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document
Effect of zoledronic acid on disseminated tumour cells in women with locally advanced breast cancer : an open label , randomised , phase 2 trial . BACKGROUND Treatment with bisphosphonates decreases bone loss and can increase disease-free survival in patients with breast cancer . The aim of our study was to assess the effect of zoledronic acid on clearance of disseminated tumour cells ( DTCs ) from the bone marrow in women undergoing neoadjuvant chemotherapy for breast cancer . METHODS Patients were recruited for this open-label , phase 2 randomised trial between March 17 , 2003 , and May 19 , 2006 , at a single centre . Eligible patients had clinical stage II-III ( > or = T2 and/or > or = N1 ) newly diagnosed breast cancer , Eastern Cooperative Oncology Group performance status of 0 or 1 , and normal cardiac , renal , and liver function . 120 women were randomly assigned , using allocation concealment , to receive 4 mg zoledronic acid intravenously every 3 weeks ( n=60 ) , or no zoledronic acid ( n=60 ) , for 1 year concomitant with four cycles of neoadjuvant epirubicin ( 75 mg/m ( 2 ) ) plus docetaxel ( 75 mg/m ( 2 ) ) and two cycles of adjuvant epirubicin plus docetaxel . The primary endpoint was the number of patients with detectable DTCs at 3 months . Final analysis was done 1 year after the last patient was enrolled . Analyses were done for all patients with available data at 3 months . This study is registered with ClinicalTrials.gov , number NCT00242203 . FINDINGS Of the 120 patients initially enrolled , one withdrew after signing consent and one patient 's baseline bone marrow was not available . Both of these patients were in the control group . At 3 months , 109 bone-marrow samples were available for analysis . In the zoledronic acid group , bone marrow was not collected from one patient because of disease progression , one patient was taken off study because of severe diarrhoea , and two patients had not consented at the time of surgery . In the control group , bone marrow was not collected from two patients because of disease progression , one patient withdrew consent , and three patients were not consented at the time of surgery . At baseline , DTCs were detected in 26 of 60 patients in the zoledronic acid group and 28 of 58 patients in the control group . At 3 months , 17 of 56 patients receiving zoledronic acid versus 25 of 53 patients who did not receive zoledronic acid had detectable DTCs ( p=0.054 ) . The most common grade 3-4 toxicities were infection ( five of 60 patients in the zoledronic acid group and six of 59 in the control group ) and thrombosis ( five of 60 in the zoledronic acid and two of 59 in the control group ) . There was one documented case of osteonecrosis in the zoledronic acid group . INTERPRETATION Zoledronic acid administered with chemotherapy resulted in a decreased proportion of patients with DTCs detected in the bone marrow at the time of surgery . Our study supports the hypothesis that the antimetastatic effects of zoledronic acid may be through effects on DTCs . FUNDING Novartis Pharmaceuticals and Pfizer Inc .
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Intervention_Pharmacological
zoledronic acid
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Intervention_Pharmacological
bisphosphonates
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Intervention_Pharmacological
zoledronic acid
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Intervention_Pharmacological
4 mg zoledronic acid intravenously every
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Intervention_Pharmacological
no zoledronic acid
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Intervention_Pharmacological
four cycles of neoadjuvant epirubicin
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Intervention_Pharmacological
docetaxel
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Intervention_Pharmacological
and two cycles of adjuvant epirubicin plus docetaxel
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Intervention_Pharmacological
zoledronic acid
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Intervention_Pharmacological
Zoledronic acid
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Intervention_Pharmacological
zoledronic acid
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Outcome_Physical
disseminated tumour cells ( DTCs )
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Outcome_Physical
detectable DTCs
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Outcome_Adverse-effects
osteonecrosis
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Participant_Sex
women
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Participant_Condition
locally advanced breast cancer
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Participant_Condition
breast cancer
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Participant_Sex
women
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Participant_Condition
neoadjuvant chemotherapy
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Participant_Condition
breast cancer
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Participant_Condition
clinical stage II-III ( > or = T2 and/or > or = N1 ) newly diagnosed breast cancer
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Participant_Sample-size
120
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Participant_Sex
women
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Participant_Sample-size
120
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Participant_Sample-size
one
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Participant_Sample-size
one
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Participant_Condition
baseline bone marrow
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Participant_Sample-size
109
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Participant_Condition
bone-marrow samples