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

NCT ID: NCT00009945

Last Updated: 2017-12-13

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 3323 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2001-01-31
• Study Completion Date: 2012-12-31

Brief 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.

Detailed Description

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.

Conditions

Breast Cancer

Keywords

stage I breast cancer; stage II breast cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Arm 1: Clodronate

Patient receives 2 tablets once daily for 3 years.

Group Type: EXPERIMENTAL

clodronate

Intervention Type: DRUG

1600 mg PO daily

Arm 2: Placebo

Patient receives 2 tablets once daily for 3 years.

Group Type: PLACEBO_COMPARATOR

placebo

Intervention Type: DRUG

2 pills PO daily

Interventions

clodronate

1600 mg PO daily

Intervention Type: DRUG

placebo

2 pills PO daily

Intervention Type: DRUG

Other Intervention Names

Bonefos; clodronate disodium

Eligibility Criteria

Inclusion Criteria

• 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

SWOG Cancer Research Network

NETWORK

Sponsor Role: collaborator

North Central Cancer Treatment Group

NETWORK

Sponsor Role: collaborator

NSABP Foundation Inc

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Norman Wolmark, MD

Role: PRINCIPAL_INVESTIGATOR

NSABP Foundation Inc

Locations

CCOP - Mayo Clinic Scottsdale Oncology Program

Scottsdale, Arizona, United States

Mayo Clinic

Jacksonville, Florida, United States

MBCCOP - Hawaii

Honolulu, Hawaii, United States

CCOP - Cedar Rapids Oncology Project

Cedar Rapids, Iowa, United States

Siouxland Hematology-Oncology

Sioux City, Iowa, United States

Veterans Affairs Medical Center - Biloxi

Biloxi, Mississippi, United States

Medcenter One Health System

Bismarck, North Dakota, United States

Altru Cancer Center

Grand Forks, North Dakota, United States

CCOP - Geisinger Clinic and Medical Center

Danville, Pennsylvania, United States

Rapid City Regional Hospital

Rapid City, South Dakota, United States

University of Tennessee Cancer Institute

Memphis, Tennessee, United States

Danville Radiation Therapy Center

Memphis, Tennessee, United States

Harrington Cancer Center

Amarillo, Texas, United States

Veterans Affairs Medical Center - Amarillo

Amarillo, Texas, United States

Fletcher Allen Health Care - University Health Center Campus

Burlington, Vermont, United States

MBCCOP - Massey Cancer Center

Richmond, Virginia, United States

University of Washington School of Medicine

Seattle, Washington, United States

Countries

United States

References

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. doi: 10.1016/j.joms.2004.02.004.

Reference Type: BACKGROUND

PMID: 15122554 (View on PubMed)

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. doi: 10.2165/00002018-200326090-00005.

Reference Type: RESULT

PMID: 12814333 (View on PubMed)

Atula ST, Paterson AHG, Powles TJ, et al.: Safety profile of oral clodronate during long-term use in primary breast cancer patients. [Abstract] Proceedings of the American Society of Clinical Oncology 22: A-100, 25, 2003.

Reference Type: RESULT

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. doi: 10.1200/JCO.2002.11.080.

Reference Type: RESULT

PMID: 12149294 (View on PubMed)

Adams A, Jakob T, Huth A, Monsef I, Ernst M, Kopp M, Caro-Valenzuela J, Wockel A, Skoetz N. Bone-modifying agents for reducing bone loss in women with early and locally advanced breast cancer: a network meta-analysis. Cochrane Database Syst Rev. 2024 Jul 9;7(7):CD013451. doi: 10.1002/14651858.CD013451.pub2.

Reference Type: DERIVED

PMID: 38979716 (View on PubMed)

Paterson AH, Anderson SJ, Lembersky BC, Fehrenbacher L, Falkson CI, King KM, Weir LM, Brufsky AM, Dakhil S, Lad T, Baez-Diaz L, Gralow JR, Robidoux A, Perez EA, Zheng P, Geyer CE Jr, Swain SM, Costantino JP, Mamounas EP, Wolmark N. Oral clodronate for adjuvant treatment of operable breast cancer (National Surgical Adjuvant Breast and Bowel Project protocol B-34): a multicentre, placebo-controlled, randomised trial. Lancet Oncol. 2012 Jul;13(7):734-42. doi: 10.1016/S1470-2045(12)70226-7. Epub 2012 Jun 14.

Reference Type: DERIVED

PMID: 22704583 (View on PubMed)

Other Identifiers

SWOG-NSABP-B-34

Identifier Type: -

Identifier Source: secondary_id

NCCTG-NSABP-B-34

Identifier Type: -

Identifier Source: secondary_id

CDR0000068426

Identifier Type: -

Identifier Source: secondary_id

NSABP B-34

Identifier Type: -

Identifier Source: org_study_id