J Breast Cancer.  2014 Mar;17(1):61-68.

Efficacy and Safety Profile of Combining Sorafenib with Chemotherapy in Patients with HER2-Negative Advanced Breast Cancer: A Meta-analysis

• Chen J
• Tian CX
• Yu M
• Lv Q
• Cheng NS
• Wang Z
• Wu X

Abstract

PURPOSE
The aim of the study was to evaluate the efficacy and safety of combining sorafenib with chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer.
METHODS
MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, American Society for Clinical Oncology abstracts, and European Society for Medical Oncology abstracts were searched. Randomized clinical trials that compared the efficacy and safety of sorafenib plus chemotherapy in patients with HER2-negative advanced breast cancer with placebo plus chemotherapy were eligible. The endpoints were progression-free survival (PFS), overall survival (OS), time to progression (TTP), duration of response (DOR), overall response rate (ORR), clinical benefits, and adverse effects. The meta-analysis was performed using Review Manager 5.2.6 (The Nordic Cochrane Centre), and the fixed-effect model weighted by the Mantel-Haenszel method was used. When considerable heterogeneity was found (p<0.1), further analysis (subgroup analysis, sensitivity analysis, or random-effect model) was performed to identify the potential cause. The results are expressed as hazard ratios or risk ratios, with their corresponding 95% confidence intervals.
RESULTS
The final analysis included four trials comprising 844 patients. The results revealed longer PFS and TTP, and higher ORR and clinical benefit rates in patients receiving sorafenib combined with chemotherapy compared to those receiving chemotherapy and placebo. OS and DOR were similar in the two groups. Meanwhile, the incidence of some adverse effects, including hand-foot skin reaction/hand-foot syndrome, diarrhea, rash, and hypertension, were significantly higher in the sorafenib arm.
CONCLUSION
Sorafenib combined with chemotherapy may prolong PFS and TTP. This treatment was associated with manageable toxicities, but frequent dose interruptions and reductions were required.

Keyword

Breast neoplasms; Meta-analysis; Sorafenib; Treatment outcome

MeSH Terms

Arm
Breast Neoplasms*
Breast*
Diarrhea
Disease-Free Survival
Drug Therapy*
Exanthema
Humans
Hypertension
Incidence
Medical Oncology
Odds Ratio
Population Characteristics
Receptor, Epidermal Growth Factor
Skin
Treatment Outcome
Receptor, Epidermal Growth Factor

Figure

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  Figure 1 Flow chart of trial selection for the meta-analysis. HER2=human epidermal growth factor receptor 2; RCT=randomized controlled trial.

• 

  Figure 2 Progression-free survival (PFS) analysis of sorafenib for human epidermal growth factor receptor 2-negative advanced breast cancer compared with placebo. Total PFS was significantly longer in sorafenib arm (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.56-0.74; p<0.00001). No matter the hormone status is positive or negative, PFS is longer (when treatment) with sorafenib combined with chemotherapy (HR, 0.67, 95% CI, 0.56-0.81, p<0.0001; HR, 0.65, 95% CI, 0.51-0.83, p=0.0005). IV=inverse variance.

• 

  Figure 3 Overall survival (OS), time to progression (TTP), and duration of response (DOR) analysis of sorafenib for human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer compared with placebo. TTP was significantly longer in sorafenib plus chemotherapy group (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.54-0.94; p=0.01). While OS and DOR were of no significance between the groups (HR, 0.95, 95% CI, 0.78-1.16, p=0.60; HR, 0.87, 95% CI, 0.73-1.03, p=0.10). IV=inverse variance; SE=Standard Error.

• 

  Figure 4 Overall response rate (ORR) and clinical benefit analysis of sorafenib for human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer compared with placebo. ORR and clinical benefit rate were significantly higher in treatment group compared with placebo group (hazard ratio [HR], 1.19, 95% confidence interval [CI], 1.01-1.39, p=0.03; HR, 1.23, 95% CI, 1.03-1.45, p=0.02). M-H=Mantel-Haenszel.

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  Figure 5 Funnel plot of the included studies for the meta-analysis. The funnel plots did not provide evidence of publication bias. SE=standard error; RR=risk ratio.

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