Efficacy and safety of cinobufacin-based combination therapy for advanced hepatocellular carcinoma: a meta-analysis of randomized controlled trials

Abstract

Background: Primary liver cancer is one of the most common malignant tumors with a rising incidence in recent years. In China, it ranks as the fourth most prevalent malignancy. Although surgery is the primary treatment, many advanced-stage patients are ineligible due to late diagnosis, rapid progression, or other contraindications. Targeted therapy, chemotherapy, and transarterial chemoembolization (TACE) are common non-surgical approaches, but these often result in significant side effects such as gastrointestinal reactions, bone marrow suppression, and high recurrence rates. In this context, integrative treatment with traditional Chinese medicine (TCM) has shown promise. Cinobufacin, a TCM drug developed in China, has demonstrated superior efficacy and safety when combined with Western treatments in patients with advanced hepatocellular carcinoma (HCC).

Methods: We conducted a systematic review and meta-analysis by searching PubMed, Embase, Cochrane Library, CNKI, WanFang Data, VIP, and the Chinese Biomedical Literature Database (CBM) for randomized controlled trials (RCTs) comparing cinobufacin combined with conventional Western treatments to Western treatments alone in advanced HCC patients. The search covered all databases up to December 30, 2024. Statistical analyses were performed using Stata 15.0, and Review Manager.

Results: A total of 30 studies were included in the meta-analysis. Cinobufacin combination therapy significantly improved the disease control rate (DCR, OR = 2.49, 95% CI 2.01 to 3.07), reduced alpha-fetoprotein (AFP) levels (SMD = - 1.86, 95% CI - 2.58 to - 1.13), alanine aminotransferase (ALT) levels (SMD = - 1.66, 95% CI - 2.48 to - 0.83), and total bilirubin (TBIL) levels (SMD = - 1.82, 95% CI - 2.36 to - 1.28). It also increased white blood cell (WBC) counts (SMD = 0.58, 95% CI 0.06 to 1.11) and improved Karnofsky Performance Status (KPS) scores (SMD = 1.24, 95% CI 0.93 to 1.56). Funnel plots and sensitivity analyses confirmed the robustness of the results.

Conclusion: Cinobufacin combined with Western treatments significantly improves clinical efficacy, reduces adverse drug reactions, and enhances the quality of life for patients with advanced HCC.

Keywords: Advanced hepatocellular carcinoma; Cinobufacin; Efficacy; Meta-analysis; Safety.

Fig. 1

PRISMA flow diagram

Fig. 2

Risk of bias assessment. A Summary of risk of bias for each included study based on the Cochrane Risk of Bias tool, categorized as low, unclear, or high risk. B Risk of bias graph showing the percentage of studies with low, unclear, and high risk of bias across various domains, including random sequence generation, allocation concealment, blinding, incomplete outcome data, and selective reporting

Fig. 3

The forest plot shows the pooled OR for the DCR comparing cinobufacin-based combination therapy to control treatments in patients with advanced hepatocellular carcinoma

Fig. 4

The forest plot illustrates the SMD for AFP levels between the intervention and control groups

Fig. 5

The forest plot depicts the SMD for ALT levels between the groups

Fig. 6

The forest plot presents the pooled SMD for TBIL levels

Fig. 7

The forest plot displays the SMD for WBC counts

Fig. 8

Forest plot of Karnofsky performance status (KPS) scores

Fig. 9

The funnel plot corresponds to the following outcomes: A DCR, B AFP levels, C ALT levels, D TBIL levels, E WBC counts, and F KPS scores

Fig. 10

The sensitivity analysis corresponds to the following outcomes: A DCR, B AFP levels, C ALT levels, D TBIL levels, E WBC counts, and F KPS scores