Although bevacizumab’s BC indication was withdrawn by the FDA in 2011, the National Comprehensive Cancer Network guidelines on BC indicated that the addition of bevacizumab to first- or second-line chemotherapy agents modestly improves time to progression and response rates but not overall survival or quality of life of patients with metastatic BC. Recent data have demonstrated efficacy of bevacizumab when it is used as first-line therapy along with paclitaxel in metastatic triple-negative BC (TNBC) and in human epidermal growth factor receptor 2 (HER2)-negative metastatic BC. Therefore, it is important to determine the safety profile of bevacizumab since it is still widely used off-label.

Using publications from Medline, Embase, Web of Science, and Cochrane Database, investigators performed a meta-analysis to assess the safety of bevacizumab for TNBC and HER2-negative metastatic BC. Inclusion criteria were phase II randomized, controlled trials (RCTs), studies with an intervention bevacizumab-treatment group and control nonbevacizumab-treatment group, and studies that included data on adverse events (AEs). A total of 18 RCTs, which involved 12,664 female patients, met the study criteria and were included in the meta-analysis.

The primary outcome was the sum of any grade AEs and grade >3 AEs in the intervention and control groups. Secondary outcomes included the specific incidence of various AEs in both treatment groups.

Of the 18 RCTs, five studies involved patients with TNBC, and the rest included patients with HER2-negative BC. As for the primary outcome, 11 RCTs included information on any grade AEs, whereas nine RCTs included data on AEs grade 3 or higher. Bevacizumab was associated with a 6% increased risk of any grade AE (relative risk [RR] 1.06; 95% CI, 1.04-1.08) and was correlated with the occurrence of AEs grade >3 (RR 1.37; 95% CI, 1.30-1.45). Among AEs grade 3 or higher, the highest RRs were associated with the development of proteinuria (RR 9.22; 95% CI, 4.49-18.93), mucosal inflammation (RR 8.12; 95% CI, 2.46-26.77), palmar-plantar erythrodyesthesia (RR 6.95; 95% CI, 2.47-19.57), increased alanine transferase (ALT) (RR 6.95; 95% CI, 1.59-30.38), and hypertension (RR 4.94; 95% CI, 3.84-6.35), but these were often associated with wide confidence intervals.

The risk of AEs to bevacizumab were higher for patients with HER2-negative BC than for those with TNBC (RR 1.57; 95% CI, 1.41-1.75 and RR 1.27; 95% CI, 1.20-1.34, respectively). In subgroup analysis, the incidence of grade >3 AEs was higher in those treated with endocrine therapy than with chemotherapy.

Taking a closer look of AEs by BC type, the most common AEs grade >3 associated with bevacizumab occurred in those with TNBC and included hypertension, febrile neutropenia, and neutropenia. The most common AEs grade >3 in HER2-negative BC patients were hypertension, proteinuria, mucosal inflammation, palmar-plantar erythrodyesthesia syndrome, and fatigue.

For any grade AEs, common AEs associated with bevacizumab in TNBC included epistaxis, headache, and diarrhea. Conversely, any grade AEs observed frequently in the HER2-negative BC group were proteinuria, thrombocytopenia, peripheral neuropathy, epistaxis, and hypertension.

Doses of bevacizumab greater than 15 mg every 3 weeks were associated with higher incidences of grade >3 nausea, diarrhea, and hypertension compared with controls, whereas doses of bevacizumab 15 mg every 3 weeks were found to be associated with higher incidences of grade >3 proteinuria, mucosal inflammation, palmar-plantar erythrodyesthesia syndrome, and increased ALT.

In the subgroup of patients on endocrine therapy, an increased incidence of grade >3 proteinuria, hypertension, and elevated aspartate transaminase was observed, whereas in the subgroup receiving chemotherapy, the most prominent AEs grade >3 included mucosal inflammation, palmar-plantar erythrodyesthesia syndrome, proteinuria, and hypertension.

As the use of bevacizumab is off-label in BC, this paper provides pharmacists with valuable information on the frequency and severity of AEs when the monoclonal antibody is used in HER2-negative BC and TNBC.

The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.

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