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

Alexander H G Paterson, Stewart J. Anderson, Barry C. Lembersky, Louis Fehrenbacher, Carla I. Falkson, Karen M. King, Lorna M. Weir, Adam M. Brufsky, Shaker Dakhil, Thomas Lad, Luis Baez-Diaz, Julie R. Gralow, André Robidoux, Edith A. Perez, Ping Zheng, Charles E. Geyer, Sandra M. Swain, Joseph P. Costantino, Eleftherios P. Mamounas, Norman Wolmark

Research output: Contribution to journalArticle

117 Citations (Scopus)

Abstract

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. 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. 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. 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. Funding: National Cancer Institute, Bayer Oy (formerly Schering Oy).

Original languageEnglish (US)
Pages (from-to)734-742
Number of pages9
JournalThe Lancet Oncology
Volume13
Issue number7
DOIs
StatePublished - Jul 2012

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Clodronic Acid
Breast
Randomized Controlled Trials
Placebos
Breast Neoplasms
Diphosphonates
Neoplasm Metastasis
Therapeutics
Bone and Bones
Disease-Free Survival
Recurrence
Osteonecrosis
Survival
National Cancer Institute (U.S.)
Osteoclasts
Progesterone Receptors
Jaw
Estrogen Receptors
Meta-Analysis
Liver Diseases

ASJC Scopus subject areas

  • Oncology

Cite this

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. / Paterson, Alexander H G; Anderson, Stewart J.; Lembersky, Barry C.; Fehrenbacher, Louis; Falkson, Carla I.; King, Karen M.; Weir, Lorna M.; Brufsky, Adam M.; Dakhil, Shaker; Lad, Thomas; Baez-Diaz, Luis; Gralow, Julie R.; Robidoux, André; Perez, Edith A.; Zheng, Ping; Geyer, Charles E.; Swain, Sandra M.; Costantino, Joseph P.; Mamounas, Eleftherios P.; Wolmark, Norman.

In: The Lancet Oncology, Vol. 13, No. 7, 07.2012, p. 734-742.

Research output: Contribution to journalArticle

Paterson, AHG, 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, Swain, SM, Costantino, JP, Mamounas, EP & Wolmark, N 2012, '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', The Lancet Oncology, vol. 13, no. 7, pp. 734-742. https://doi.org/10.1016/S1470-2045(12)70226-7
Paterson, Alexander H G ; Anderson, Stewart J. ; Lembersky, Barry C. ; Fehrenbacher, Louis ; Falkson, Carla I. ; King, Karen M. ; Weir, Lorna M. ; Brufsky, Adam M. ; Dakhil, Shaker ; Lad, Thomas ; Baez-Diaz, Luis ; Gralow, Julie R. ; Robidoux, André ; Perez, Edith A. ; Zheng, Ping ; Geyer, Charles E. ; Swain, Sandra M. ; Costantino, Joseph P. ; Mamounas, Eleftherios P. ; Wolmark, Norman. / 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. In: The Lancet Oncology. 2012 ; Vol. 13, No. 7. pp. 734-742.
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abstract = "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. 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. 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. 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. Funding: National Cancer Institute, Bayer Oy (formerly Schering Oy).",
author = "Paterson, {Alexander H G} and Anderson, {Stewart J.} and Lembersky, {Barry C.} and Louis Fehrenbacher and Falkson, {Carla I.} and King, {Karen M.} and Weir, {Lorna M.} and Brufsky, {Adam M.} and Shaker Dakhil and Thomas Lad and Luis Baez-Diaz and Gralow, {Julie R.} and Andr{\'e} Robidoux and Perez, {Edith A.} and Ping Zheng and Geyer, {Charles E.} and Swain, {Sandra M.} and Costantino, {Joseph P.} and Mamounas, {Eleftherios P.} and Norman Wolmark",
year = "2012",
month = "7",
doi = "10.1016/S1470-2045(12)70226-7",
language = "English (US)",
volume = "13",
pages = "734--742",
journal = "The Lancet Oncology",
issn = "1470-2045",
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}

TY - JOUR

T1 - Oral clodronate for adjuvant treatment of operable breast cancer (National Surgical Adjuvant Breast and Bowel Project protocol B-34)

T2 - A multicentre, placebo-controlled, randomised trial

AU - Paterson, Alexander H G

AU - Anderson, Stewart J.

AU - Lembersky, Barry C.

AU - Fehrenbacher, Louis

AU - Falkson, Carla I.

AU - King, Karen M.

AU - Weir, Lorna M.

AU - Brufsky, Adam M.

AU - Dakhil, Shaker

AU - Lad, Thomas

AU - Baez-Diaz, Luis

AU - Gralow, Julie R.

AU - Robidoux, André

AU - Perez, Edith A.

AU - Zheng, Ping

AU - Geyer, Charles E.

AU - Swain, Sandra M.

AU - Costantino, Joseph P.

AU - Mamounas, Eleftherios P.

AU - Wolmark, Norman

PY - 2012/7

Y1 - 2012/7

N2 - 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. 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. 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. 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. Funding: National Cancer Institute, Bayer Oy (formerly Schering Oy).

AB - 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. 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. 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. 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. Funding: National Cancer Institute, Bayer Oy (formerly Schering Oy).

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