Sage Journals: Discover world-class research

Abstract

Background: Ginsenosides (GS), including total GS, Rh2, Rg3 and compound K (CK), have been utilized as adjuvants in transarterial chemoembolization (TACE), surgery, and chemotherapy for hepatocellular carcinoma (HCC) therapy. However, the safety and efficacy of such combination treatments have been contradictory across different studies. This study aims to systematically evaluate the efficacy and safety of GS as adjuvant therapy for HCC. Methods: A literature search of PubMed, CNKI, Wanfang Data, Cochrane Library, Embase, and Web of Science was conducted up to May 2024 for clinical randomized controlled trials (RCTs) on GS-based adjuvant treatments for HCC. Two researchers independently screened the literature, extracted relevant data, and assessed study quality. Meta-analysis was conducted using RevMan 5.4. Results: Nineteen articles involving 1448 patients were included. Meta-analysis showed that GS as an adjuvant therapy for HCC improved disease control rate (risk ratio (RR) = 1.42, 95% CI [1.26, 1.60]), objective response rate (RR = 1.20, 95% CI [1.09, 1.32]), life quality (RR = 1.49, 95% CI [1.23, 1.79]), 1-year overall survival rate (RR = 1.27, 95% CI [1.06, 1.52]), 2-year overall survival rate (RR = 1.43, 95% CI [1.06, 1.95]), ehanced Child-Pugh in A level (RR = 1.59, 95% CI [1.08, 2.34]), Child-Pugh in B level (RR = 1.28, 95% CI [1.08, 1.52]); increased CD3⁺ (MD = 8.81, 95% CI [3.91, 13.71]), NKC (MD = 8.00, 95% CI [6.76, 9.24]) and CD4⁺ (MD = 9.38, 95% CI [8.04, 10.72]), and reduced incidence of adverse reactions including nausea and vomiting (RR = 0.66, 95% CI [0.57, 0.77]), anorexia (RR = 0.33, 95% CI [0.21, 0.50]), leukopenia (RR = 0.55, 95% CI [0.46, 0.67]) and myelosuppression (RR = 0.54, 95% CI [0.40, 0.74]); decreased Child-Pugh in C level (RR = 0.43, 95% CI [0.27, 0.68]) and CD4⁺/CD8⁺ ratio (MD = 0.50, 95% CI [0.47, 0.57]). Conclusions: In summary, GS combined with Western medical approaches (TACE, surgery, chemotherapy) for the treatment of HCC can improve clinical efficacy, increase overall survival rates, enhance patient life quality, and reduce the occurrence of adverse reactions. However, due to the generally low quality of the included studies, more large-sample, multi-center, high-quality, RCTs are warranted to further consolidate these findings.

Keywords

ginsenosides hepatocellular carcinoma objective response rate disease control rate adverse reactions clinical efficacy

Introduction

Hepatocellular carcinoma (HCC), a prevalent form of primary liver cancer, stands as sixth most common neoplasm and third leading cause of cancer-related deaths.¹ A World Health Organization report underscores HCC’s emergence as a significant contemporary health challenge, with its incidence on the rise.² In 2018, it was approximated that there were ~1 million new cases of liver cancer and ~0.7 million associated deaths globally.³ By 2022, the morbidity and mortality of HCC reached a pinnacle worldwide.⁴ Regions such as East and Southeast Asia, along with Middle and Western Africa, exhibit the highest rates of HCC compared to other parts of the world.⁵ While HCC traditionally carries a poor prognosis, early detection through ultrasonography surveillance provides a glimmer of hope by identifying HCC at its early stage (single tumors or up to 3 nodules ≤3 cm).⁶ At this stage, interventions like resection, liver transplantation, or ablation offer the potential for curing the tumor, with a 5-year survival rate exceeding 50%.^7,8 However, for patients in intermediate or advanced stages of HCC, palliative measures such as transcatheter hepatic arterial chemoembolization (TACE) or intravenous chemotherapy become viable options.⁹ These approaches, however, are limited by their associated toxicities, drug resistance, and various adverse effects, particularly for patients in the advanced stages, and their survival benefits remain uncertain.^10,11 Recognizing the limitations of conventional therapies for HCC, there has been a growing trend toward the utilization of complementary and alternative medicine in managing the disease over recent decades. Presently, the integration of traditional Chinese medicine into modern comprehensive therapy is emerging as a significant aspect in the research and treatment landscape of HCC.^12,13 Numerous studies demonstrated the therapeutic efficacy of Chinese medicine and its ability to complement Western medical treatments.^14,15 Scholars have suggested that combining Chinese and Western medical approaches represents the future direction for innovative HCC management.^14,15 For example, the compound Phyllanthus Urinaria L. is effective in attenuating the progression of HBV-associated cirrhosis to HCC.¹⁶ Additionally, a combination of Phyllanthus urinaria and lenvatinib was found to inhibit HCC progression.¹⁷ Ginsenosides (GS), the active constituents of ginseng, have been noted for their anticancer properties¹⁸ and their ability to mitigate chemotherapy-induced adverse drug reactions.¹⁹ As a result, they have been recommended as adjuncts to Western medical approaches for treating HCC.¹⁹ However, observations regarding efficacy and safety of this combined therapy are contentious or even contradictory.²⁰ Additionally, the duration of ginsenosides treatment has varied widely, ranging from 1 week to 26 weeks,²¹ with the impact of treatment duration on combination therapy effectiveness remaining uncertain. Moreover, 4 GS regimens—total ginsenosides (GS), compound K (CK), Rh2, and Rg3—used clinically used in combination therapy, but it remains inconclusive which regimen offers the highest efficacy.²² Thus, there is an urgent need to objectively assess whether combining Western medical approaches with GS is more effective than Western medical approaches alone for treating HCC, and to determine the optimal GS regimen for maximal efficiency. This study conducts meta-analyses to evaluate the efficacy of combining Western medical approaches (TACE, chemotherapy, and surgery) with GS therapy for HCC.

Methods

Study Design

This systematic review and meta-analysis were conducted in accordance with the standard guideline of “Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)”

Search Strategy

A literature search was conducted across China National Knowledge Infrastructure (CNKI), Wanfang Data, PubMed, Cochrane Library, Embase, Web of Science up until May 2024 for clinical randomized controlled trials (RCTs) on the adjuvant treatment of HCC with GS. The search terms included “ginsenoside,” “Shenyi capsule,” “ginsenoside Rg3,” “hepatocellular carcinoma,” “hepatocellular carcinomas,” “liver cell carcinomas,” “liver cell carcinoma,” “liver cancers,” and “liver Cancer.” The search formula was: (ginsenoside OR ginsenoside Rg3 OR Shenyi Capsule) AND (Hepatocellular Carcinoma OR Hepatocellular Carcinomas OR Liver Cell Carcinomas OR Liver Cell Carcinoma OR Liver Cancers OR Liver Cancer).

Inclusion and Exclusion Criteria

The inclusion criteria were as follows: (1) Study type was a randomized controlled trial (RCT); (2) Study population include patients diagnosed with primary liver cancer confirmed by imaging, pathology, or cytology; (3) For the intervention, experimental group received treatment with GS combined with Western medicine methods (TACE, surgery, chemotherapy), while the control group received Western medicine treatment methods (TACE, surgery, chemotherapy); (4) Outcome measures: Near-term objective efficacy was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST), including objective response rate (ORR), disease control rate, Karnofsky Performance Status (KPS) score improvement rate, overall survival rate, alpha-fetoprotein (AFP) reduction rate, and incidence rate of adverse reactions.

The exclusion criteria were as follows: (1) Non-RCT studies; (2) Experimental studies or reviews; (3) Studies not observing the efficacy of GS in the treatment of liver cancer; (4) Studies lacking outcome measures; (5) Duplicate publications retained one article.

Data Extraction and Quality Assessment

For each eligible study, data sheets were used for the independent collection of extracted information by 2 investigators (RZ and YL). Any disparities were addressed through discussion or by consulting other investigators (YG, HT, SW, and QZ). The extracted information covered various aspects, including study characteristics such as treatment strategies, follow-up duration, and primary outcomes; patient details, including case numbers; clinical intervention characteristics like different chemotherapy/surgeries for HCC; and the specific components of GS (total GS, Rg3, Rh2, CK) utilized in the RCTs, as well as distinctions between GS group and GS-free group.

Bias risk assessment in included studies was conducted using the Cochrane Collaboration’s tool. The evaluation criteria consisted of 7 items: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other potential sources of bias. Each item was classified as “yes” (indicating a low risk of bias), “unclear” (suggesting an uncertain risk of bias), or “no” (indicating a high risk of bias).

Data Analysis and Statistical Methods

Extracted data underwent analysis using Review Manager 5.4 software from the Cochrane Library. To illustrate efficacy analysis statistics for continuous data, the mean difference (MD) and 95% confidence interval (CI) were utilized, with a significance level set at P < .05. Heterogeneity among the studies was evaluated using the Cochrane Q-test and I² statistics (where P < .10 indicates significance, and I² > 50% indicates high heterogeneity). When minimal or no heterogeneity was detected among the included studies (P ≥ .10, I² ≤ 50%), the fixed-effect model was employed for analysis. Conversely, in cases of significant heterogeneity among the included results (P < .10, I² > 50%), the random effects model was utilized for analysis, accompanied by subgroup analyses. During subgroup analysis, if data in one or more subgroups displayed notable heterogeneity (P < .10, I² > 50%), the random effects statistical model was employed for overall data analysis.

Results

Literature Search and Selection

Figure 1 shows study flow. During the initial search phase, a comprehensive exploration of multiple databases, including “Embase,” “PubMed,” “CNKI,” “WOS,” “Wanfang,” and “Cochrane library,” yielded a total of 1578 records. Subsequent screening led to the exclusion of 776 records, primarily due to duplication. The remaining 802 articles underwent further examination. Among these, 133 articles were excluded for various reasons, including review, studies presenting graphical data only, and some articles lacking complete data or a control group, non-clinical studies, other liver diseases. Ultimately, 19 studies meeting the inclusion criteria were selected for meta-analysis.

Figure 1.

Flow diagram of the meta-analysis.

Study Characteristics

Over a span of 12 years, from 2005 to 2019, 19 independent studies were published, collectively evaluating the efficacy and safety of GS as adjuvant therapy for primary liver cancer. The detailed study characteristics are succinctly summarized in Table 1.

Table 1.

Study Characteristics of Included Studies.

References	Publication date	Main treatments		Sample size		Treatment duration (day)	Outcomes used for meta-analysis
References	Publication date	Control group	Experimental group	Control group	Experimental group	Treatment duration (day)	Outcomes used for meta-analysis
Chen and Ge²³	2012	TACE	TACE+Rg3	30	30	56	Objective response rate, disease control rate, life quality, overall survival, GI adverse effects, AFP, Anorexia, Leukopenia, CD3⁺, CD4⁺, NKC, CD4⁺/CD8⁺
Feng et al,²⁴	2005	TACE	TACE+GS	20	20	7	GI adverse effects
Feng et al²⁵	2006	TACE	TACE+GS	30	30	7	ALT
Gong et al²⁶	2015	TACE	TACE+Rg3	33	34	56	Objective response rate, disease control rate, overall survival, GI adverse effects, myelosuppression
Hu et al²⁷	2016	TACE	TACE+Rg3	35	35	56	Objective response rate, life quality, GI adverse effects, myelosuppression
Li and Li²⁸	2009	TACE	TACE+Rg3	40	40	180	Objective response rate, disease control rate, GI adverse effects
Li et al,²⁹	2015	TACE	TACE+Rg3	30	30	180	Objective response rate, disease control rate, life quality, ALT
Liao et al³⁰	2013	TACE+PEGIFN	TACE+PEGIFN+Rh2	52	56	63	Objective response rate, disease control rate, GI adverse effects, Leukopenia
Liu and Li³¹	2015	TACE	TACE+Rg3	32	32	90	Objective response rate, disease control rate, GI adverse effects
Luo et al³²	2012	As2O3	As2O3+Rg3	40	41	56	Life quality, AFP
Ouyang and Yu²⁰	2009	TACE	TACE+Rg3	31	30	112	Objective response rate, disease control rate, life quality, overall survival, GI adverse effects, myelosuppression, AFP, ALT
Tan et al³³	2018	Surgical resection	Surgical resection +Rg3	33	34	60	Objective response rate, disease control rate
Wang and Yang³⁴	2014	Surgery/Chemotherapy	Surgery/Chemotherapy+Rg3	24	24	56	Objective response rate, disease control rate, ALT
Wei et al³⁵	2019	Chemotherapy	Chemotherapy+Rg3	42	42	60	Objective response rate, disease control rate,GI adverse effects, myelosuppression
You³⁶	2008	TACE	TACE+GS	30	30	6	GI adverse effects, ALT
Zhang³⁷	2007	TACE	TACE+Rg3	33	33	56	Life quality, overall survival
Zhao³⁸	2013	TACE	TACE+CK	25	25	56	Objective response rate, disease control rate,Leukopenia, CD3⁺, CD4⁺, NKC, CD4⁺/CD8⁺
Zhou³⁹	2011	TACE	TACE+Rg3	36	38	56	Objective response rate, disease control rate, life quality, myelosuppression
Zhou et al¹⁸	2016	TACE	TACE+Rg3	76	152	60	Objective response rate, disease control rate, overall survival, GI adverse effects, anorexia, leukopenia

Risk of Bias Assessment for Eligible Studies

The assessment of bias risk revealed varying levels of uncertainty and potential bias across the eligible studies. Specifically, 9 studies were labeled with an “unclear risk” of selection bias due to insufficient descriptions of random sequence generation. Similarly, 15 studies were designated with an “unclear risk” of selection bias, and one study was marked as having a “high risk” of selection bias due to ambiguity regarding allocation concealment. Fifteen studies were classified with an “unclear risk,” primarily due to inadequate details concerning blinding of participants and personnel. Seventeen studies were considered to have an “unclear risk” of detection bias because of incomplete information regarding blinding of outcomes assessment. Two studies were categorized with an “unclear risk” of attrition bias due to incomplete outcome data. Lastly, 18 studies were identified as having an “unclear risk” of reporting bias due to potential selective reporting. It is important to note that 10 studies were labeled with an “unclear risk” of other forms of bias. A visual representation of quality assessment was shown in Figure 2.

Figure 2.

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

Meta-Analysis of Disease Control Rate

For disease control rate, 14 studies were included, comprising 602 patients in experimental group and 519 controls. Heterogeneity analysis indicated no heterogeneity among studies. Therefore, fixed effects were employed (Figure 3A). Meta-analysis revealed that GS treatment improved disease control rate compared to controls (RR = 1.42, 95% CI [1.26, 1.60], P < .001; Figure 3A). Evaluation of funnel plots generated from the included studies displayed no noticeable irregularities, signifying the absence of publication bias (Supplemental Figure S5A).

Figure 3.

Forest plot of meta-analysis of disease control rate (A) response rate(B) and life quality (C).

Subgroup analyses based on whether patients received TACE or other treatments were presented in Supplemental Figure S1A. In the TACE subgroup, GS treatment significantly enhanced disease control rate compared to controls (RR = 1.15, 95% CI [1.04, 1.27], P = .005; Supplemental Figure S1A), while in the “without TACE” subgroup, GS treatment improved disease control rate compared to controls (RR = 1.37, 95% CI [1.12, 1.67], P = .002; Supplemental Figure S1A).

Further subgroup based on components of GS was conducted (Supplemental Figure S1B). In the Rg3 subgroup, Rg3 treatment significantly enhanced the disease control rate compared to controls (RR = 1.23, 95% CI [1.14, 1.33], P < .001; Supplemental Figure S1B). Conversely, in the CK subgroup, CK treatment did not improve disease control rate (RR = 1.09, 95% CI [0.95, 1.24], P = .24; Supplemental Figure S1B), and in the Rh2 subgroup, Rh2 treatment failed to improve disease control rate (RR = 0.93, 95% CI [0.82, 1.05], P = .22; Supplemental Figure S1B).

Meta-Analysis of Objective Response Rate

For the analysis of objective response rate, 14 studies were included, comprising 603 patients in experimental group and 520 controls. Heterogeneity analysis suggested no significant heterogeneity among studies; therefore, fixed effects were employed (Figure 3B). Meta-analysis revealed that GS treatment improved objective response rate comparing with controls (RR = 1.20, 95% CI [1.09, 1.32], P < .001; Figure 3B). Evaluation of funnel plots generated from the included studies displayed no noticeable irregularities, indicating the absence of publication bias (Supplemental Figure S5B).

Subgroup analyses based on whether patients received TACE or other treatments were presented in Supplemental Figure S2A. In the TACE subgroup, GS treatment significantly enhanced objective response rate compared to controls (RR = 1.42, 95% CI [1.22, 1.65], P < .001; Supplemental Figure S2A), while in the “without TACE” subgroup, GS treatment also significantly improved the objective response rate compared to controls (RR = 1.39, 95% CI [1.12, 1.72], P = .003; Supplemental Figure S2A).

Further subgroup analyses based on components of GS were conducted (Supplemental Figure S2B). In the Rg3 subgroup, Rg3 treatment significantly improved objective response rate compared to controls (RR = 1.47, 95% CI [1.26, 1.71], P < .001; Supplemental Figure S2B). Conversely, in the CK subgroup, CK treatment failed to improve objective response rate (RR = 1.43, 95% CI [0.96, 2.13], P = .08; Supplemental Figure S2B), and in the Rh2 subgroup, Rh2 treatment did not improve objective response rate (RR = 1.19, 95% CI [0.95, 1.48], P = .13; Supplemental Figure S2B).

Meta-Analysis of Life Quality

For life quality, 7 studies were included, comprising 239 patients from experimental group and 237 controls. Heterogeneity analysis implied no significant heterogeneity among studies; therefore, fixed effects were employed (Figure 3C). GS treatment improved life quality compared to controls (RR = 1.49, 95% CI [1.23, 1.79], P < .001; Figure 3C). Evaluation of funnel plots generated from the included studies displayed no noticeable irregularities, indicating the absence of publication bias (Supplemental Figure S5C).

Subgroup analyses based on components of GS are presented in Supplemental Figure S3, with no heterogeneity detected in these subgroups (Supplemental Figure S3). In the Rg3 subgroup, Rg3 treatment significantly improved life quality compared to controls (RR = 1.38, 95% CI [1.12, 1.69], P = .002; Supplemental Figure S3). Conversely, in the CK subgroup, CK treatment failed to improve life quality (RR = 1.40, 95% CI [0.77, 2.53], P = .27; Supplemental Figure S3).

Meta-Analysis of Overall Survival

For the analysis of 6-month overall survival, 3 studies were included, comprising 215 patients from experimental group and 140 controls. Heterogeneity analysis implied no significant heterogeneity among studies. Therefore, fixed effects were employed (Figure 4A). However, GS treatment failed to improve 6-month overall survival rate compared to controls (RR = 1.07, 95% CI [0.99, 1.16], P = .09; Figure 4A). Evaluation of funnel plots generated from the included studies displayed no noticeable irregularities, signifying the absence of publication bias (Supplemental Figure S5D).

Figure 4.

Forest plot of meta-analysis of 6-month overall survival rate (A), 1 year overall survival rate (B), 2 year overall survival rate (C) and 3 year overall survival rate (D).

For 1-year overall survival rate, 4 studies were included, comprising 127 patients from experimental group and 127 controls. Heterogeneity analysis implied no significant heterogeneity among studies. Therefore, fixed effects were employed (Figure 4B). In this analysis, GS treatment significantly improved 1-year overall survival rate compared to controls (RR = 1.27, 95% CI [1.06, 1.52], P = .008; Figure 4B). Evaluation of funnel plots generated from the included studies displayed no noticeable irregularities, signifying the absence of publication bias (Supplemental Figure S5E).

For 2-year overall survival rate, 3 studies were included, comprising 94 patients from experimental group and 94 controls. Heterogeneity analysis implied no significant heterogeneity among studies. Therefore, fixed effects were employed for the analysis (Figure 4C). In this analysis, GS treatment significantly improved 2-year overall survival rate compared to controls (RR = 1.43, 95% CI [1.06, 1.95], P = .02; Figure 4C). Evaluation of funnel plots generated from the included studies displayed no noticeable irregularities, indicating the absence of publication bias (Supplemental Figure S5F).

Regarding 3-year overall survival rate, only one study was included, with 30 patients from experimental group and 30 controls. However, GS treatment failed to improve 3-year overall survival rate compared to the control group (RR = 1.60, 95% CI [0.59, 4.33], P = .36; Figure 4D). Evaluation of funnel plots generated from the included studies displayed no noticeable irregularities, signifying the absence of publication bias (Supplemental Figure S5G).

Meta-Analysis of Nausea and Vomiting

For nausea and vomiting, 11 studies were included, comprising 477 patients from experimental group and 396 controls. Heterogeneity analysis indicated no significant heterogeneity among the included studies. Therefore, fixed effects were employed (Figure 5A). The meta-analysis demonstrated that GS treatment significantly reduced nausea and vomiting comparing with controls (RR = 0.66, 95% CI [0.57, 0.77], P < .001; Figure 5A). Evaluation of funnel plots generated from the included studies displayed no noticeable irregularities, indicating the absence of publication bias (Supplemental Figure S5H).

Figure 5.

Forest plot of meta-analysis of nausea and vomiting (A), anorexia (B), leukopenia (C), and myelosuppression (D).

Subgroup analyses based on whether patients received TACE or other treatments were presented in Supplemental Figure S4A. In the TACE subgroup, GS treatment significantly reduced nausea and vomiting compared to controls (RR = 0.66, 95% CI [0.57, 0.77], P < .001; Supplemental Figure S4A). However, in the “without TACE” subgroup, GS failed to reduce nausea and vomiting compared to controls (RR = 0.22, 95% CI [0.28, 1.33], P = .22; Supplemental Figure S4A).

Further subgroup analyses based on components of GS were conducted (Supplemental Figure S4B). In the Rg3 subgroup, Rg3 treatment significantly reduced nausea and vomiting compared to controls (RR = 0.67, 95% CI [0.57, 0.79], P < .001; Supplemental Figure S4B). Similarly, in the Rh2 subgroup, Rh2 treatment also significantly reduced nausea and vomiting compared to controls (RR = 0.61, 95% CI [0.46, 0.82], P = .001; Supplemental Figure S4B).

Meta-Analysis of Anorexia

For anorexia, 2 studies were included, comprising 182 patients from experimental group and 106 controls. Heterogeneity analysis indicated no significant heterogeneity among studies; therefore, fixed effects were employed (Figure 5B). Meta-analysis demonstrated that GS reduced anorexia comparing with controls (RR = 0.33, 95% CI [0.21, 0.50], P < .001; Figure 5B). Evaluation of funnel plots generated from the included studies displayed no noticeable irregularities, indicating the absence of publication bias (Supplemental Figure S5I).

Meta-Analysis of Leukopenia

For leukopenia, 4 studies were included, comprising 263 patients from experimental group and 183 controls. Heterogeneity analysis indicated no significant heterogeneity among studies. Therefore, fixed effects were employed (Figure 5C). Meta-analysis revealed that GS reduced leukopenia compared to controls (RR = 0.55, 95% CI [0.46, 0.67], P < .001; Figure 5C). Evaluation of funnel plots generated from the included studies displayed no noticeable irregularities, indicating the absence of publication bias (Supplemental Figure S5J).

Meta-Analysis of Myelosuppression

For myelosuppression, 5 studies were included, comprising 179 patients from experimental group and 177 controls. Heterogeneity analysis suggested no significant heterogeneity among studies. Therefore, fixed effects were employed (Figure 5D). Meta-analysis revealed that GS treatment significantly reduced myelosuppression compared to controls (RR = 0.54, 95% CI [0.40, 0.74], P < .001; Figure 5D). Evaluation of funnel plots generated from the included studies displayed no noticeable irregularities, indicating the absence of publication bias (Supplemental Figure S5K).

Meta-Analysis of AFP and ALT

For AFP, 3 studies were included, comprising 105 patients from experimental group and 105 controls. Heterogeneity analysis showed significant heterogeneity among studies. Therefore, random effects were employed (Figure 6A). Meta-analysis revealed that GS treatment had no effects on AFP comparing with controls (RR = 1.78, 95% CI [0.69, 4.60], P = .23; Figure 6A). Evaluation of funnel plots generated from the included studies displayed no noticeable irregularities, signifying the absence of publication bias (Supplemental Figure S5L).

Figure 6.

Forest plot of meta-analysis of AFP (A) and ALT (B).

For ALT, 5 studies were included, comprising 168 patients from experimental group and 168 controls. Heterogeneity analysis showed no significant heterogeneity among studies. Therefore, fixed effects were employed (Figure 6B). Meta-analysis revealed that GS treatment reduced ALT compared to controls (RR = 0.76, 95% CI [0.58, 0.98], P = .04; Figure 6B). Evaluation of funnel plots generated from the included studies displayed no noticeable irregularities, indicating the absence of publication bias (Supplemental Figure S5M).

Meta-Analysis of CD3⁺, CD4⁺, NKC, and CD4⁺/CD8⁺ Ratio

For CD3⁺, 2 studies were included comprising 55 patients from experimental group and 55 controls. Heterogeneity analysis showed heterogeneity among studies. Therefore, random effects were employed (Figure 7A). Meta-analysis revealed that GS treatment increased CD3⁺ levels compared to controls (MD = 8.81, 95% CI [3.91, 13.71], P < .001; Figure 7A). Evaluation of funnel plots generated from the included studies displayed no noticeable irregularities, indicating the absence of publication bias (Supplemental Figure S5N).

Figure 7.

Forest plot of meta-analysis of CD3⁺ (A), CD4⁺ (B), NKC (C), and CD4⁺/CD8⁺ ratio (D).

For CD4⁺, 2 studies were included, comprising 55 patients from experimental group and 55 controls. Heterogeneity analysis indicated no heterogeneity. Therefore, fixed effects were employed (Figure 7B). Meta-analysis revealed that GS treatment increased CD4⁺ levels compared to controls (MD = 9.38, 95% CI [8.04, 10.72], P < .001; Figure 7B). Evaluation of funnel plots generated from the included studies displayed no noticeable irregularities, indicating the absence of publication bias (Supplemental Figure S5O).

For NKC, 2 studies were included, comprising 55 patients from experimental group and 55 controls. Heterogeneity analysis showed no significant heterogeneity among studies. Therefore, fixed effects were employed (Figure 7C). Meta-analysis revealed that GS treatment increased NKC ratio compared to controls (MD = 8.00, 95% CI [6.76, 9.24], P < .001; Figure 7C). Evaluation of funnel plots generated from the included studies displayed no noticeable irregularities, indicating the absence of publication bias (Supplemental Figure S5P).

For CD4⁺/CD8⁺ ratio, 2 studies were included, comprising 55 patients from experimental group and 55 controls. Heterogeneity analysis showed no heterogeneity among. Therefore, fixed effects were employed (Figure 7D). Meta-analysis revealed that GS treatment increased CD4⁺/CD8⁺ ratio compared to controls (MD = 0.50, 95% CI [0.47, 0.57], P < .001; Figure 7D). Evaluation of funnel plots generated from the included studies displayed no noticeable irregularities, indicating the absence of publication bias (Supplemental Figure S5Q).

Liver Function

For the analysis of Child-Pugh in A level, 6 studies were included, comprising 173 patients from experimental group and 173 controls. Heterogeneity analysis indicated no significant heterogeneity among the included studies; therefore, fixed effects were employed (Figure 8A). Meta-analysis revealed that GS treatment increased proportions of patients with Child-Pugh in A level compared to controls (RR = 1.59, 95% CI [1.08, 2.34], P = .02; Figure 8A). Evaluation of funnel plots generated from the included studies displayed no noticeable irregularities, indicating the absence of publication bias (Supplemental Figure S5R).

Figure 8.

Forest plot of meta-analysis of Child-Pugh in A level (A), Child-Pugh in B level (B) and Child-Pugh in C level (C).

For Child-Pugh in B level, 6 studies were included, comprising 173 patients from experimental group and 173 controls. Heterogeneity analysis indicated no significant heterogeneity; therefore, fixed effects were employed (Figure 8B). Meta-analysis revealed that GS treatment increased proportions of patients with Child-Pugh in B level compared to controls (RR = 1.28, 95% CI [1.08, 1.52], P = .004; Figure 8B). Evaluation of funnel plots generated from the included studies displayed no noticeable irregularities, indicating the absence of publication bias (Supplemental Figure S5S).

For Child-Pugh in C level, 6 studies were included, comprising 173 from experimental group and 173 controls. Heterogeneity analysis indicated no significant heterogeneity. Therefore, fixed effects were employed (Figure 8C). In this analysis, GS treatment decreased proportions of patients with Child-Pugh in C level compared to controls (RR = 0.43, 95% CI [0.27, 0.68], P < .001; Figure 8C). Evaluation of funnel plots generated from the included studies displayed no noticeable irregularities, indicating the absence of publication bias (Supplemental Figure S5T).

Discussion

HCC is a prevalent malignant tumor of the digestive system, often manifesting insidiously without apparent symptoms in its early stages.^2,40 By the time patients typically seek medical attention, the disease has usually progressed to intermediate or advanced stages, thus missing the optimal treatment window and resulting in a grim prognosis.^2,40 The incidence-to-mortality ratio stands at 1:0.9, with a 5-year overall survival of ~18% in North American countries and regions, and a mere 12.1% in China, posing a grave threat to patients’ health and survival.^2,40 This study conducted a meta-analysis to assess efficacy and safety of GS as an adjuvant therapy for HCC. The evaluation of outcome indicators is a prominent focus in international clinical medical research. When appraising treatment efficacy for diseases, internationally and domestically recognized outcome indicators should ideally be utilized to authentically reflect the study’s conclusions.⁴¹ This study extracted all efficacy indicators from 19 included studies, encompassing treatment effectiveness rate, disease control rate, increased overall survival rate, quality of life, adverse reactions to anti-cancer drugs, liver function improvement and immune indicators (CD3⁺, CD4⁺, CD4⁺/CD8⁺ ratio, and NKC), which collectively represent current clinical efficacy evaluation indicators for HCC.

Our findings revealed that: (i) GS in combination with Western medicinal methods can effectively improve objective response rate and disease control rate; (ii) significant differences were noted in overall survival rate comparisons between the treatment and control groups, suggesting that GS can augment the 1-year, 2-year, and overall survival rates of intermediate and advanced liver cancer patients, albeit without statistical significance in the 6-month and 3-year overall survival periods; (iii) life quality, assessed using KPS score, indicated that GS notably enhances patient quality of life. (iv) Regarding adverse reactions, results exhibited notable differences in adverse reactions between the treatment and control groups, suggesting that GS can significantly mitigate the incidence of adverse reactions induced by anti-cancer drugs and TACE. (v) TACE has been shown to compromise liver function, particularly in Chinese liver cancer patients, most of whom have hepatitis B, rendering them vulnerable to this treatment.^42
-44 This can lead to liver parenchymal damage, diminished liver compensatory function, and even liver atrophy, affecting patient treatment and long-term survival. Liver function assessment in this study employed the Child-Pugh classification evaluation method, with improvement, stability, and reduction serving as outcome indicators for efficacy evaluation. Statistical analysis unveiled significant differences in improvement, stability, and reduction between the treatment and control groups, indicating that GS can ameliorate and stabilize liver function impairment caused by TACE/chemotherapy and deter liver function deterioration. (vi) Qualitative analysis of alanine aminotransferase (ALT) displayed a statistically significant difference between the treatment and control groups, implying that ginsenosides aid in reducing ALT levels.

Ginsenoside Rg3, a trace compound of tetracyclic triterpene saponin found in ginseng, was initially identified at the molecular level by the esteemed Japanese pharmacist Kunio Hikino.⁴⁵ Subsequent research has uncovered its pharmacological effects, particularly its selective inhibition of tumor cell infiltration and metastasis. Basic experimental studies have demonstrated that ginsenoside Rg3 may hinder HepG2 cell progression by down-regulating the expression of alginate transferase IV.⁴⁶ Additionally, it inhibits neovascularization in liver cancer and modulates immunity, exhibiting inhibitory effects on mouse liver cancer xenografts.⁴⁷ Through down-regulating Bcl-2, up-regulating Bax, and activating caspase-3, Rg3 triggers apoptosis in human liver cancer cells.⁴⁸ By up-regulating caspase-3, down-regulating survivin, and reducing vascular endothelial growth factor, Rg3 induces apoptosis of mouse liver cancer cells and inhibits blood vessel formation in mouse liver cancer xenografts.⁴⁸ Moreover, combining ginsenoside Rg3 with oxaliplatin and sorafenib can expedite the apoptosis of human liver cancer cells.⁴⁸ Rg3 and sorafenib alleviate HCC progression by regulating HK2-mediated PI3K/Akt pathway.⁴⁶ Ginsenoside Rh2, another active component of GS, has also shown promise in inhibiting hepatocellular carcinoma. Yang et al demonstrated that ginsenoside Rh2 inhibits HCC through β-catenin and autophagy.⁴⁹ Additionally, ginsenoside Rh2 has been found to suppress HCC progression by modulating CDKN2A-2B by targeting EZH2.⁵⁰ Xu et al revealed that ginsenoside Rh2 inhibits HCC by suppressing angiogenesis and GPC3-mediated Wnt/β-catenin signaling pathway.⁵¹ Ginsenoside compound K exerted apoptotic effects in HCC cells via Akt/mTOR/c-Myc signaling pathway⁵²; Zhang et al showed that ginsenoside CK inhibited hypoxia-induced HCC EMT through HIF-1α/NF-κB singaling pathway.⁵³ Recently, Zhang et al showed that CK ameliorated hepatic lipid accumulation via activating LKB1/AMPK pathway.⁵⁴ These results indicate that active components of ginsenosides showed the promising anti-tumor effects, while the underlying molecular mechanisms remain to be explored. Clinical studies have demonstrated that incorporating ginsenoside Rg3 as the primary ingredient in San Yi capsules alongside transarterial chemoembolization (TACE), surgery, and chemotherapy in HCC management can enhance clinical effectiveness, increase patient overall survival rates, improve life quality, and mitigate the occurrence of adverse reactions.^{24,25,27,30,34,36,37}

This study has certain limitations: (1) The inclusion of 9 studies did not specify blinding methods, and most studies did not detail specific randomization methods. (2) The number of studies for each outcome indicator was fewer than 10, precluding analysis for publication bias. (3) There were a limited number of studies included for each outcome indicator, with a small sample size in each study, resulting in a restricted total sample size for meta-analysis. (4) There was a lack of reporting on progression-free survival, making it impossible to analyze progression-free survival of GS combined with Western medicine treatment for HCC.

Conclusions

In summary, GS combined with Western medicine methods (TACE, surgery, chemotherapy) for the treatment of primary liver cancer can improve clinical efficacy, increase overall survival rates, enhance patient life quality, and reduce the occurrence of bone marrow suppression adverse reactions. However, owing to generally low quality of included studies, more large-sample, multicenter, high-quality, RCTs are warranted to further validate these results.

Supplemental Material

sj-docx-1-ict-10.1177_15347354241293790 – Supplemental material for Evaluation of the Efficacy, Safety, and Clinical Outcomes of Ginsenosides as Adjuvant Therapy in Hepatocellular Carcinoma: A Meta-Analysis and Systematic Review

Supplemental material, sj-docx-1-ict-10.1177_15347354241293790 for Evaluation of the Efficacy, Safety, and Clinical Outcomes of Ginsenosides as Adjuvant Therapy in Hepatocellular Carcinoma: A Meta-Analysis and Systematic Review by Renjie Zhang, Yiling Liao, Yuan Gao, Hengyu Tian, Shenfeng Wu, Qingteng Zeng, Qinghua He, Ruikun Zhang, Chunshan Wei and Jialin Liu in Integrative Cancer Therapies

Footnotes

Acknowledgements

None.

Authors’ Contributions

RZ and YL collected the data and performed the analysis; YG, HT, SW, QZ, QH, RZ, and CW prepared the tables and figures; RZ, JL and CW review and edited the manuscript; RZ and JL wrote the manuscript; JL conceptualized the whole study. All the authors approved the manuscript for submission.

Data Availability

All the data are available upon request.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by Shenzhen Science and Technology Program (No. JCYJ20220531092202006).

Ethical Statement

Not applicable.

ORCID iD

Jialin Liu

Supplemental Material

Supplemental material for this article is available online.

References

Llovet

Kelley

Villanueva

, et al. Hepatocellular carcinoma. Nat Rev Dis Primers. 2021;7:6. doi:10.1038/s41572-020-00240-3

Vogel

Meyer

Sapisochin

Salem

Saborowski

Hepatocellular carcinoma. Lancet. 2022;400:1345-1362. doi:10.1016/S0140-6736(22)01200-4

Brown

Tsilimigras

Ruff

, et al. Management of hepatocellular carcinoma: a review. JAMA Surg. 2023;158:410-420. doi:10.1001/jamasurg.2022.7989

Gilles

Garbutt

Landrum

Hepatocellular carcinoma. Crit Care Nurs Clin North Am. 2022;34:289-301. doi:10.1016/j.cnc.2022.04.004

Chidambaranathan-Reghupaty

Fisher

Sarkar

Hepatocellular carcinoma (HCC): epidemiology, etiology and molecular classification. Adv Cancer Res. 2021;149:1-61. doi:10.1016/bs.acr.2020.10.001

Hartke

Johnson

Ghabril

The diagnosis and treatment of hepatocellular carcinoma. Semin Diagn Pathol. 2017;34:153-159. doi:10.1053/j.semdp.2016.12.011

Wang

Qin

Liu

Sheng

Zhang

Precision diagnosis of hepatocellular carcinoma. Chin Med J. 2023;136:1155-1165. doi:10.1097/cm9.0000000000002641

Alawyia

Constantinou

Hepatocellular carcinoma: a narrative review on current knowledge and future prospects. Curr Treat Options Oncol. 2023;24:711-724. doi:10.1007/s11864-023-01098-9

Raoul

Forner

Bolondi

, et al. Updated use of TACE for hepatocellular carcinoma treatment: how and when to use it based on clinical evidence. Cancer Treat Rev. 2019;72:28-36. doi:10.1016/j.ctrv.2018.11.002

10.

Sidali

Trépo

Sutter

Nault

JC.

New concepts in the treatment of hepatocellular carcinoma. United Eur Gastroenterol J. 2022;10:765-774. doi:10.1002/ueg2.12286

11.

Zhou

Song

Conversion therapy and maintenance therapy for primary hepatocellular carcinoma. Biosci Trends. 2021;15:155-160. doi:10.5582/bst.2021.01091

12.

Liang

Sun

GC.

Traditional Chinese medicine for prevention and treatment of hepatocellular carcinoma: a focus on epithelial-mesenchymal transition. J Integr Med. 2021;19:469-477. doi:10.1016/j.joim.2021.08.004

13.

Jia

Liang

Cheng

Ling

The role of cancer-associated fibroblasts in hepatocellular carcinoma and the value of traditional Chinese medicine treatment. Front Oncol. 2021;11:763519. doi:10.3389/fonc.2021.763519

14.

Wei

Wang

Jing

, et al. Frontier progress of the combination of modern medicine and traditional Chinese medicine in the treatment of hepatocellular carcinoma. Chin Med. 2022;17:90. doi:10.1186/s13020-022-00645-0

15.

Ting

Chen

Tsai

TH.

Preventive and therapeutic role of traditional Chinese herbal medicine in hepatocellular carcinoma. J Chin Med Assoc. 2015;78:139-144. doi:10.1016/j.jcma.2014.09.003

16.

Tong

Zhang

Zhou

, et al. Efficacy of early treatment on 52 patients with preneoplastic hepatitis B virus-associated hepatocellular carcinoma by compound Phyllanthus urinaria L. Chin J Integr Med. 2014;20:263-271. doi:10.1007/s11655-013-1320-7

17.

Liao

Qin

Liu

, et al. Exosomal microRNA profiling revealed enhanced autophagy suppression and anti-tumor effects of a combination of compound Phyllanthus urinaria and lenvatinib in hepatocellular carcinoma. Phytomedicine. 2024;122:155091. doi:10.1016/j.phymed.2023.155091

18.

Zhou

Yan

Liu

, et al. Prospective study of transcatheter arterial chemoembolization (TACE) with ginsenoside Rg3 versus TACE alone for the treatment of patients with advanced hepatocellular carcinoma. Radiology. 2016;280:630-639. doi:10.1148/radiol.2016150719

19.

Zhu

Liu

Zhu

, et al. Efficacy of ginseng and its ingredients as adjuvants to chemotherapy in non-small cell lung cancer. Food Funct. 2021;12:2225-2241. doi:10.1039/d0fo03341c

20.

Ouyang

Efficacy of combined ginsenoside Rg3 interventional therapy in the treatment of advanced hepatocellular carcinoma. Chin Clin Oncol. 2009;14:150-153.

21.

Yinglu

Changquan

Xiaofeng

, et al. A new way: alleviating postembolization syndrome following transcatheter arterial chemoembolization. J Altern Complement Med. 2009;15:175-181. doi:10.1089/acm.2008.0093

22.

Shah

Abuzar

Ilyas

, et al. Ginsenosides in cancer: targeting cell cycle arrest and apoptosis. Chem Biol Interact. 2023;382:110634. doi:10.1016/j.cbi.2023.110634

23.

Chen

Clinical evaluation of ginsenoside combined with hepatic artery embolization in the treatment of primary hepatocellular carcinoma. Zhejiang J Trad Chin Med. 2012;47:111-112.

24.

Feng

Y-L

Ling

C-Q

Zhu

D-Z

, et al. [Ginsenosides combined with dexamethasone in preventing and treating postembolization syndrome following transcatheter arterial chemoembolization: a randomized, controlled and double-blinded prospective trial]. J Chin Integrat Med. 2005;3:99-102.

25.

Feng

Ling

Chen

[Ginsenosides and dexamethasone in managing the liver injury and renal function after transcatheter arterial chemoembolization for hepatic carcinoma patient]. Chin J Oncol. 2006;28:844-847.

26.

Gong

Yin

Liu

Shen

Liu

Curative effects of Shenyi capsule combined with transcatheter arterial chemoembolization in the treatment of advanced hepatocellular carcinoma. J Mod Med Heal. 2015;31:3626-3627.

27.

Wang

Xie

Synergetic effect of transcatheter arterial chemoembolization and Shenyi capsule on the treatment of intermediate and advanced hepatocellular carcinoma. Heilongjiang Med Pharm. 2016;39:35-36.

28.

Clinical study on interventional therapy combined with Rg3 in the treatment of liver cancer. China New Technol Prod. 2009;11:11.

29.

, et al. Clinical study of ginsenoside Rh2 combined with transcatheter arterial chemoembolization for advanced hepatocellular carcinoma patients. Guid J Tradit Chin Med Pharm. 2015;21:81-83.

30.

Liao

Guo

Yang

TY.

The efficacy of arterial chemotherapy, interferon and ginsenoside Rh2 combination in the treatment of hepatitis B-derived hepatoma. Immunological J. 2013;29:639-641.

31.

Liu

A western ginseng capsules combined with advanced hepatocellular carcinoma randomized parallel group study treatment. J Pr Tradit Chin Intern Med. 2015;29:98-100.

32.

Luo

Tang

Zhu

Arsenic trioxide combined with Ginseng saponins Rg3 in the treatment for primary liver cancer with positive AFP after interventional treatment. J Oncol. 2012;18:362-364.

33.

Tan

M-g

Shen

, et al. Effects of Shenyi capsule combined with laparoscopic anatomical segmentectomy in treatment of elderly liver cancer. Chin J Surg Integr Tradit West Med. 2018;24:21-26.

34.

Wang

Yang

Clinical application of Rg3 Shenyi capsule in postoperative chemotherapy for liver cancer. Mod Med Health. 2014;30:576-578.

35.

Wei

Guo

Wang

Clinical efficacy of Shenyi capsule combined with SOX regimen in the treatment of primary liver cancer study. Chin Arch Tradit Chin Med. 2019;37:2758-2761.

36.

You

Clinical study on the enhancement of glucocorticoid effects by ginsenosides. Thesis. 2008;56:1-151.

37.

Zhang

Influence of ginsenosides on the VEGF and AFPh during transcatheter arterial chemoembolization on hepatocellular carcinoma. Shandong Med J. 2007;47:39-40.

38.

Zhao

Clinical observation of adjuvant therapy of ginsenoside CK on primary hepatocellular carcinoma. Med Recapitulate. 2013;19:2837-2840.

39.

Zhou

Clinical observation on hepatic arterial chemoembolization combined with Shenyi capsule in the treatment of primary liver cancer. J Pr Tradit Chin Med. 2011;27:762-763.

40.

Ganesan

Kulik

LM.

Hepatocellular carcinoma: new developments. Clin Liver Dis. 2023;27:85-102. doi:10.1016/j.cld.2022.08.004

41.

Al-Jundi

Sakka

Critical appraisal of clinical research. J Clin Diagn Res. 2017;11:Je01-je05. doi:10.7860/JCDR/2017/26047.9942

42.

Chakraborty

Sarkar

Emerging therapies for hepatocellular carcinoma (HCC). Cancers. 2022;14:2798. doi:10.3390/cancers14112798

43.

Malagari

Pomoni

Filippiadis

Kelekis

Chemoembolization of hepatocellular carcinoma with HepaSphere™. Hepat Oncol. 2015;2:147-157. doi:10.2217/hep.15.2

44.

Jansen

van Hillegersberg

Chamuleau

, et al. Outcome of regional and local ablative therapies for hepatocellular carcinoma: a collective review. Eur J Surg Oncol. 2005;31:331-347. doi:10.1016/j.ejso.2004.10.011

45.

Nakhjavani

Smith

Townsend

Price

Hardingham

JE.

Anti-angiogenic properties of ginsenoside Rg3. Molecules. 2020;25:4905. doi:10.3390/molecules25214905

46.

Wei

Ren

Zheng

, et al. Ginsenoside Rg3 and sorafenib combination therapy relieves the hepatocellular carcinomaprogression through regulating the HK2-mediated glycolysis and PI3K/Akt signaling pathway. Bioengineered. 2022;13:13919-13928. doi:10.1080/21655979.2022.2074616

47.

Wang

, et al. Ginsenoside-Rg3 inhibits the proliferation and invasion of hepatoma carcinoma cells via regulating long non-coding RNA HOX antisense intergenic. Bioengineered. 2021;12:2398-2409. doi:10.1080/21655979.2021.1932211

48.

Fei

Zhang

Synergistic anticancer activity of 20(S)-ginsenoside Rg3 and Sorafenib in hepatocellular carcinoma by modulating PTEN/Akt signaling pathway. Biomed Pharmacother. 2018;97:1282-1288. doi:10.1016/j.biopha.2017.11.006

49.

Yang

Zhao

Liu

Zhang

Ginsenoside Rh2 inhibits hepatocellular carcinoma through β-catenin and autophagy. Sci Rep. 2016;6:19383. doi:10.1038/srep19383

50.

Dong

Wang

20(S)-Ginsenoside Rh2 suppresses proliferation and migration of hepatocellular carcinoma cells by targeting EZH2 to regulate CDKN2A-2B gene cluster transcription. Eur J Pharmacol. 2017;815:173-180. doi:10.1016/j.ejphar.2017.09.023

51.

Hou

, et al. 20(S)-Ginsenoside Rh2 inhibits hepatocellular carcinoma by suppressing angiogenesis and the GPC3-mediated Wnt/β-catenin signaling pathway. Acta Biochim Biophys Sin. 2024;56:688-696. doi:10.3724/abbs.2024038

52.

Shin

Lee

Sim

, et al. Apoptotic effect of compound K in hepatocellular carcinoma cells via inhibition of glycolysis and Akt/mTOR/c-Myc signaling. Phytother Res. 2021;35:3812-3820. doi:10.1002/ptr.7087

53.

Zhang

Fan

Ginsenoside CK inhibits hypoxia-induced epithelial-mesenchymal transformation through the HIF-1α/NF-κB feedback pathway in hepatocellular carcinoma. Foods. 2021;10:1195. doi:10.3390/foods10061195

54.

Zhang

Fan

Ginsenoside CK ameliorates hepatic lipid accumulation via activating the LKB1/AMPK pathway in vitro and in vivo. Food Funct. 2022;13:1153-1167. doi:10.1039/d1fo03026d

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

1.87 MB

Evaluation of the Efficacy,Safety,and Clinical Outcomes of Ginsenosides as Adjuvant Therapy in Hepatocellular Carcinoma: A Meta-Analysis and Systematic Review

Abstract

Keywords

Introduction

Methods

Study Design

Search Strategy

Inclusion and Exclusion Criteria

Data Extraction and Quality Assessment

Data Analysis and Statistical Methods

Results

Literature Search and Selection

Study Characteristics

Risk of Bias Assessment for Eligible Studies

Meta-Analysis of Disease Control Rate

Meta-Analysis of Objective Response Rate

Meta-Analysis of Life Quality

Meta-Analysis of Overall Survival

Meta-Analysis of Nausea and Vomiting

Meta-Analysis of Anorexia

Meta-Analysis of Leukopenia

Meta-Analysis of Myelosuppression

Meta-Analysis of AFP and ALT

Meta-Analysis of CD3+, CD4+, NKC, and CD4+/CD8+ Ratio

Liver Function

Discussion

Conclusions

Supplemental Material

sj-docx-1-ict-10.1177_15347354241293790 – Supplemental material for Evaluation of the Efficacy, Safety, and Clinical Outcomes of Ginsenosides as Adjuvant Therapy in Hepatocellular Carcinoma: A Meta-Analysis and Systematic Review

Footnotes

Acknowledgements

Authors’ Contributions

Data Availability

Declaration of Conflicting Interests

Funding

Ethical Statement

ORCID iD

Supplemental Material

References

Supplementary Material

Meta-Analysis of CD3⁺, CD4⁺, NKC, and CD4⁺/CD8⁺ Ratio