According to recent international research statistics, the global incidence of hepatocellular carcinoma (HCC) in 2020 was reported to be 905,600, resulting in 830,100 deaths—an increase of 48,500 cases compared to 2018. Notably, China accounted for over half of the new cases and fatalities (Sung et al., 2021). Numerous patients were in middle to late stages of HCC when diagnosed because of the liver’s robust ability to compensate, the absence of early HCC symptoms, and the disease’s quick progression (Zhong et al., 2017). Microvascular invasion and macrovascular invasion (MVI) are two types of vascular invasion. The growth of microvascular invasion over time leads to MVI, which is a sign of advanced HCC, according to BCLC recommendations. Research has shown that patients with HCC had an incidence of MVI up to 62.2%. Median survival times of patients with MVI are only up to 4 months once a tumor thrombus has formed in the portal vein (Forner et al., 2018). As a result, MVI is frequently present in HCC patients and the prognosis once it occurs is very poor.

The field of HCC treatment is characterized by multi-disciplinary participation and the coexistence of multiple treatment methods. The common treatment methods include hepatectomy, liver transplantation, ablation, transarterial chemoembolization (TACE), radiotherapy, systematic anti-tumor therapy and so on. Choosing reasonable treatment methods for patients with different stages of HCC can maximize the curative effect (Omata et al., 2017). TACE, radiofrequency ablation (RFA), and surgical various surgical procedures (transplantation of the liver, resection) and other treatments are available for HCC patients without MVI. RFA and TACE are common treatment approaches that can be used for various tumor stages among them (Llovet et al., 2021a). Vascular endothelial growth factor (VEGF) is a cytokine. After treatment with RFA (Guan et al., 2015; Markezana et al., 2021) and TACE (Petrillo et al., 2018), the concentration of VEGF in HCC patients increases. The growth of tumors and vascular invasion can be accelerated by VEGF by impairing T cell function, increasing the recruitment of T regulatory cells, myelogenous suppressor cells (MDSC), and mast cells, and preventing dendritic cell development and activation (Fukumura et al., 2018; Yang et al., 2018). Interestingly, as an effective multi kinase inhibitor against the VEGF receptor, sorafenib combined with TACE is considered to have synergistic effect in the treatment of HCC. Unfortunately, throughout the past 10 years, a number of multicenter randomised controlled trials (Lencioni et al., 2016; Meyer et al., 2017; Park et al., 2019) failed to show the BCLC and TACE combination’s anticipated synergistic effects as a unique treatment for patients with advanced disease. Brivanib, a humanized monoclonal antibody against VGEF, has become a widely administered choice for anti-angiogenesis therapy (Galanopoulos et al., 2016). Unfortunately, TACE combined with brivanib and tyrosine kinase inhibitors (such as orantinib) also showed negative treatment benefits (Kudo et al., 2014; Kudo et al., 2018). Therefore, the ideal candidate for TACE combined with molecular targeted drugs for the treatment of HCC or biomarkers for predicting MVI remain to be unequivocally identified. In order to reduce the incidence of MVI and weaken the adverse reactions caused by treatment, patients are given supplementary replacement therapy (Shi et al., 2017).

In China, traditional Chinese medicine (TCM) is the predominant alternative therapy for individuals with chronic liver disease. Studies have demonstrated that TCM can prevent tumour escape, progression, and metastasis as well as liver cancer growth in the particular immunological tolerance setting of HCC (Wang et al., 2015; Jia and Wang, 2020). It has been found that TCM can block the mTOR/HIF-1α/VEGF signaling pathway which effectively inhibits the migration, invasion and angiogenesis of colon cancer cells (Peng et al., 2018). So far, TCM derived metabolites have shown great potential in slowing tumor progression by downregulating VEGF-related signal pathways (Zhang C. et al., 2018). There has been, however, only limited clinical research on MVI and anti-tumor Chinese patent medication in patients with HCC. Assessing the influence of TCM adjuvant therapy in combination with conventional chemoradiotherapy on the occurrence of MVI, the research analyzed the impact of TCM treatment on HCC from various causes. The findings of this study offer robust guidelines for the utilization of adjuvant TCM therapy for patients with HCC.

So far, TCM has shown potential in slowing down tumor progression by downregulating VEGF-related signaling pathways. A number of studies have shown that the metabolite of TCM has significant therapeutic uses to suppress tumor angiogenesis in breast cancer, colon cancer, prostate cancer, glioblastoma and so on (Jiang et al., 2010; Yu et al., 2017; Zhu et al., 2017; Wang et al., 2018). The present study demonstrated that TCM can be used as a potential chemoprophylaxis to provide a lasting and significant inhibitory effect on tumor angiogenesis. Most studies focus on metabolites derived from TCM, rather than formulations, targeting tumor angiogenesis. It is worth noting that in the theory of TCM, the formula containing a variety of botanical drug combinations is the main form and are more commonly used as a treatment for cancer. Therefore, more research on the anti-tumor neovascularization of TCM should be conducted in order to explore further potential TCM therapeutic effects. Although one study has reported that a TCM metabolite can inhibit HCC angiogenesis by blocking the migration and invasion of vascular endothelial cells derived from tumor (Wei et al., 2017), there is a paucity of information on the potential effects of proprietary Chinese medicine at different tumor stages. This study analyzed the effect of proprietary Chinese medicine on MVI in patients diagnosed with HCC according to the clinical stage. The administration of proprietary Chinese medicine was shown to be a protective factor in reducing the rate of occurrence of 1-year MVI in patients with HCC, and any treatment of clinical tumor stages with TCM is related to the lower incidence of MVI.

In the early stage of tumor development, TCM can be used as a treatment to limit tumor progression. This study found that TCM significantly reduced the risk of developing MVI for patients treated with TACE combined with RFA. A randomized controlled trial reported that TCM combined with TACE could increase OS and PFS in patients with HCC, especially those with early HCC. TCM can effectively inhibit the proliferation and migration of HCC cells (Yang et al., 2021). In addition, a randomized, double-blind clinical trial showed that TCM can reduce the risk of recurrence of HCC after TACE and alleviate the postembolization syndrome (Xu et al., 2016). The curative effect of TCM is dependent on the treatment duration. Research has found that patients with HCC who have taken TCM for >36 months had a 90% lower risk of mortality than those who have not (Liu et al., 2019), findings in good agreement with our results, indicating that taking TCM for a long time will produce a stronger protective effect.

Recent research has shown that Fufang Banmao Capsule, a popular TCM, can be used as an adjuvant therapy for patients with HCC. It contains several active metabolites, including cantharidin, ginsenosides Rg1, Rg3, Rb1, Re, astragaloside A, and isofraxidin. Cantharidin is the main substance present in a concentration of at least 0.0175 mg/g (Naz et al., 2020). Studies have demonstrated that its active metabolite, astragaloside A effectively inhibits hepatocarcinogenesis by interfering with the NRF2/HO-1 signal pathway (Fang Gong et al., 2023). Another active metabolite of Fufang Banmao Capsule called Ginsenoside Rg3 has been found to inhibit tumor progression and metastasis in an orthotopic HCC transplantation mouse model by reducing VEGF levels and downregulating VEGF-R2 (Zhou et al., 2014). The results of studies on Fufang Banmao Capsule suggest that it is a preferred choice for adjuvant cancer therapy due to minimal adverse reactions and independent prediction of OS(Liu et al., 2020). Jinlong Capsule is a Chinese patent medicine derived from animal sources, commonly used in TCM for treating HCC. The capsule contains 17 amino acids and various bioactive peptides, including histidine, serine, arginine, glycine, aspartic acid, glutamate, threonine, alanine, proline, cystine, lysine, tyrosine, methionine, valine, isoleucine, leucine, and phenylalanin (Li C. et al., 2022). A meta-analysis conducted on the Chinese population showed that combining TACE with Jinlong Capsule significantly prolonged patients’ OS times and improved liver functions compared to TACE alone. This study also found that proprietary Chinese medicine had a protective effect on patients with compromised liver functions (Jia et al., 2020). Another meta-analysis evaluated the efficacy and safety of Jinlong Capsule as an adjuvant treatment for HCC, demonstrating its effectiveness in reducing adverse reactions such as leukopenia, gastrointestinal events, hepatotoxicity, and bone marrow suppression (Xu et al., 2020). Previous studies have shown that Kanglixin Capsule contains various metabolites, including costunolide, dehydrocostus lactone, aloe-emodin, rhein, emodin, physcion, bisdemethoxycurcumin, demethox-ycurcumin, and curcumin (Li and Kong, 2017). Curcumin is particularly noteworthy as it possesses strong anti-inflammatory and antioxidant properties (Lim et al., 2010). Research has indicated that when combined with metformin, curcumin can activate the mitochondrial pathway to induce apoptosis in cancer cells. Additionally, this combination treatment enhances the metastasis and invasion capabilities of HCC cells while promoting angiogenesis in HUVEC cells (Zhang H.-H. et al., 2018). UPLC-QTOF-MS analysis Ganfule Capsule showed that it contained 13 key metabolites. These metabolites include akebia saponin D, chlorogenic acid, amygdalin, 3′-deoxysappanone A, 10-O-Methylprotosappanin B, saikosaponin C and astragaloside I (Xu et al., 2022). Studies have shown that akebia saponin D inhibits the survival, proliferation, adhesion, migration and invasion of HCC cells in a concentration-dependent manner (Lu et al., 2019). The metabolites of Huaier Granule include proteoglycan, 2-Hydroxybutanoic acid, 2-Isopropyl-3-oxosuccinate, 2′-O-Methyladenosine, 3-Ethyl-1,2-benzenediol, and others. A multicenter study involving 1,044 patients demonstrated that Huaier Granule significantly improved postoperative intrahepatic metastasis (Chen et al., 2018). Additionally, Huaier Granule has shown promise as a prognostic tool for early-stage HCC patients treated with thermal ablation by increasing the PFS rate and reducing the rate of extrahepatic metastasis without notable side effects (Wang et al., 2021).

This study’s research methodology and data sources had several drawbacks including its retrospective nature. The clinical features of TCM and non-TCM users varied to some extent. There were still some biochemical discrepancies even after the patient groups were PS score matched to remove various confounding factors. Therefore, a prospective randomised controlled clinical trial should be conducted to validate the impact of TCM on MVI in HCC patients. The study excluded those individuals who were treated with decoction and only included patients who received proprietary Chinese medication. This study did not perform a thorough investigation because the majority of patients who consumed the decoction went to the clinic and only a tiny percentage of patients consumed it for longer than 3 months. Because there is no effective drug to treat HCC, there was no positive control drug. Most patients were in BCLC stage B and sorafenib should be considered as first-line treatment for advanced HCC patients. The patients in our study were not suitable for this treatment.

In our retrospective cohort study, we found that adjuvant TCM treatment reduced the occurrence of MVI in patients with HCC. The use of TCM over an extended period showed a gradual decrease in the proportion of MVI, indicating its potential in preventing MVI in HCC patients. These findings suggest that TCM therapy is effective in preventing MVI in HCC patients. However, it is important to acknowledge the study limitations, including its retrospective design and reliance on observational data. To validate the efficacy and safety of TCM therapy in HCC treatment, future research should conduct prospective randomized controlled trials (RCTs) with robust experimental designs. Additionally, further investigations are needed to understand the mechanisms of action and identify optimal treatment protocols.