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Does Adjuvant Zoledronic Acid Reduce Recurrence in Patients With High Risk Localized Breast Cancer?

Phase 3
18 Years
Open (Enrolling)
Breast Cancer, Metastatic Cancer

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Trial Information

Does Adjuvant Zoledronic Acid Reduce Recurrence in Patients With High Risk Localized Breast Cancer?



- Compare disease-free survival of women with stage II or III breast cancer at high risk
of relapse treated with neoadjuvant or adjuvant chemotherapy and/or hormonal therapy
with vs without zoledronate.


- Compare time to bone metastases, as first recurrence, in patients treated with these

- Compare time to bone metastases, per se, in patients treated with these regimens.

- Compare time to distant metastases in patients treated with these regimens.

- Compare overall survival in patients treated with these regimens.

- Compare the reduction in skeletal-related events (fractures, spinal cord compression,
radiotherapy to the bone, surgery to the bone, and hypercalcemia) before and after the
development of bone metastases in patients treated with these regimens.

- Determine the safety and toxicity of zoledronate in patients treated with these

- Correlate prognostic factors, such as estrogen-receptor and progesterone-receptor
status, TNM stage, tumor grade, HER2/neu status, and menopausal status with treatment
outcome in patients treated with these regimens.

- Determine more specific prognostic indicators for the development of bone metastases
and factors that are able to predict specific benefit from bisphosphonate treatment
using proteomics, tissue micro-array, and other modern techniques in these patients.

OUTLINE: This is a randomized, open-label, parallel-group, multicenter study. Patients are
stratified according to participating center. Patients are randomized to 1 of 2 treatment

- Arm I: Patients receive neoadjuvant or adjuvant chemotherapy and/or hormonal therapy.
Patients also receive concurrent zoledronate IV over 15 minutes every 3-4 weeks for 6
doses, every 3 months for 8 doses, and then every 6 months for 5 doses in the absence
of disease progression or unacceptable toxicity.

- Arm II: Patients receive neoadjuvant or adjuvant chemotherapy and/or hormonal therapy

After completion of study treatment, patients are followed annually for 5 years.

PROJECTED ACCRUAL: A total of 3,300 patients (1,650 per treatment arm) will be accrued for
this study within 3 years.

Inclusion Criteria


- Diagnosis of primary breast cancer, meeting 1 of the following staging criteria:

- Stage II

- Stage III

- T stage ≥ T1

- Receiving OR scheduled to receive chemotherapy and/or endocrine therapy

- For patients receiving neoadjuvant therapy

- Tumor > 5 cm (T3), features of locally advanced disease (T4), OR
biopsy-proven lymph node involvement (N1)

- Scheduled to proceed to definitive surgery and/or radical radiotherapy with
curative intent within 6 months of starting neoadjuvant therapy

- No more than 30 days between initiation of neoadjuvant therapy and start of
study drug

- For patients receiving adjuvant therapy

- Must have undergone complete primary tumor resection and treatment of
axillary lymph nodes*

- Must have lymph node involvement

- No prior neoadjuvant therapy**

- No more than 60 days since prior definitive surgery NOTE: *Patients whose
treatment plan includes further primary tumor resection and/or treatment of
the axillary lymph nodes (e.g., clearance or radiotherapy) with curative
intent after completion of chemotherapy are eligible provided the treatment
is completed within 9 months of study entry

NOTE: **Preoperative endocrine therapy with a duration of < 30 days is not considered
prior neoadjuvant therapy

- No evidence of recurrent or metastatic disease

- No history of breast cancer, except ductal carcinoma in situ or lobular carcinoma in

- Hormone receptor status:

- Not specified



- 18 and over


- Female

Menopausal status

- Premenopausal or postmenopausal

Performance status

- Karnofsky 80-100% OR

- ECOG 0-1

Life expectancy

- Not specified


- Not specified


- Not specified


- Creatinine ≤ 1.5 times upper limit of normal


- Not pregnant or nursing

- Fertile patients must use effective contraception

- No active dental problems, including dental abscess or infection of the jaw bone
(e.g., maxilla or mandible)

- No prior or current diagnosis of osteonecrosis of the jaw

- No other malignancy within the past 5 years (including prior contralateral breast
cancer) except nonmelanoma skin cancer or curatively treated carcinoma in situ of the

- No history of disease with influence on bone metabolism, including any of the

- Paget's disease of the bone

- Primary hyperparathyroidism

- Osteoporosis requiring treatment or likely to require treatment within the next
6 months

- No other severe physical or psychological disease that would preclude study

- No known hypersensitivity to bisphosphonates



- See Disease Characteristics

Endocrine therapy

- See Disease Characteristics


- See Disease Characteristics


- See Disease Characteristics

- More than 4 weeks since prior and no concurrent dental or jaw surgery (e.g.,
extractions or implants)

- Dental fillings, teeth scaling and polishing, or minor gingival surgery within
the past 4 weeks are allowed


- More than 1 year since prior bisphosphonates

- More than 30 days since prior investigational drugs

- No concurrent investigational drugs (i.e., not locally approved for any indication)

Type of Study:


Study Design:

Allocation: Randomized, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Disease-free survival as assessed annually for 10 years

Safety Issue:


Principal Investigator

Robert E. Coleman, MD, FRCP

Investigator Affiliation:

Cancer Research Centre at Weston Park Hospital


United States: Federal Government

Study ID:




Start Date:

August 2003

Completion Date:

Related Keywords:

  • Breast Cancer
  • Metastatic Cancer
  • bone metastases
  • stage II breast cancer
  • stage IIIA breast cancer
  • stage IIIB breast cancer
  • stage IIIC breast cancer
  • Breast Neoplasms
  • Neoplasm Metastasis
  • Neoplasms
  • Neoplasms, Second Primary