Meta-analysisBreast cancer

Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials

The Lancet · 201518,766 women

The Lancet. 2015. 386:1353-1361

Study type: Meta-analysis
Study name: EBCTCG Bisphosphonate 2015
Design: Individual-patient-data meta-analysis of randomised trials (bisphosphonate versus control) in early breast cancer
Sample size: 18,766 women
Source: The Lancet · 2015

In plain words

This research brought together information on more than 18 thousand women with early breast cancer from several studies to look at the effect of bisphosphonate drugs (bone-strengthening drugs). In women who were past the menopause when treatment started, these drugs reduced the cancer coming back, especially in the bone, and deaths from breast cancer, and also reduced bone fractures. In women who had not yet reached the menopause, no clear benefit was seen.

Key results

RR 0.94 (95% CI 0.87–1.01)

Recurrence (all patients)

2p=0.08; borderline significance

RR 0.92 (0.85–0.99)

Distant recurrence (all patients)

2p=0.03

RR 0.91 (0.83–0.99)

Breast cancer mortality (all patients)

2p=0.04

RR 0.83 (0.73–0.94)

Bone recurrence (all patients)

2p=0.004

RR 0.86 (0.78–0.94)

Recurrence (postmenopausal women, 11,767)

2p=0.002

RR 0.82 (0.74–0.92)

Distant recurrence (postmenopausal women)

2p=0.0003

RR 0.72 (0.60–0.86)

Bone recurrence (postmenopausal women)

2p=0.0002

RR 0.82 (0.73–0.93)

Breast cancer mortality (postmenopausal women)

2p=0.002

No apparent effect on any outcome

Premenopausal women

RR 0.85 (0.75–0.97)

Bone fractures (all patients)

2p=0.02

No difference observed

Non-breast-cancer mortality

Dose and schedule cards

Adjuvant zoledronic acid (early breast cancer)

Postmenopausal women (natural, or with ovarian suppression or removal) who are candidates for adjuvant systemic therapyCycle length: Every 6 monthsOn the page “10 cheap steps that save patients' lives” · Regimens and doses

Postmenopausal women (natural, or with ovarian suppression or removal) who are candidates for adjuvant systemic therapy

Drug	Dose	Route	Schedule
Zoledronic acid	4 mg	Intravenous	Every 6 months

Cycle length: Every 6 months
Duration: Duration in the full CCO/ASCO guideline

Alternative: clodronate 1,600 mg a day orally. Before starting, assess risk factors for osteonecrosis of the jaw and renal impairment, and treat dental and oral problems. A definite benefit is seen only in the postmenopausal setting; denosumab was not recommended for this use.

On the page “10 cheap steps that save patients' lives” · Regimens and doses

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Bisphosphonate group

Adjuvant bisphosphonate treatment: aminobisphosphonates (such as zoledronic acid, ibandronate, pamidronate) or other bisphosphonates (i.e. clodronate).

Meta-analysis of multiple trials; dose and schedule varied between trials and no single dose is reported.

2Control group

No bisphosphonate (control group).

Source of the regimen details: Abstract of the paper (meta-analysis; no single dose)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Women with early breast cancer in all unconfounded trials that randomised patients between bisphosphonate and control. Of the 18,766 women, 18,206 (97%) were in trials of 2 to 5 years of bisphosphonate treatment. Of these, 11,767 women were postmenopausal (natural or artificial menopause).

Endpoints

Primary endpoints: recurrence, distant recurrence and breast cancer mortality. Main subgroups: site of first distant recurrence (bone or other), menopausal status (postmenopausal [natural or artificial] or not) and bisphosphonate class (aminobisphosphonate or other, i.e. clodronate). First-event rate ratios (RR) for bisphosphonate versus control were obtained by log-rank analysis by intention to treat.

Safety and side effects

The abstract reports no data on grade ≥3 adverse events. No difference was seen in non-breast-cancer mortality, and bone fractures were reduced (RR 0.85; 95% CI 0.75–0.97; 2p=0.02). Safety details in the full text.

Clinical significance and place in guidelines

This meta-analysis shows that the definite benefit of adjuvant bisphosphonates in early breast cancer is limited to women who were postmenopausal when treatment started. According to the abstract, in this group recurrence, distant recurrence, bone recurrence and breast cancer mortality were reduced. The status of the recommendation in current clinical guidelines and drug approvals should be checked separately, as the abstract does not mention them.

Limitations

In all patients, the reduction in recurrence was only borderline significant. Evidence of heterogeneity of effect by menopausal status or age was weak (for bone recurrence 2p=0.06 and 0.03). 97% of patients were in trials of 2 to 5 years of treatment. Dose and schedule details of each trial are not given in the abstract. This record has a published erratum.

Original article (DOI)PubMed

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.