Hepatocellular carcinoma (HCC) is the leading cause of cancer-related deaths, with an incidence of 9.3 and a mortality rate of 8.5 per 100,000 in 2018 worldwide (1). Since most HCCs are asymptomatic until they reach an advanced or late stage, HCC is difficult to diagnose and has a very poor prognosis (2). The mortality of patients with HCC has remained unchanged over the past decade (3, 4).

Adequate treatments for HCC, including surgical resection, chemotherapy, radiation therapy, radiofrequency ablation, and transarterial chemoembolization (TACE), have improved the 5-year survival rate of HCC from 9% to 18% between 2001 and 2019 (4–7). Among those therapeutics, TACE is the first-line treatment for patients with early-stage and localized HCC and causes tumor necrosis by injection of chemotherapeutic agents into the hepatic artery (8). TACE is not only applied in the early stage but is also frequently used in the unresectable and late stages for palliative care in HCC patients (9).

Approximately 80% of patients with HCC have liver fibrosis, resulting in liver cirrhosis due to chronic inflammation in the liver (10). Although TACE is a topical treatment that can minimize systemic inflammation, TACE accelerates the hepato-fibrotic changes because of its inevitable cytotoxic effects (11). Patients who receive TACE therapy sometimes suffer from complications such as acute cholecystitis, leukopenia, pulmonary embolism, hepatic abscess, bile duct injury, and gastric mucosa injury (12–14). The limitations of TACE in the clinic include not only an insufficient response but also the adverse effects listed above (15).

On the other hand, herbal medicine has been prescribed as an option for patients with hepatic inflammation and liver fibrosis in Asian countries (16, 17). In 1996, the effect of combination therapy of TACE and herbal drugs was first reported (18), and a systematic review of the beneficial outcomes of herbal medicine on TACE was published in 2013 (19). To date, the adjuvant therapy of herbal drugs on TACE for patients with HCC has been further practiced and has been continued; however, no comprehensive evaluation of the combination therapy has been conducted in the last 10 years.

Herein, we conducted a systematic review and meta-analysis to evaluate the adjuvant effect of herbal medicine on TACE in patients with HCC.

The well-known risk factors for HCC are infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), excessive alcohol consumption, and nonalcoholic fatty liver disease (NAFLD) (47–49). In Asian countries, including China, 70~80% of HCC cases are known to be caused by HBV infections (50), while most of our data for meta-analysis did not describe the causes of HCC. As it is known, there is a male-predominance of HCC patients, and our data showed a 3.0-fold higher number of male patients than female patients (Table 1).

From 25 studies containing 2,623 participants (1,322 herbal interventions), we found a 1.29-fold survival benefit compared to the TACE-only group (primary endpoint) (Figure 2). The present results may indicate that the add-on therapy on TACE obtained a positive clinical outcome on survival gain. In fact, TACE therapy is usually coadapted with chemotherapies (51). A study reported a 1.6-fold improvement in the survival rate in patients with HCC with Child−Pugh score A using an adjuvant therapy of sorafenib with TACE (52), and that study’s data was slightly superior to our data. In our study, the majority of the participants for whom the stage information was provided (only 25% of the total participants) were stages II and III, and the majority of the patients (from 50% of participants) were Child−Pugh score A. TACE had significant survival advantages compared to supportive care (21.2 vs. 14.5 months for 4 years of observation time) for patients with late-stage HCC (53); thus, the evaluation of the adjuvant effects of herbal medicine are necessary. As for the types of TACE, novel treatment of chemoembolization with drug-eluting beads (DEB-TACE) has been introduced to reduce drawbacks of conventional TACE (c-TACE) and to improve the overall results (54). However, 21 studies except 4 RCTs not described the types of TACE used cTACE in this systematic review (Table 2).

Patients with HCC suffer from various symptoms, such as abdominal pain, diarrhea, nausea, vomiting, jaundice, cholangitis, and fever (55). Surgical resection or TACE can cause pain or discomfort and deteriorate the quality of life (56). In our results, the adjuvant treatment of herbal drugs improved the quality of life after treatment by 10.6 out of 100 points compared to the TACE-alone group. This finding is similar to the result of one article that reported quality of life improvements of 10.0 out of 100 points in three-dimensional conformal radiotherapy, which is typically used for adjuvant therapy with TACE (57). Our study supported that herbal medicine could improve the quality of life by relieving symptoms when combined with TACE. On the other hand, hepatic fibrosis is a crucial factor in determining the prognosis of HCC patients, and hepatic fibrosis progresses gradually and leads to fatal outcomes (58). However, there is no optimal therapeutic for liver fibrosis to date (59). Herbal medicines have been investigated as potential treatments for liver fibrosis due to their anti-inflammatory and antiviral properties (60). For example, Chunggan syrup (CGX), a standardized herbal formula in Korea, improved liver fibrosis, as assessed by the decreases in liver stiffness measurement score, in a clinical trial (61). In another trial, oxymatrin, extracted from Sophora alopecuraides L., showed a significant antifibrotic effect (with a total effective rate of 48% vs. 4% compared to placebo after 24 weeks of administration) (62). These antifibrotic actions may contribute to survival benefits in patients with HCC treated by TACE. Besides antifibrotic properties, there would be other mechanisms corresponding to adjuvant effects of herbal drugs on TACE, we however currently cannot identify them from present data.

In this review, mostly different kinds of herbal medicine were used in 25 studies, except for in 3 of the patients (Supplementary Table 1), and the compositions of these therapies were also diverse (Supplementary Table 2). The heterogeneity of the herbal medicines was the main limitation of this study, which makes it difficult to clarify the interaction between herbal medicine and TACE, and their corresponding mechanisms. Other limitations would include the unsatisfactory initial data from relatively poorly designed clinical trials and the possibility of publication bias due to only a very few studies reporting negative outcomes. To strengthen the clinical evidence for the adjuvant efficacy of herbal medicine on TACE therapy to treat HCC patients, further strictly designed clinical trials should be performed that have standardized herbal remedies. Herbal drugs have been adopted worldwide, but concerns regarding their safety have arisen (63). Regarding the adverse effects of combination therapy on HCC, the present data did not show any notable frequency compared to only TACE therapy.

In conclusion, this systematic review and meta-analysis showed survival benefits in patients with HCC by combined treatment with herbal medicine and TACE. The adjuvant effect of herbal drugs on TACE needs to be further evaluated by well-designed RCTs in the future.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

H-MO: wrote the main manuscript text, and conducted statistical analysis; E-JK, H-RB: contributed to the data collection and manuscript preparation including revision process; J-HC, C-GS: supervised the manuscript; N-HL: supervised the manuscript, and directed final version of all contents. All authors reviewed and approved this manuscript.