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.

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Citation: Lancet Oncology. 13(7):734-42, 2012 Jul.PMID: 22704583Institution: Washington Cancer InstituteForm of publication: Journal ArticleMedline article type(s): Journal Article | Multicenter Study | Randomized Controlled Trial | Research Support, N.I.H., Extramural | Research Support, Non-U.S. Gov'tSubject headings: *Bone Density Conservation Agents/tu [Therapeutic Use] | *Breast Neoplasms/dt [Drug Therapy] | *Clodronic Acid/tu [Therapeutic Use] | Administration, Oral | Adult | Age Factors | Aged | Breast Neoplasms/mo [Mortality] | Clodronic Acid/ae [Adverse Effects] | Disease-Free Survival | Double-Blind Method | Female | Humans | Middle AgedYear: 2012Local holdings: Available online from MWHC library: 2001 - presentISSN:
  • 1470-2045
Name of journal: Lancet | The lancet oncologyAbstract: BACKGROUND: Bisphosphonates are thought to act through the osteoclast by changing bone microenvironment. Previous findings of adjuvant clodronate trials in different populations with operable breast cancer have been mixed. The National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-34 aims to ascertain whether oral clodronate can improve outcomes in women with primary breast cancer.FINDINGS: Median follow-up was 90.7 months (IQR 82.7-100.0) and 3311 patients had data for this period. Disease-free survival did not differ between groups (286 events in the clodronate group vs 312 in the placebo group; hazard ratio 0.91, 95% CI 0.78-1.07; p=0.27). Moreover, no differences were recorded for overall survival (0.84, 0.67-1.05; p=0.13), recurrence-free interval (0.83, 0.67-1.04; p=0.10), or bone metastasis-free interval (0.77, 0.55-1.07; p=0.12). Non-bone metastasis-free interval was slightly increased with clodronate (0.74, 0.55-1.00; p=0.047). Analyses in women age 50 years or older on study entry showed benefits of clodronate for recurrence-free interval (0.75, 0.57-0.99; p=0.045), bone metastasis-free interval (0.62, 0.40-0.95; p=0.027), and non-bone metastasis-free interval (0.63, 0.43-0.91; p=0.014), but not for overall survival (0.80, 0.61-1.04, p=0.094). Adherence to treatment at 3 years was 56% for the clodronate group and 60% for the placebo group. Grade 3 or higher liver dysfunction was noted in 23 of 1612 patients in the clodronate group and 12 of 1623 patients in the placebo group; grade 3-4 diarrhoea was noted in 28 patients in the clodronate group and in ten in the placebo group. There was one possible case of osteonecrosis of the jaw in the clodronate group.FUNDING: National Cancer Institute, Bayer Oy (formerly Schering Oy). Copyright 2012 Elsevier Ltd. All rights reserved.INTERPRETATION: Findings of NSABP B-34 suggest that bisphosphonates might have anticancer benefits for older postmenopausal women. A meta-analysis of adjuvant bisphosphonate trials is suggested before recommendations for use in non-osteoporotic postmenopausal women with primary breast cancer are made.METHODS: NSABP B-34 is a multicentre, randomised, double-blind, placebo-controlled study in 3323 women with stage 1-3 breast cancer. After surgery to remove the tumour, patients were stratified by age, axillary nodes, and oestrogen and progesterone receptor status and randomly assigned in a 1:1 ratio to either oral clodronate 1600 mg daily for 3 years (n=1662) or placebo (1661). The primary endpoint was disease-free survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00009945.All authors: Anderson SJ, Baez-Diaz L, Brufsky AM, Costantino JP, Dakhil S, Falkson CI, Fehrenbacher L, Geyer CE Jr, Gralow JR, King KM, Lad T, Lembersky BC, Mamounas EP, Paterson AH, Perez EA, Robidoux A, Swain SM, Weir LM, Wolmark N, Zheng PFiscal year: FY2013Digital Object Identifier: Date added to catalog: 2013-09-17
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Item type Current library Collection Call number Status Date due Barcode
Journal Article MedStar Authors Catalog Article 22704583 Available 22704583

Available online from MWHC library: 2001 - present

BACKGROUND: Bisphosphonates are thought to act through the osteoclast by changing bone microenvironment. Previous findings of adjuvant clodronate trials in different populations with operable breast cancer have been mixed. The National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-34 aims to ascertain whether oral clodronate can improve outcomes in women with primary breast cancer.

FINDINGS: Median follow-up was 90.7 months (IQR 82.7-100.0) and 3311 patients had data for this period. Disease-free survival did not differ between groups (286 events in the clodronate group vs 312 in the placebo group; hazard ratio 0.91, 95% CI 0.78-1.07; p=0.27). Moreover, no differences were recorded for overall survival (0.84, 0.67-1.05; p=0.13), recurrence-free interval (0.83, 0.67-1.04; p=0.10), or bone metastasis-free interval (0.77, 0.55-1.07; p=0.12). Non-bone metastasis-free interval was slightly increased with clodronate (0.74, 0.55-1.00; p=0.047). Analyses in women age 50 years or older on study entry showed benefits of clodronate for recurrence-free interval (0.75, 0.57-0.99; p=0.045), bone metastasis-free interval (0.62, 0.40-0.95; p=0.027), and non-bone metastasis-free interval (0.63, 0.43-0.91; p=0.014), but not for overall survival (0.80, 0.61-1.04, p=0.094). Adherence to treatment at 3 years was 56% for the clodronate group and 60% for the placebo group. Grade 3 or higher liver dysfunction was noted in 23 of 1612 patients in the clodronate group and 12 of 1623 patients in the placebo group; grade 3-4 diarrhoea was noted in 28 patients in the clodronate group and in ten in the placebo group. There was one possible case of osteonecrosis of the jaw in the clodronate group.

FUNDING: National Cancer Institute, Bayer Oy (formerly Schering Oy). Copyright 2012 Elsevier Ltd. All rights reserved.

INTERPRETATION: Findings of NSABP B-34 suggest that bisphosphonates might have anticancer benefits for older postmenopausal women. A meta-analysis of adjuvant bisphosphonate trials is suggested before recommendations for use in non-osteoporotic postmenopausal women with primary breast cancer are made.

METHODS: NSABP B-34 is a multicentre, randomised, double-blind, placebo-controlled study in 3323 women with stage 1-3 breast cancer. After surgery to remove the tumour, patients were stratified by age, axillary nodes, and oestrogen and progesterone receptor status and randomly assigned in a 1:1 ratio to either oral clodronate 1600 mg daily for 3 years (n=1662) or placebo (1661). The primary endpoint was disease-free survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00009945.

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