Bisphosphonates in the adjuvant setting of breast cancer therapy--effect on survival: a systematic review and meta-analysis

Irit Ben-Aharon, Liat Vidal, Shulamith Rizel, Rinat Yerushalmi, Ofer Shpilberg, Aaron Sulkes, Salomon M Stemmer, Irit Ben-Aharon, Liat Vidal, Shulamith Rizel, Rinat Yerushalmi, Ofer Shpilberg, Aaron Sulkes, Salomon M Stemmer

Abstract

Background: The role of bisphosphonates (BP) in early breast cancer (BC) has been considered controversial. We performed a meta-analysis of all randomized controlled trials (RCTs) that appraised the effects of BP on survival in early BC.

Methods: RCTs were identified by searching the Cochrane Library, MEDLINE databases and conference proceedings. Hazard ratios (HRs) of overall survival (OS), disease-free survival (DFS) and relative risks of adverse events were estimated and pooled.

Results: Thirteen trials met the inclusion criteria, evaluating a total of 15,762 patients. Meta-analysis of ten trials which reported OS revealed no statistically significant benefit in OS for BP (HR 0.89, 95% CI = 0.79 to 1.01). Meta-analysis of nine trials which reported the DFS revealed no benefit in DFS (HR 0.95 (0.81-1.12)). Meta-analysis upon menopausal status showed a statistically significant better DFS in the BP-treated patients (HR 0.81(0.69-0.95)). In meta-regression, chemotherapy was negatively associated with HR of survival.

Conclusions: Our meta-analysis indicates a positive effect for adjuvant BP on survival only in postmenopausal patients. Meta-regression demonstrated a negative association between chemotherapy use BP effect on survival. Further large scale RCTs are warranted to unravel the specific subgroups that would benefit from the addition of BP in the adjuvant setting.

Conflict of interest statement

Competing Interests: Salomon M. Stemmer is an editor of PLOS ONE. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Figures

Figure 1. Randomized controlled trials search and…
Figure 1. Randomized controlled trials search and selection.
Figure 2. Forest plot of hazard ratios…
Figure 2. Forest plot of hazard ratios (HRs) comparing (A) overall survival or (B) disease-free survial (DFS) for patients who received BP in addition to standard therapy vs. those who received standard therapy only.
Hazard ratios for each trail are represented by the squares, the size of the square represents the weight of the trial in the meta-analysis, and the horizontal line crossing the square represents the 95% confidence interval (CI). The diamonds represent the estimated overall effect based on the meta-analysis random effect of all trials.
Figure 3. Forest plot of hazard ratios…
Figure 3. Forest plot of hazard ratios comparing disease-free survival for most-menopausal patients who received BP in addition to standard therapy vs. those who received standard therapy only.
Hazard ratios for each trail are represented by the squares, the size of the square represents the weight of the trial in the meta-analysis, and the horizontal line crossing the square represents the 95% confidence interval (CI). The diamonds represent the estimated overall effect based on the meta-analysis random effect of all trials.
Figure 4. Meta regression of hazard ratios…
Figure 4. Meta regression of hazard ratios of overall survival in individual studies assessing the effect of percentage of patients receiving chemotherapy in addition to endocrine therapy.

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