Effectiveness and Safety of a Combination of the Canonical Chinese Medicine Formula Xiaoyaosan with Chemotherapy for Treatment of Breast Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials with Trial Sequential Analysis

Xiaoyaosan (XYS), a standardized traditional Chinese medicine (TCM) formula, can sooth the liver and invigorate the spleen, and is widely used in the adjuvant treatment of breast cancer (BC) in China. This study aimed to assess the effectiveness and safety of XYS combined with chemotherapy in the treatment of BC based on the available data.MethodsA comprehensive search for randomized controlled trials (RCTs) published up to April 15, 2023 was performed in the PubMed, EMBASE, the China National Knowledge Infrastructure, the Chinese Scientific Journals Database, the Wanfang, and the Chinese Biomedicine Database. We used Stata 16 for the data analysis of the included studies, and assessed the quality of evidence according to the GRADE criteria. We also used TSA to calculate the final required sample size in this meta-analysis and to verify whether the results present a reliable conclusion. The protocol for this systematic review was registered on PROSPERO (CRD42022306554).ResultsSeventeen RCTs involving 1058 patients were included in this meta-analysis. The results showed that, compared with chemotherapy alone, XYS combined with chemotherapy significantly improved the objective response rate (ORR) (relative risk (RR) = 1.27, 95% confidence interval (CI): 1.09-1.47), disease control rate (DCR) (RR = 1.08, 95% CI: 1.01-1.15), Karnofsky performance status improvement rate (RR= 1.58, 95% CI: 1.39-1.81), decreased the Self-rating Depression Scale points (mean difference (MD)= -11.56, 95% CI: -13.86- -9.25), and reduced the incidence of gastrointestinal adverse reactions (RR = 0.68, 95% CI: 0.54-0.86), myelosuppression (RR = 0.77, 95% CI: 0.68-0.88) and cardiotoxicity (RR = 0.25, 95% CI:0.10-0.62). According to subgroup analysis of chemotherapy drugs, ORR was improved when XYS was combined with anthracyclines (RR = 1.24, 95% CI: 1.02-1.50) and non-anthracyclines (RR = 1.31, 95% CI: 1.04-1.64), but DCR was improved only when XYS was combined with non-anthracyclines (RR = 1.12, 95% CI: 1.01-1.24). The TSA showed that firm results in ORR were established, but the results of DCR were more likely to be false positives.ConclusionThe evidence provided in this study supports the conclusion that XYS combined with chemotherapy has statistical significance and clinical importance in improving ORR, DCR, depressive state, quality of life, and reducing the occurrence of adverse events in patients with BC. More rigorously designed, large-scale, and multi-center RCTs are required to further improve the quality of evidence to support this conclusion.