Efficacy and Safety of Compound Kushen Injection for Advanced Colorectal Cancer: A Systematic Review and Meta-Analysis of Randomized Clinical Trials with Trial Sequential Analysis

Colorectal cancer (CRC) is one of the common malignant tumors, with a gradually increasing incidence. Due to late detection and poor sensitivity to chemotherapy, it has become a difficult problem in tumor prevention and treatment at present. Exploring or discovering new combinations is a significant strategy for the treatment of CRC. Compound kushen injection (CKI) is a traditional Chinese medicine injection extracted from Ait. and Roxb., which is widely used in the comprehensive treatment of CRC in China. This systematic review is aimed to ascertain the clinical efficacy and safety of CKI combined with chemotherapy in the treatment of advanced CRC based on available data. On this basis, the specific application of CKI in combination with chemotherapy in clinical practice is further discussed. PubMed, Web of Science, the Cochrane Library, EMBASE, China National Knowledge Infrastructure, Chinese Scientific Journals Database, Wanfang Database, Chinese Biomedicine Database Searches, the Chinese Clinical Trial Registry, and ClinicalTrials.gov were searched systematically, from inception to April 20, 2024. We adopted the ROB2 tool to assess quality of the included trials, Stata 16 for data analysis, and evaluated the publication bias with the funnel plot and Egger's test. The quality of the evidence was justified according to GRADE. We also used trial sequential analysis (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 (CRD42022380106) and has been published. Sixteen trials that examined 1378 patients were included in this study. Meta-analysis revealed that compared with chemotherapy, objective response rate (ORR, RR = 1.30, 95% CI: 1.18-1.44), disease control rate (DCR, RR = 1.08, 95% CI: 1.03-1.13), and KPS score improvement rate were improved (RR = 1.18, 95% CI: 1.07-1.31) by the combination of CKI and chemotherapy in patients with advanced CRC. Additionally, CKI combined with chemotherapy was associated with lower adverse reactions such as leukopenia (RR = 0.74, 95% CI: 0.62-0.87), thrombocytopenia (RR = 0.68, 95% CI: 0.49-0.94), gastrointestinal reactions (RR = 0.72, 95% CI: 0.55-0.94), and liver damage (RR = 0.48, 95% CI: 0.30-0.79), higher CD4 ratio (MD = 9.70, 95% CI:8.73-10.68) and CD4 /CD8 ratio (MD = 0.25, 95% CI: 0.22-0.28), and lower CD8 T cell ratio (MD = -5.25, 95% CI: -5.94 to -4.56). Subgroup