzentrum, Frauenklinik
    • Böblingen, Baden-Württemberg, Germany, 71032
      • Klinikum Sindelfingen-Böblingen / Kliniken Böblingen, Frauenklinik
    • Karlsruhe, Baden-Württemberg, Germany, 76135
      • St. Vincentius Kliniken Karlsruhe
    • Lörrach, Baden-Württemberg, Germany, 79539
      • Onkol. Schwerpunktpraxis Dr. Knoblich
    • Mannheim, Baden-Württemberg, Germany, 68167
      • Universitätsklinikum Mannheim, Frauenklinik
    • Pforzheim, Baden-Württemberg, Germany, 75179
      • Krankenhaus Siloah, Gynäkologie und Geburtshilfe
    • Reutlingen, Baden-Württemberg, Germany, 72764
      • Klinikum am Steinenberg
    • Rheinfelden, Baden-Württemberg, Germany, 79618
      • Frauenklinik Rheinfelden
    • Stuttgart, Baden-Württemberg, Germany, 70374
      • Krankenhaus Bad Cannstatt, Frauenklinik
    • Tübingen, Baden-Württemberg, Germany, 72076
      • Universitätsklinikum Tübingen, Frauenklinik
  • Bayern
    • Ebersberg, Bayern, Germany, 85560
      • Kreiskrankenhaus Ebersberg, Gynäkologisch-onkologische Abteilung
    • Erlangen, Bayern, Germany, 91054
      • Universitätsklinikum Erlangen, Frauenklinik mit Poliklinik
    • Regensburg, Bayern, Germany, 93053
      • Caritas-Krankenhaus St. Josef, Klinik für Frauenheilkunde und Geburtshilfe
    • Rosenheim, Bayern, Germany, 83022
      • Klinikum Rosenheim, Abt. Gynäkologie u. Geburtshilfe
  • Berlin
    • Berlin-Tempelhof, Berlin, Germany, 12107
      • Schwerpunktpraxis Gynäkologie, Onkologie, Naturheilverfahren
  • Brandenburg
    • Bernau, Brandenburg, Germany, 16321
      • Praxis Dr. Gottschalk, Fachärztin für Frauenheilkunde und Geburtshilfe
    • Fuerstenwalde, Brandenburg, Germany, 15517
      • Schwerpunktpraxis der Gynäkologie und Onkologie
    • Neuruppin, Brandenburg, Germany, 16816
      • Ruppiner Kliniken, Frauenklinik
  • Hessen
    • Frankfurt, Hessen, Germany, 60389
      • Onkologie Bethanien, Onkologie / Tagesklinik
    • Frankfurt, Hessen, Germany, 60431
      • St. Markus Krankenhaus, Frauenklinik
    • Frankfurt/Höchst, Hessen, Germany, 65929
      • Städt. Kliniken Frankfurt-Höchst, Frauenklinik
    • Hanau, Hessen, Germany, 63450
      • Klinikum Stadt Hanau
    • Kassel, Hessen, Germany, 34125
      • Klinikum Kassel GmbH, Gynäkologische Ambulanz
    • Langen, Hessen, Germany, 63225
      • Asklepios Klinik, Frauenklinik
    • Lich, Hessen, Germany, 35423
      • Asklepios-Klinik Lich, Frauenklinik
    • Limburg, Hessen, Germany, 65549
      • St. Vincenz Krankenhaus, Frauenklinik
    • Marburg, Hessen, Germany, 35043
      • Universitätsklinikum, Frauenklinik / Mutter-Kind-Zentrum
    • Neu-Isenburg, Hessen, Germany, 63263
      • GBG Forschungs GmbH
    • Wiesbaden, Hessen, Germany, 65189
      • St. Josefs-Hospital, Gynäkologie und Geburtshilfe
    • Wiesbaden, Hessen, Germany, 65197
      • Asklepios Paulinen Klinik, Frauenklinik
    • Wiesbaden, Hessen, Germany, 65199
      • Dr.-Horst-Schmidt-Kliniken GmbH, Klinik f. Gyn. und gyn. Onkologie
  • Mecklenburg-Vorpommern
    • Greifswald, Mecklenburg-Vorpommern, Germany, 17487
      • Universität Greifswald, Klinik für Frauenheilkunde und Geburtshilfe
    • Neubrandenburg, Mecklenburg-Vorpommern, Germany, 17039
      • Dietrich-Bonhoeffer Klinikum, Frauenklinik
    • Rostock, Mecklenburg-Vorpommern, Germany, 18059
      • Klinikum Südstadt, Universitätsfrauenklinik
  • Niedersachsen
    • Celle, Niedersachsen, Germany, 29223
      • Allgm. Krankenhaus Celle, Frauenklinik
    • Cuxhaven, Niedersachsen, Germany, 27474
      • Krankenhaus Cuxhaven, Frauenklinik
    • Gifhorn, Niedersachsen, Germany, 38518
      • Kreiskrankenhaus Gifhorn, Interdisziplinäres Brustzentrum
    • Goslar, Niedersachsen, Germany, 38642
      • Onkologische Schwerpunktpraxis Dr. Tessen
    • Hameln, Niedersachsen, Germany, 31785
      • Kreiskrankenhaus Hameln, Brustzentrum
    • Hannover, Niedersachsen, Germany, 30559
      • Henriettenstiftung
    • Hannover, Niedersachsen, Germany, 30559
      • Vinzenzkrankenhaus, Gynäkologie
    • Hildesheim, Niedersachsen, Germany, 31134
      • Gemeinschaftspraxis Gynäkologie
    • Ilsede, Niedersachsen, Germany, 31241
      • Facharzt für Frauenheilkunde und Geburtshilfe
    • Stadhagen, Niedersachsen, Germany, 31655
      • Klinikum Schaumburg, Kreiskrankenhaus Stadthagen, Gynäkologie und Geburtshilfe
  • Niedersachsen.
    • Lüneburg, Niedersachsen., Germany, 21339
      • Schwerpunktpraxis, Internistisch-gynäkolog.-onkolog.
  • Nordrhein-Westfalen
    • Bielefeld, Nordrhein-Westfalen, Germany, 33604
      • Onkologische Schwerpunktpraxis, Dres. Schäfer / Just / Görner
    • Bochum, Nordrhein-Westfalen, Germany, 44787
      • Praxis für Innere Medizin, Hämatologie, internistische Onkologie
    • Coesfeld, Nordrhein-Westfalen, Germany, 48653
      • Onkologische Schwerpunktpraxis Dr. Glados, Hämatologie / Internistische Onkologie
    • Düsseldorf, Nordrhein-Westfalen, Germany, 40235
      • Luisenkrankenhaus, Senologie, Brustzentrum
    • Erkelenz, Nordrhein-Westfalen, Germany, 41812
      • Hermann-Josef Krankenhaus, Frauenklinik
    • Eschweiler, Nordrhein-Westfalen, Germany, 52249
      • St. Antonius Hospital, Klinik für Hämatologie u. Onkologie
    • Essen, Nordrhein-Westfalen, Germany, 45122
      • Universitätsklinikum Essen, Klinik für Frauenheilkunde und Geburtshilfe
    • Essen, Nordrhein-Westfalen, Germany, 45130
      • Gynäkologische Praxis Dr. Deertz
    • Essen, Nordrhein-Westfalen, Germany, 45131
      • Alfried-Krupp-Krankenhaus, Frauenklinik
    • Essen, Nordrhein-Westfalen, Germany, 45329
      • Marienhospital Altenessen
    • Herne, Nordrhein-Westfalen, Germany, 44625
      • Marienhospital Herne, Onkologische / Hämatologische Ambulanz
    • Ibbenbüren, Nordrhein-Westfalen, Germany, 49477
      • Elisabeth-Hospital, Frauenklinik
    • Köln, Nordrhein-Westfalen, Germany, 50924
      • Klinikum der Universität zu Köln, Klinik und Poliklinik für Gyn. und Geburtshilfe
    • Köln, Nordrhein-Westfalen, Germany, 50924
      • Klinikum der Universität zu Köln
    • Köln, Nordrhein-Westfalen, Germany, 50935
      • St. Elisabeth-KKH, Brustzentrum Koeln-Hohenlind
    • Witten, Nordrhein-Westfalen, Germany, 58452
      • Marienhospital Witten, Brustzentrum
  • Rheinland-Pfalz
    • Mainz, Rheinland-Pfalz, Germany, 55131
      • St. Vincenz und Elisabeth-Hospital
    • Mainz, Rheinland-Pfalz, Germany, 55131
      • Uniklinikum, Klinik für Geburtshilfe und Gynäkologie
  • Saarland
    • Neunkirchen, Saarland, Germany, 66538
      • Krankenhaus Neunkirchen gGmbH, Frauenklinik
  • Sachsen
    • Chemnitz, Sachsen, Germany, 09116
      • Klinikum Chemnitz gGmbH, Frauenklinik
    • Dresden, Sachsen, Germany, 01307
      • Technische Universität Dresden
    • Dresden, Sachsen, Germany, 01127
      • Gemeinschaftspraxis, Fachärzte für Innere Medizin, Hämatologie und Internistische Onkologie
  • Sachsen-Anhalt
    • Halle / Saale, Sachsen-Anhalt, Germany, 06110
      • Krankenhaus St. Elisabeth und St. Barbara Halle, Klinik für Gynäkologie und Geburtshilfe
    • Magdeburg, Sachsen-Anhalt, Germany, 39108
      • Klinikum der Otto-v.-Guericke-Universität, Frauenklinik
    • Quedlinburg, Sachsen-Anhalt, Germany, 06484
      • Klinikum Quedlinburg, Frauenklinik
    • Stendal, Sachsen-Anhalt, Germany, 39576
      • Johanniter-Krankenhaus Genthin-Stendal GmbH, Frauenheilkunde und Geburtshilfe
  • Schleswig-Holstein
    • Kiel, Schleswig-Holstein, Germany, 24105
      • Universitätsklinikum Schleswig-Holstein Campus Kiel
    • Lübeck, Schleswig-Holstein, Germany, 23538
      • Universitätsklinikum Schleswig-Holstein
    • Oldenburg, Schleswig-Holstein, Germany, 23758
      • Ostholstein Kliniken GmbH Klinik Oldenburg, Zentrum für Gynäkologie und Geburtshilfe Sana Kliniken Ostholstein
  • Thüringen
    • Gera, Thüringen, Germany, 07548
      • SRH Wald-Klinikum Gera gGmbH, Brustzentrum Ostthüringen
    • Jena, Thüringen, Germany, 07743
      • Universitätsklinikum, Klinik für Frauenheilkunde und Geburtshilfe

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Treatment; Patients receive zoledronic acid (4mg) for 5 years. Additionally patients receive standard endocrine, radiologic and trastuzumab treatment, respectively	Drug: Zoledronic acid; Infusion of zoledronic acid (4 mg) every 4 weeks for six doses, followed by every 3 months for 8 doses, followed by every 6 months for 5 doses; Other Names: Zometa
No Intervention: Observation; Patients will be under observation and receive standard endocrine, radiologic and trastuzumab treatment, respectively

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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.	5 years

Secondary Outcome Measures

Outcome Measure	Time Frame
The overall survival in both treatment arms.	5 years
The EFS with respect to the interval between surgery and randomization.	5 years
The bone-metastasis free-survival in both arms.	5 years
The toxicity of and compliance to zoledronic acid.	5 years
The predictive value of primary breast tumor response on the effect of postoperative treatment.	5 years
The prognostic impact of chemotherapy induced amenorrhea in premenopausal patients.	5 years

Collaborators and Investigators

• Sponsor: German Breast Group
• Collaborators: Novartis Pharmaceuticals; Austrian Breast & Colorectal Cancer Study Group
• Investigators: Study Chair: Gunter von Minckwitz, Prof. MD, GBG Forschungs GmbH, Hessen, Germany; Study Chair: Peter Dubsky, MD, Austrian Breast & Colorectal Cancer Study Group

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: December 1, 2004
• Primary Completion (Actual): November 1, 2013
• Study Completion (Actual): November 1, 2013

Study Registration Dates

• First Submitted: August 3, 2007
• First Submitted That Met QC Criteria: August 7, 2007
• First Posted (Estimate): August 8, 2007

Study Record Updates

• Last Update Posted (Estimate): March 5, 2015
• Last Update Submitted That Met QC Criteria: March 4, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Keywords: Postoperative treatment with zoledronic acid; Preoperative anthracycline/taxane containing chemotherapy
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Bone Density Conservation Agents; Zoledronic Acid
• Other Study ID Numbers: GBG 36; NATAN; ABCSG 29