Comparison between doublet agents versus single agent in metastatic breast cancer patients previously treated with an anthracycline and a taxane: a meta-analysis of four phase III trials.

AIM: To compare doublet agents with single agent as salvage treatment in metastatic breast cancer (MBC) patients pre-treated with an anthracycline and a taxane.
METHODS: We systematically searched for randomised clinical trials that compared doublet agents with single agent in MBC patients pre-treated with an anthracycline and a taxane. The primary end point was overall survival (OS). Secondary end points were progression-free survival, overall response rate and grade 3 or 4 toxicity. Data were extracted from the studies by two independent reviewers. The meta-analysis was performed by Stata version 10.0 software (Stata Corporation, College Station, TX, USA).
RESULTS: Four trials comprising 2373 patients were eligible for inclusion. Meta-analysis showed that there was significant improvement in progression-free survival (PFS) (hazard ratio (HR) 0.79, 95% confidence interval (CI) 0.72-0.86, P = 0.000) and overall response rate (risk ratio (RR) 1.47, 95%CI 1.13-1.91; p = 0.004) in doublet agents group, though the pooled HR for OS (HR 0.96, 95%CI 0.87-1.05; p = 0.356) showed no significant difference. Subgroup analysis also favoured capecitabine-based doublet agents therapy in terms of PFS (HR 0.77, 95%CI 0.70-0.86; p = 0.000) and overall response rate (ORR) (RR 1.65, 95%CI 1.06-2.56; p = 0.026), but gemcitabine-based doublet agents therapy gained no clinical benefits. There were more incidences of grade 3 or 4 anaemia (RR 1.610, 1.212-2.314, p = 0.01), neutropenia (RR 2.239, 1.231-4.071, p = 0.008), thrombocytopaenia (RR 2.401, 1.595-3.615, p = 0.000), fatigue (RR 2.333, 1.338-4.006, p = 0.000) and nausea and vomiting (RR 2.233, 1.558-3.199, p = 0.000) in the combination group. With regard to the risk of grade 3 or 4 stomatitis (RR 1.666, 0.818-3.392, p = 0.160), diarrhoea (RR 0.739, 0.542-1.008, p = 0.056) and hand-foot syndrome (RR 1.002, 0.835-1.203, p = 0.983), equivalent frequencies were found between the two groups.
CONCLUSION: Combination chemotherapy offered a significant improvement in PFS and ORR in patients with MBC pre-treated with an anthracycline and a taxane but did not benefit OS. With present available data from randomised clinical trials, we were still unable to clearly set the role of combination therapy in the treatment of MBC in this setting.