• Skeletal metastasis [ Time Frame: Time from randomization to first diagnosis of skeletal metastasis ] [ Designated as safety issue: No ]
• Overall survival [ Time Frame: Time from randomization to death from any cause ] [ Designated as safety issue: No ]
• Relapse free survival [ Time Frame: Time from randomization to any local, regional, or distant recurrence of breast cancer ] [ Designated as safety issue: No ]
• Incidence of non-skeletal metastasis [ Time Frame: Time from randomization to incidence of non-skeletal metastasis ] [ Designated as safety issue: No ]

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.

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.

• Arm I: Patients receive oral clodronate daily.
• Arm II: Patients receive oral placebo daily. 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.

• Drug: clodronate disodium
• Drug: placebo
• Drug: Adjuvant systemic chemotherapy
• Drug: Hormonal therapy

• Atula S, Powles T, Paterson A, McCloskey E, Nevalainen J, Kanis J. Extended safety profile of oral clodronate after long-term use in primary breast cancer patients. Drug Saf. 2003;26(9):661-71.
• Powles T, Paterson S, Kanis JA, McCloskey E, Ashley S, Tidy A, Rosenqvist K, Smith I, Ottestad L, Legault S, Pajunen M, Nevantaus A, Mannisto E, Suovuori A, Atula S, Nevalainen J, Pylkkanen L. Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol. 2002 Aug 1;20(15):3219-24.
• Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL. Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg. 2004 May;62(5):527-34.

DISEASE CHARACTERISTICS:

• Histologically proven invasive adenocarcinoma of the breast

  • Stage I or II (T1-3, N0-1, M0)

• Must have undergone total mastectomy OR lumpectomy with an axillary dissection or sentinel node biopsy

  • If any sentinel node is proven histologically positive by hematoxylin-eosin stain (H&E) or deemed suspicious by H&E and confirmed positive by immunohistochemistry, axillary dissection is required
• No bilateral malignancy or mammographically suspicious mass or abnormality within the contralateral breast unless histologically benign

• Lumpectomy patients eligible if the following conditions are met:

  • Tumor less than 5 cm (tumor 5 cm or greater allowed at discretion of protocol investigator)

  • Margins of resected specimen must be histologically free of invasive tumor and ductal carcinoma in situ

    • Additional surgical resections to obtain clear margins allowed even if axillary dissection has been performed
    • If residual tumor at resected margins after re-excision(s), total mastectomy is required
  • No diffuse tumors by mammography that would not be considered surgically amenable to lumpectomy
  • No other clinically dominant mass or mammographically suspicious abnormality within the ipsilateral breast remnant unless histologically benign or, if malignant, surgically removed with clear margins

• No ulceration, erythema, infiltration of the skin or underlying chest wall (complete fixation), peau d'orange, or skin edema of any magnitude

  • Tethering or dimpling of skin or nipple inversion allowed and not considered skin infiltration
• No ipsilateral lymph nodes fixed to one another or to other structures (cN2 disease) by clinical examination
• No suspicious palpable nodes in the contralateral axilla or palpable supraclavicular or infraclavicular nodes, unless biopsy evidence of no tumor involvement
• No significant nonmalignant bone disease that is likely to interfere with interpretation of bone x-rays

• Skeletal pain allowed only 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
• No prior breast cancer except lobular carcinoma in situ

• Hormone receptor status:

  • Must have an analysis of estrogen receptor (ER) and progesterone receptor (PR) status on the primary tumor before randomization

PATIENT CHARACTERISTICS:

Age:

• Not specified

Sex:

• Female

Menopausal status:

• Not specified

Performance status:

• Zubrod 0-2

Life expectancy:

• At least 10 years (excluding diagnosis of breast cancer)

Hematopoietic:

• Absolute neutrophil count at least 1,500/mm^3 (unless due to ethnic or racial variation)
• Platelet count at least 100,000/mm^3

Hepatic:

• No hepatic disease that would preclude study entry
• Bilirubin no greater than upper limit of normal (ULN)
• Alkaline phosphatase less than 2.5 times ULN
• SGOT less than 1.5 times ULN
• Albumin normal

Renal:

• No renal disease that would preclude study entry
• Creatinine normal
• Calcium normal

Cardiovascular:

• No cardiovascular disease that would preclude study entry

Other:

• No nonmalignant systemic disease that would preclude study entry
• No psychiatric or addictive disorders that would preclude informed consent
• Not pregnant or nursing
• Fertile patients must use effective contraception

• No other prior malignancy within the past 5 years except:

  • Effectively treated squamous cell or basal cell skin cancer
  • Carcinoma in situ of the cervix treated by surgery only
  • Lobular carcinoma in situ of the ipsilateral or contralateral breast treated by hormonal therapy and/or surgery
  • Patients with other malignancy who have been disease free for at least 5 years and are at low risk of recurrence

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• No prior biologic therapy for breast cancer

Chemotherapy:

• No prior chemotherapy for breast cancer
• Concurrent chemotherapy allowed at the discretion of the protocol investigator

Endocrine therapy:

• No prior hormonal therapy for breast cancer except adjuvant tamoxifen initiated within 4 weeks prior to study
• No concurrent sex hormonal therapy (e.g., birth control pills or ovarian hormone replacement therapy)
• No concurrent calcitonin

• No other concurrent hormonal agents for the management of menopausal symptoms until time of first breast cancer recurrence or development of second primary cancer except:

  • Low-dose estrogen vaginal creams or conjugated estrogen ring (Estring) for symptomatic vaginal dryness
  • Raloxifene or other selective estrogen receptor modulators for prevention of osteoporosis
  • Adjuvant luteinizing hormone-releasing hormone agonists/antagonists for medical ovarian ablation
• No concurrent tamoxifen during study chemotherapy

Radiotherapy:

• No prior radiotherapy for breast cancer
• No other concurrent radiotherapy, including regional node radiotherapy, for patients with node-negative breast cancer

Surgery:

• See Disease Characteristics
• No more than 84 days since last surgery (lumpectomy, mastectomy, sentinel node biopsy, axillary dissection, or re-excision of lumpectomy margins) for breast cancer

Other:

• No concurrent participation in any other clinical trials of systemic therapy for early stage breast cancer except for the following radiotherapy trials:

  • NCIC-MA.20 for node-positive patients
  • SWOG-S9927 for node-positive mastectomy patients
• No concurrent alendronate or other bisphosphonates (e.g., pamidronate) until time of osseous metastasis
• No concurrent calcitonin for treatment or prevention of osteoporosis

• National Cancer Institute (NCI)
• Southwest Oncology Group
• North Central Cancer Treatment Group