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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00512993
Recruitment Status : Completed
First Posted : August 8, 2007
Last Update Posted : March 5, 2015
Austrian Breast & Colorectal Cancer Study Group
Novartis Pharmaceuticals
Information provided by (Responsible Party):
German Breast Group

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

Condition or disease Intervention/treatment Phase
Breast Cancer Drug: Zoledronic acid Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 654 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : December 2004
Actual Primary Completion Date : November 2013
Actual Study Completion Date : November 2013

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

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 Name: Zometa

No Intervention: Observation
Patients will be under observation and receive standard endocrine, radiologic and trastuzumab treatment, respectively

Primary Outcome Measures :
  1. 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. [ Time Frame: 5 years ]

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

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00512993

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Sponsors and Collaborators
German Breast Group
Austrian Breast & Colorectal Cancer Study Group
Novartis Pharmaceuticals
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Study Chair: Gunter von Minckwitz, Prof. MD GBG Forschungs GmbH, Hessen, Germany
Study Chair: Peter Dubsky, MD Austrian Breast & Colorectal Cancer Study Group
Additional Information:
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Responsible Party: German Breast Group Identifier: NCT00512993    
Other Study ID Numbers: GBG 36
First Posted: August 8, 2007    Key Record Dates
Last Update Posted: March 5, 2015
Last Verified: March 2015
Keywords provided by German Breast Group:
Postoperative treatment with zoledronic acid
Preoperative anthracycline/taxane containing chemotherapy
Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Zoledronic Acid
Bone Density Conservation Agents
Physiological Effects of Drugs