Magnitude of risks and benefits of the addition of bevacizumab to chemotherapy for advanced breast cancer patients: Meta-regression analysis of randomized trials

Abstract

Background: Although the addition of bevacizumab significantly improves the efficacy of chemotherapy for advanced breast cancer, regulatory concerns still exist with regard to the magnitude of the benefits and the overall safety profile.

Methods: A literature-based meta-analysis to quantify the magnitude of benefit and safety of adding bevacizumab to chemotherapy for advanced breast cancer patients was conducted. Meta-regression and sensitivity analyses were also performed to identify additional predictors of outcome and to assess the influence of trial design.

Results: Five trials (3,841 patients) were gathered. A significant interaction according to treatment line was found for progression-free survival (PFS, p = 0.027); PFS was significantly improved for 1(st) line (Hazard Ratio, HR 0.68, p < 0.0001), with a 1-yr absolute difference (AD) of 8.4% (number needed to treat, NNT 12). A non-significant trend was found in overall survival (OS), and in PFS for 2(nd) line. Responses were improved with the addition of bevacizumab, without interaction between 1(st) line (Relative Risk, RR 1.46, p < 0.0001) and 2(nd) line (RR 1.58, p = 0.05). The most important toxicity was hypertension, accounting for a significant AD of 4.5% against bevacizumab (number needed to harm, NNH 22). Other significant, although less clinically meaningful, adverse events were proteinuria, neurotoxicity, febrile neutropenia, and bleeding. At the meta-regression analysis for 1(st)-line, more than 3 metastatic sites (p = 0.032), no adjuvant chemotherapy (p = 0.00013), negative hormonal receptor status (p = 0.009), and prior anthracyclines-exposure (p = 0.019), did significantly affect PFS.

Conclusions: Although with heterogeneity, the addition of bevacizumab to 1st-line chemotherapy significantly improves PFS, and overall activity. Hypertension should be weighted with the overall benefit on the individual basis.

Figure 1

Outline of the search - Flow diagram. RCTs: randomized clinical trials; pts: patients; PFS: progression free survival; OS: overall survival; ORR: overall response rate; HTN: hypertension; neuro: neurotixicity; FN: febrile neutropenia; GI: gastro-intestinal.

Figure 2

Combined Results - Efficacy Outcomes (PFS, OS). CI: confidence intervals; A: anthracyclines; T: taxanes; Cap: capecitabine; Beva: bevacizumab; PFS: progression free survival; OS: overall survival.