Clodronate With or Without Chemotherapy and/or Hormonal Therapy in Treating Women With Stage I or Stage II Breast Cancer

OBJECTIVES:

- Determine whether clodronate administered alone or in addition to adjuvant chemotherapy
and/or hormonal therapy improves disease-free survival in women with early stage breast
cancer.

- Determine whether clodronate reduces the incidence of skeletal metastases and
non-skeletal metastases in these patients.

- Determine whether clodronate improves overall and relapse-free survival in these
patients.

- Determine whether clodronate reduces the incidence of skeletal morbidity (e.g., skeletal
fractures, hypercalcemia, skeletal pain, need for radiotherapy, spinal cord compression)
in these patients.

- Investigate the relevance of serum markers of bone turnover as a prognostic factor for
the development of bone metastasis in these patients.

OUTLINE: This is a randomized, double-blind, placebo-controlled study. Patients are
stratified by age (under 50 vs 50 and over), number of positive lymph nodes (0 vs 1-3 vs 4 or
more), and hormone receptor status (estrogen receptor [ER] and progesterone receptor [PR]
negative vs ER and/or PR positive). Patients are randomized to one of two treatment arms.

Patients in both arms commence treatment within 2 weeks of randomization and continue
treatment for 3 years in the absence of bone metastasis or unacceptable toxicity. Study
medication must be continued in the case of documented visceral or soft tissue metastasis or
other event without skeletal metastasis.

Patients in both arms may also receive adjuvant chemotherapy and/or tamoxifen at the
discretion of the protocol investigator. Patients receiving hormonal therapy begin hormonal
therapy within 3-12 weeks after the last dose of chemotherapy and continue for a minimum of 5
years.

Patients who have undergone a prior lumpectomy receive adjuvant whole breast radiotherapy.
Patients who have undergone a prior mastectomy may receive radiotherapy at the investigator's
discretion.

Patients are followed every 6 months for 5 years and then annually thereafter.

PROJECTED ACCRUAL: A total of 3,323 patients will be accrued for this study within 3.5 years.

Eligibility

- Patients must have undergone either a total mastectomy or a lumpectomy with either an
axillary dissection or sentinel node biopsy. If any sentinel node is histologically
positive by H & E, or histologically suspicious on H & E and confirmed positive by
immunohistochemistry (IHC), then the patient must have a completion axillary
dissection.

- The tumor must be invasive adenocarcinoma on histologic examination with clinical
assessment T1-3, N0-1, M0.

- Patients must not be participating in any other clinical trials of systemic therapy
for early-stage breast cancer. Patients may participate in the following radiation
therapy trials:

- Node-positive patients may participate in the National Cancer Institute of Canada
Clinical Trials Group protocol MA.20, provided the requirements of the B-34
protocol continue to be met. (Node-negative B-34 patients may not participate in
MA.20.)

- Node-positive mastectomy patients may participate in Southwest Oncology Group
protocol S9927, provided the requirements of the B-34 protocol continue to be
met.

- Patients must have an analysis of both estrogen and progesterone receptors on the
primary tumor performed prior to randomization. Tumors will be defined as ER or
progesterone receptor (PgR) positive if: 1) the Dextran-coated charcoal or
sucrose-density gradient method shows them to have greater than or equal to 10 fmol/mg
cytosol protein, or 2) if using individual laboratory criteria they can be shown to be
positive by the enzyme immunoassay method (EIA) or immunocytochemical assay. "Marginal
or borderline," results (i.e., those not definitively negative) will also be
considered positive.

- At the time of randomization, the patient must have had the following within the past
3 months: history and physical exam, a bone scan, thoracic and lumbar spine x-rays,
and a chest x-ray. Within the past 12 months patients must have had a gynecologic exam
(for women who have a uterus and who will be taking tamoxifen) and a bilateral
mammogram.

- At the time of randomization:

- the postoperative absolute neutrophil count (ANC) must be greater than or equal
to 1500/mm3 (or less than 1500/mm3 if, in the opinion of the investigator, this
represents an ethnic or racial variation of normal);

- the postoperative platelet count must be greater than or equal to 100,000;

- there must be postoperative evidence of adequate hepatic function, i.e.,

- total bilirubin at or below the upper limit of normal (ULN) for the laboratory;
and

- alkaline phosphatase less than 2.5 x the ULN; and

- the serum glutamate oxaloacetate transaminase (SGOT)/ aspartate transaminase
(AST) less than 1.5 x the ULN;

- there must be postoperative evidence of adequate renal function (serum creatinine
within or less than the laboratory's normal range).

- Serum albumin and serum calcium must be within normal limits.

- A patient with skeletal pain is eligible for inclusion in the study if bone scan
and/or roentgenological examination fails to disclose metastatic disease. Suspicious
findings must be confirmed as benign by x-ray, MRI, or biopsy.

- Patients with prior nonbreast malignancies are eligible if they have been disease-
free for greater than or equal to 5 years before randomization and are deemed at low
risk for recurrence by their treating physicians. Patients with squamous or basal cell
carcinoma of the skin that has been effectively treated, carcinoma in situ of the
cervix that has been treated by surgery only, or lobular carcinoma in situ (LCIS) of
the ipsilateral or contralateral breast treated by hormone therapy and/or surgery only
are eligible, even if these were diagnosed within 5 years before randomization.

- Patients must have a Zubrod performance status of 0, 1, or 2.

- Special conditions for eligibility of lumpectomy patients: Irradiation and surgery.
Patients treated by lumpectomy and axillary node dissection (or no axillary dissection
if sentinel node biopsy is negative) to be followed by breast radiation therapy must
meet all the eligibility criteria in addition to the following:

- Generally, lumpectomy should be reserved for tumors less than 5 cm. However, at
the investigator's discretion, patients treated with lumpectomy for tumors
greater than or equal to 5 cm are eligible.

- The margins of the resected specimen must be histologically free of invasive
tumor and ductal carcinoma in situ (DCIS). For patients in whom pathologic
examination demonstrates tumor present at the line of resection, additional
operative procedures may be performed to obtain clear margins. This is
permissible even if axillary dissection has been performed. Patients in whom
tumor is still present at the resected margins after re-excision(s) must undergo
total mastectomy to be eligible.

Ineligibility.

- Significant non-malignant bone disease that is likely to interfere with the
interpretation of bone x-rays.

- Ulceration, erythema, infiltration of the skin or the underlying chest wall (complete
fixation), peau d'orange, or skin edema of any magnitude. (Tethering or dimpling of
the skin or nipple inversion should not be interpreted as skin infiltration. Patients
with these conditions are eligible.)

- Ipsilateral lymph nodes that on clinical examination are found to be fixed to one
another or to other structures (cN2 disease).

- Suspicious palpable nodes in the contralateral axilla or palpable supraclavicular or
infraclavicular nodes, unless there is biopsy evidence that these are not involved
with tumor.

- Prior therapy for breast cancer, including irradiation, chemotherapy, biotherapy,
and/or hormonal therapy, with the exception of tamoxifen. Tamoxifen may be given as
adjuvant therapy before study entry, but only if it was started within 28 days before
randomization. Patients who started tamoxifen within 28 days before randomization and
who are being considered for chemotherapy must have their tamoxifen stopped at the
start of chemotherapy.

- Prior history of breast cancer, except LCIS.

- Any sex hormonal therapy, e.g., birth control pills, ovarian hormonal replacement
therapy, etc. (These patients are eligible only if this therapy is discontinued prior
to randomization.) Exceptions: patients may use low-dose estrogen vaginal creams or
Estring® for symptomatic vaginal dryness, raloxifene (or other selective estrogen
receptor modulators [SERMs]) for the prevention of osteoporosis, and
luteinizing-hormone-releasing hormone (LHRH) agonists/antagonists for the purpose of
medical ovarian ablation as a component of adjuvant therapy for the breast cancer.

- Patients currently taking alendronate (Fosamax®) or other bisphosphonates or
calcitonin to treat or prevent osteoporosis are not eligible.

- Non-malignant systemic disease (cardiovascular, renal, hepatic, etc.) that would
preclude a patient from being subjected to any of the treatment options or would
prevent prolonged follow-up.

- Psychiatric or addictive disorders that would preclude obtaining informed consent.

- Pregnancy or lactation at the time of proposed randomization. This protocol excludes
pregnant or lactating women because the effects of clodronate on such women have not
been studied fully.

- Bilateral malignancy or a mass or mammographic abnormality in the opposite breast
suspicious for malignancy unless there is biopsy proof that the mass is not malignant.

- Special conditions for ineligibility of lumpectomy patients: Irradiation and surgery.
The following patients will also be ineligible:

- Patients with diffuse tumors (as demonstrated on mammography) that would not be
considered surgically amenable to lumpectomy.

- Patients treated with lumpectomy in whom there is another clinically dominant
mass or mammographically suspicious abnormality within the ipsilateral breast
remnant. Such a mass must be biopsied and demonstrated to be histologically
benign prior to randomization or, if malignant, must be surgically removed with
clear margins.

- Patients in whom the margins of the resected specimen are involved with invasive
tumor or ductal carcinoma in situ (DCIS). Additional surgical resections to
obtain free margins are allowed. Patients in whom tumor is still present after
the additional resection(s) must undergo mastectomy to be eligible.