Clodronate With or Without Chemotherapy and/or Hormonal Therapy in Treating Women With Stage I or Stage II Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: clodronate; placebo
Intervention description: 1600 mg PO daily; 2 pills PO daily
Intervention MeSH terms: Clodronic Acid
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 3323.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: stage I breast cancer; stage II breast cancer

Summary:

      RATIONALE: Clodronate may be effective in preventing the spread of cancer to the bones and
      other parts of the body. It is not yet known whether clodronate is more effective alone or
      combined with chemotherapy and /or hormonal therapy in preventing metastatic breast cancer.

      PURPOSE: Randomized phase III trial to determine the effectiveness of clodronate with or
      without chemotherapy and /or hormonal therapy in preventing metastases in women who have
      stage I or stage II breast cancer.
    

Eligibility criteria:

        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.