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

Abstract

Backgrounds: 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 Sophora flavescens Ait. and Smilax glabra 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.

Methods: 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.

Results: 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 analysis demonstrated that ORR and DCR in patients with advanced CRC were improved when CKI combined with FOLFOX and 5Fu + L-OHP. Both 15 and 20 ml/day of CKI combined with FOLFOX provided a significant effect in ORR. Moreover, ORR was improved when the accumulated CKI dose reached 280 ml per course and 420 ml in total. 7 days/course as well as 14 days/course of CKI combined with FOLFOX were effective durations in ORR. As for DCR, 7 days/course of CKI combined with FOLFOX could improve efficacy. Furthermore, CKI + FOLFOX may be useful in ORR and DCR for at least 4 cycles of combination therapies. The TSA showed that firm results in ORR and DCR were established and additional trials were unlikely to change the results.

Conclusion: CKI combined with chemotherapy provides a statistically significant and clinically important effect in the improvement of ORR, DCR, performance status, ADR reduction, and immune function in patients with CRC. However, more rigorously designed, large-scale, and multi-center RCTs are needed in the future.

Keywords: Compound Kushen injection; TSA; chemotherapeutic drugs; colorectal cancer; traditional Chinese medicine.

Figure 1.

Flow diagram of the literature search.

Figure 2.

Risk of bias of included study. (A) risk of bias summary; (B) risk of bias graph.

Figure 3.

Forest plot of ORR in CKI combined with chemotherapy versus chemotherapy: subgroup according to chemotherapy regimens.

Figure 4.

Forest plot of CKI combined with FOLFOX versus FOLFOX in ORR: subgroup according to dosage of CKI. (A) Dosage of CKI/day; (B) dosage of CKI/course; (C) total dosage of CKI.

Figure 5.

Forest plot of CKI combined with FOLFOX versus FOLFOX in ORR: subgroup according to duration of CKI/course.

Figure 6.

Forest plot of CKI combined with FOLFOX versus FOLFOX in ORR: subgroup according to number of chemotherapy cycles.

Figure 7.

Forest plot of DCR combined with chemotherapy versus chemotherapy: subgroup according to chemotherapy regimens.

Figure 8.

Forest plot of CKI combined with FOLFOX versus FOLFOX in DCR: subgroup according to dosage of CKI. (A) Dosage of CKI/day; (B) dosage of CKI/course; (C) total dosage of CKI.

Figure 9.

Forest plot of CKI combined with FOLFOX versus FOLFOX in DCR: subgroup according to duration of CKI/course.

Figure 10.

Forest plot of CKI combined with FOLFOX versus FOLFOX in DCR: subgroup according to number of chemotherapy cycles.

Figure 11.

Forest plot of KPS improvement rate.

Figure 12.

Forest plot of ADRs.

Figure 13.

Forest plot of CD4⁺.

Figure 14.

Forest plot of CD8⁺.

Figure 15.

Forest plot of CD4⁺/CD8⁺.

Figure 16.

Publication bias analysis:(A) ORR; (B) DCR was treated by the nonparametric trim and fill method.

Figure 17.

Sensitivity analyses of primary outcomes: (A) ORR; (B) DCR.

Figure 18.

Outcomes of TSA. The blue cumulative Z-curve was constructed by using a fixed-effects model. The green horizontal dotted lines on the plot indicated the conventional boundaries for benefit, while the horizontal red lines signified the TSA boundaries for benefit. (A) TSA of ORR: A required information size of 288 patients was calculated, based on an event proportion of 47.8% observed in the control group. (B) TSA of DCR: A required information size of 729 patients was calculated, based on an event proportion of 78.2% observed in the control group.