Evidence tables

Evidence tables

Table 5 Early Breast Cancer Trialists' Collaborative Group (EBCTCG) (2015)

Study reference

EBCTCG (2015) Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials. Lancet 386: 1353–61

Unique identifier

Not applicable

Study type

Meta-analysis of individual participant data from 26 RCTs

Aim of the study

To clarify whether adjuvant bisphosphonates reduce the risk of breast cancer recurring, breast cancer mortality, and of bone and other metastases. Also, whether menopausal status affects efficacy in women with early breast cancer

Study dates

Trials were eligible if they began before 2008. Information on individual participants was sought between 2012 and 2014

Setting

The trials in the meta-analysis were undertaken worldwide, including the USA, the UK and many other European countries

Number of participants

18,766 women (25% aged below 45 years, 36% aged 45–54 years, 34% aged 55–69 years and 6% aged 70 years or over; 33% premenopausal, 4% perimenopausal and 63% postmenopausal)

Population

Women with early breast cancer (not defined)

Inclusion criteria

No additional inclusion criteria were reported

Exclusion criteria

No exclusion criteria were reported

Intervention(s)

Adjuvant bisphosphonate treatment (mainly zoledronic acid 50%, clodronate 27% and ibandronic acid 16%)

Comparator(s)

Control group with no bisphosphonate treatment (open label or placebo)

Length of follow-up

Median follow-up was 5.6 woman-years (IQR 3.7 to 8.0 years). Mean scheduled treatment duration was 3.4 years and 97% of participants were in trials of 2–5 years' treatment

Outcomes

Primary outcomes:

  • any recurrence of breast cancer (distant, locoregional or new primary in the contralateral breast)

  • distant recurrence (ignoring any previous locoregional or contralateral recurrence) and

  • breast cancer mortality

Secondary outcomes:a

  • all-cause mortality

  • death without recurrence

  • bone recurrence as the first distant recurrence (with or without concurrent other recurrence)

  • other first (extraskeletal) distant recurrence (with all analyses of distant recurrence ignoring any previous locoregional or contralateral recurrence)

  • locoregional recurrence as first event (ipsilateral breast, chest wall, or locoregional lymph nodes)

  • contralateral new primary breast cancer as first event, and

  • any bone fractures

Prespecified primary subgroup investigations included site of first distant recurrence (bone or other site), menopausal status (or, if menopausal status was unavailable, years of age [ less than 45 years, 54–54 years, 55 years or more]), and class of bisphosphonate (clodronate or aminobisphosphonate)

Safety outcomes:b

  • Non-fatal adverse events such as ischaemic heart disease, stroke and osteonecrosis of the jaw

Source of funding

Funding for individual trials was chiefly from manufacturers. Funding for this analysis was from Cancer Research UK and the UK Medical Research Council. Clinical Trial Service Unit staff policy excludes honoraria or consultancy fees for any member of the EBCTCG

Overall risk of bias/quality assessment (CASP systematic review checklist and checklist for IPD meta-analysesc)

Did the review address a clearly focused question?

Yes

Did the authors look for the right type of papers?

Yes

Do you think all the important, relevant studies were included?

Yesd

Did the review's authors do enough to assess the quality of the included studies?

Uncleare

If the results of the review have been combined, was it reasonable to do so?

Yes

What are the overall results of the review?

See table 6

How precise are the results?

See table 6

Can the results be applied to the local population?

Yes

Were all important outcomes considered?

Yesf

Are the benefits worth the harms and costs?

See key points

Study limitations

  • Information on how trials were identified, assessment of trial quality, and citations for excluded and included papers were not reported

  • Little or no information is available for some commonly used bisphosphonates, such as risedronate and alendronic acid

  • Limited information is available comparing different bisphosphonates, or different dosages of bisphosphonates

  • No information is available on managing breast cancer in men

  • Safety and quality of life outcome data are not reported

  • Combining the data for all bisphosphonates in the meta-analysis was controversial, as was including small trials not designed to measure the outcomes of interest and performing a meta-analysis of subgroups (CCO/ASCO and Jacobs C et al. 2015)

Comments

a Results for many of these outcomes are not reported in this evidence summary. See the published paper for more details

b Although data were collected, results for safety outcomes are not reported in the paper

c Checklist for IPD meta-analyses of RCTs from Tierney et al. 2015

d A systematic review appears to have been undertaken but the methods of identifying trials, seeking collaboration, data collection, collation, checking, and presentation have not been fully reported, apart from to note these were undertaken as in previous EBCTCG reports. A protocol of the methods for this particular study is not reported. Individual participant data were not obtained for 6 of the 32 completed RCTs that recorded recurrence data, but these included only 525 women and would have been unlikely to change the outcomes of the meta-analysis

e No assessment of quality or risk of bias of the individual trials is reported, including randomisation, allocation concealment, blinding and adjudication of outcomes. It is unclear whether or not the integrity of the IPD meta-analysis was checked

f Outcomes and analyses were prespecified, although detailed methods of analyses were not reported (for example, methods for checking heterogeneity, and whether 1- or 2-stage IPD meta-analyses were performed). Safety outcomes were not reported for the study population; however, the adverse effect profile of bisphosphonates is well-established

Abbreviations: EBCTCG, Early Breast Cancer Trialists' Collaborative Group; IQR, interquartile range; IPD, individual participant meta-analysis; RCT, randomised controlled trial