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Immunomodulatory effects of Huaier granule in cancer therapy: a meta-analysis of randomized controlled trials

European Journal of Medical Research volume 29, Article number: 467 (2024) Cite this article

Abstract

Background

This meta-analysis aimed to summarize the immunomodulatory effect of Huaier (Trametes robiniophila Murr) granule as adjuvant therapy in patients with cancer.

Materials and methods

Two authors conducted a search for literature indexed on various databases including PubMed, Embase, Cochrane Library, CNKI, Sinomed, VIP, and WanFang. Randomized controlled trials (RCTs) that investigated the immunomodulatory effect of Huaier granule as adjuvant therapy in cancer patients were included. The outcome of interest included T-lymphocyte subsets (CD3+, CD4+, CD8+ and CD4+/CD8+), immunoglobulin (IgA, IgG, IgM), and natural killer (NK) cells.

Results

We identified 29 RCTs involving a total of 2206 cancer (including hepatocellular, breast, gastric, colorectal, lung, or nasopharyngeal carcinoma) patients. Compared with conventional treatment alone, Huaier combined conventional treatment significantly improved CD3+ (mean difference [MD] 6.95; 95% confidence intervals [CI] 4.42–9.48), CD4+ (MD 5.53; 95%CI 4.22–6.83), CD4+/CD8+ (MD 0.35; 95%CI 0.25–0.45), IgA (standardized mean difference [SMD] 1.18; 95%CI 0.44–1.93), IgG(SMD 1.71; 95%CI 1.11–2.30), IgM (SMD 0.83; 95%CI 0.59–1.07), and NK cells (MD 5.01; 95%CI 3.61–6.40). However, the effect of Huaier on CD8+ (MD − 1.35; 95%CI − 2.80 to 0.11) was not statistically significant between the groups.

Conclusions

Huaier granule as adjuvant therapy may significantly improve immune function in patients with cancers. However, additional well-designed RCTs are needed to validate the current findings considering the methodological flaws of the analyzed trials.

Introduction

Cancer is a worldwide public health concern, with an estimated 19.3 million new cancer cases and 10.0 million cancer mortality in 2020 [1]. Surgery, chemotherapy, and radiotherapy, alone or in combination, are the most common methods for treating cancer. New approaches for cancer treatment include stem cell therapy, targeted therapy, ablation therapy, natural antioxidants, radionics, and ferroptosis-based therapy [2]. Despite progress in therapeutic strategies, the long-term prognosis remains poor for advanced cancer patients [3]. Therefore, identification of novel anti-tumor agents is still an unmet demand in cancer patients.

Tumor immune microenvironment, including both the innate and adaptive systems (macrophages, neutrophils, natural killer cells, and T and B lymphocytes), plays an important role in regulating disease progression and treatment response [4]. Targeting the tumor immune milieu has achieved substantial benefits from immune checkpoint therapies across multiple cancer types [5]. Traditional Chinese medicine has been proven to exert anti-tumor effects by regulating immune cells in the tumor microenvironment [6]. Huaier, also known as Trametes robiniophila Murr, is a sandy beige mushroom found on the trunks of trees and has been widely used as adjuvant therapy for cancer [7]. Huaier granule is a common preparation of Huaier, and its main active ingredient is proteoglycan [8]. Huaier in combination with conventional treatment has been proven to improve the short-term and long-term survival of cancer patients [9]. However, the immunomodulatory effect of Huaier remains controversial in patients with cancer [10,11,12,13,14,15,16,17,18,19,20,21].

No previous study has systematically reviewed the immunomodulatory effect of Huaier in patients with cancer. The objective of this meta-analysis was to evaluate the immunomodulatory effect of Huaier granules as adjuvant therapy in cancer patients.

Materials and methods

Search strategy

This study were performed strictly in accordance with the checklists of the Preferred Reporting Items for Systematic Reviews and Meta-analyses Statement [22]. Two authors systematically searched PubMed, Embase, Web of Science, Cochrane Library, CNKI, Sinomed, and WanFang databases until July 11, 2023. The following items in combination were used for literature search: (“Huaier” OR “Trametes robiniophila Murr”) AND (“cancer” OR “carcinoma” OR “tumor” OR “neoplasms” OR “malignancy”) AND “randomized controlled trial” OR “RCT” OR “randomization” OR “control”). To avoid any possible missing study, we also manually scanned the reference lists of pertinent articles.

Study selection

Studies meeting the following criteria were included: (1) participants: adult patients with cancer; (2) intervention: Huaier granules in combination with conventional treatment versus conventional treatment alone; (3) outcomes: T-lymphocyte subsets (CD3+, CD4+, CD8+ and CD4+/CD8+), immunoglobulin (IgA, IgG, IgM), and natural killer (NK) cells; (4) randomized controlled trials (RCTs). The criteria for exclusion included: (1) cohort, self-control trial; (2) Huaier was not used as adjuvant therapy; and (3) without report outcomes of interest.

Data extraction and methodological quality assessment

Two authors independently extracted relevant data into a standardized table. These extracted data included the first author’s name, publication year, design of study, patients’ diagnosis, number of patients, baseline age, cancer stage, intervention, course of treatment, and blood levels of T-lymphocyte subsets, immunoglobulin, or NK cells. The Cochrane risk bias tool was applied to evaluate the methodological quality of the included RCTs [23]. The risk of bias was divided into “high risk”, “low risk”, or “unclear risk”. Discrepancy between two authors was settled by discussion.

Statistical analysis

RevMan 5.0 (Cochrane, London, UK) and STATA 12.0 software (Stata Corporation, College Station, TX, USA) were used data analysis. A mean difference (MD) or standard mean difference (SMD) was used for pool the continuous variables. The pooling SMD < 0.20, 0.20–0.50, and > 0.80 represents a small, middle, or large effect size, respectively [24]. Statistical heterogeneity was detected using Cochrane Q test and I2 statistic. In the case of significant heterogeneity (Cochrane Q test < 0.10 or I2 ≥ 50%), we chose a random effect model to pool the data, Subgroup analyses were performed based on the sample sizes, type of cancer, cancer stage, and course of Huaier treatment. Publication bias was assessed using the Begg’s and Egger’s test when at least 10 trials were included in the meta-analysis. In the case of publication bias, a “Trim-and-Fill” analysis was conducted to evaluate the potential influence of publication bias. To investigate the credibility of pooling results, we carried out the sensitivity analysis by deleting single study each turn from the overall analysis.

Results

Search results and characteristic of included studies

The initial search produced a total of 690 records, out of which 427 were removed due to duplicates. After reviewing the titles and abstracts, 62 articles were selected for full-text assessment. Applying the predefined inclusion and exclusion criteria, 33 articles were further excluded, mainly because they were not RCTs or did not report outcomes of interest. Ultimately, 29 RCTs [10,11,12,13,14,15,16,17,18,19,20,21, 25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41] included in the meta-analysis (Fig. 1).

Fig. 1
figure 1

Flowchart of trial selection process

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Table 1 presents the main characteristics of the included trials. These trials were conducted in China and were published between 2006 and 2023. The sample sizes ranged from 30 to 200 cases, with a total of 2206 cancer patients. The included trials enrolled patients with breast cancer [12, 13, 15, 16, 29, 30, 33, 37, 39], hepatocellular carcinoma [17, 18, 25, 28, 34, 35, 40, 41], gastric cancer [14, 19, 26, 38], colorectal cancer [10, 21, 32], lung cancer [11, 20, 27, 31], or nasopharyngeal carcinoma [36]. Huaier granule was administered 60 g/d, and the duration of treatment varied from 1 week to 12 months. The risk of bias in the included trials is presented in supplemental Figure S1. While all included RCTs claimed to have a randomized controlled design, only 4 trials provided detailed information on random sequence generation [16, 21, 38, 41]. Allocation concealment and blinding method were not mentioned in any of the trials. Overall, these included RCTs were rated as having unclear risk of bias because lack of sufficient information for judgement.

Table 1 Main characteristic of included trials
Full size table

T-lymphocytes subtype

The pooled analysis showed that when compared with conventional treatment, Huaier in combination with conventional treatment significantly improved the percentage of CD3 + (MD 6.95; 95%CI 4.42–9.48; I2 = 96.0%, p < 0.001; Fig. 2) [10, 12,13,14, 16,17,18,19,20,21, 25,26,27, 31, 33, 35,36,37,38, 41], CD4+ (MD 5.53; 95%CI 4.22–6.83; I2 = 88.0%, p < 0.001; Fig. 3) [10, 12, 13, 15,16,17,18,19,20,21, 27,28,29,30,31, 33,34,35,36,37,38,39,40,41,42], and CD4+/CD8+ (MD 0.35; 95%CI 0.25–0.45; I2 = 95.0%, p < 0.001; Fig. 4) [10,11,12,13, 15,16,17,18,19,20,21, 25,26,27,28,29,30, 33,34,35,36,37,38,39,40,41]. However, there was no significant difference in percentage of CD8+ (MD − 1.35; 95%CI − 2.80 to 0.11; I2 = 95.0%, p < 0.001; Figure S2) [10,11,12,13, 15, 16, 18,19,20,21, 26,27,28,29,30,31, 33,34,35,36, 38,39,40,41] between the two groups. Subgroup analysis indicated that the effects of Huaier on CD4+, and CD4+/CD8+ were statistically significant in sample sizes, type of cancer, cancer stage, and course of Huaier treatment subgroups (Table 2).

Fig. 2
figure 2

Forest plots showing MD with 95% CI of T-lymphocytes CD3+ percentage for Huaier combined conventional treatment versus conventional treatment alone

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Fig. 3
figure 3

Forest plots showing MD with 95% CI of T-lymphocytes CD4+ percentage for Huaier combined conventional treatment versus conventional treatment alone

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Fig. 4
figure 4

Forest plots showing MD with 95% CI of CD4+/CD8+ ratio for Huaier combined conventional treatment versus conventional treatment alone

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Table 2 Results of subgroup analysis on CD4+ and CD4+/CD8+
Full size table

Immunoglobulin level

Four trials [12, 32, 34, 35] reported the effects of Huaier on blood immunoglobulin level. The pooled analysis showed that compared with conventional treatment, Huaier in combination with conventional treatment significantly improved the blood level of IgA (SMD 1.18; 95%CI 0.44–1.93; I2 = 88.0%, p < 0.001; Figure S3), IgG (SMD 1.71; 95%CI 1.11–2.30; I2 = 78.0%, p = 0.003; Figure S4), and IgM (SMD 0.83; 95%CI 0.59–1.07; I2 = 23.0%, p = 0.270; Figure S5).

Natural killer cells

The pooled analysis suggested that Huaier in combination with conventional treatment significantly improved the NK cells (MD 5.01; 95%CI 3.61–6.40; I2 = 95.0%, p < 0.001; Fig. 5) [11, 13, 14, 16, 18, 19, 26, 28, 30, 31, 33, 37] when compared with conventional treatment.

Fig. 5
figure 5

Forest plots showing MD with 95% CI of natural killer cells percentage for Huaier combined conventional treatment versus conventional treatment alone

Full size image

Sensitivity analysis and publication bias

Leave-one-out sensitivity analysis showed that no individual trial significantly affected the overall effect size, suggesting the credibility of the pooling result. We assessed the publication bias for outcomes that included at least 10 trials. Table S1 indicates that publication bias was evident for the CD4+, CD4+/CD8+, and NK cells. However, the “Trim-and-Fill” analyses showed that the publication bias only slightly overestimated the pooling effect sizes but did not alter the original statistical significance.

Discussion

This is the first meta-analysis that focused on the immunomodulatory effect of Huaier granule as adjuvant therapy in cancer patients. The main findings of our meta-analysis showed that Huaier granule as adjuvant therapy could increase the percentages of CD3+, CD4+, CD4+/CD8+, NK cells, as well as IgA, IgG, and IgM level in cancer patients. These findings suggest adjuvant treatment with Huaier granule can improve immune function of cancer patients.

The body’s immune response to cancer includes both innate and adaptive immunity. NK cells, as the cytotoxic lymphocytes of the innate immune system, can directly kill cancer cells and inhibit their infiltration [43]. T-lymphocytes are mainly divided into CD4+ and CD8+ subsets, which play an important role in adaptive immunity [44]. CD4+ and CD8+ are precursors of T helper (Th) cell and T suppressor (Ts) cells, respectively. CD4+ T-lymphocyte can mediate anti-tumor immunity through killing tumor cells or activating innate immune cells, whereas CD8+ T-lymphocyte can serve as effector cells of the adaptive immune response against tumors [45]. CD4+/ CD8+ reflects the balance of immune system. CD3+ represents as mature T-lymphocytes. B cells are the main immune cells mediating humoral immunity, which can generate the anti-tumor immunoglobulin. Our meta-analysis showed Huaier combined conventional treatment could improve the percentages of NK cells, CD3+, CD4+, and CD4+/CD8+ by 5.01%, 6.95%, 5.53%, and 0.35%, respectively. The recovery of NK cells, CD3+, and CD4+ T-lymphocytes are robust indicators of the ability to restore immune function. In addition to the balance of CD4+ and CD8+ cells, Huaier also can regulate the Th/Ts cell ratio [14]. These findings reveal that adjuvant therapy with Huaier can enhance both innate and adaptive immune responses in cancer patients. Moreover, adjuvant treatment with Huaier significantly improved humoral immunity, including blood IgA, IgG, IgM level.

The primary malignancies in our analyzed RCTs widely and included lung cancer, breast cancer, gastric cancer, hepatocellular carcinoma, colorectal cancer, and nasopharyngeal carcinoma. Our subgroup analysis revealed that the magnitude of the pooling effect sizes of CD4+ and CD4+/CD8+ was similar for breast cancer, hepatocellular carcinoma, and gastric/colorectal cancer. However, we observed a weaker effect of Huaier on the percentage of CD4+ and a stronger effect on CD4+/CD8+ in lung cancer patients. This differential response in different cancer types suggests that the effect of Huaier granule may vary depending on the specific cancer type. Particularly, the results of our meta-analysis may be confounded by the cancer stages. Additional clinical trials incorporating cancer stage-specific analyses are necessary to explore the immunomodulatory effects of Huaier granule.

Our pooled results indicated that Huaier granule as adjuvant therapy could increase the percentages of CD3+, CD4+, CD4+/CD8+. However, it is essential to consider studies that have reported no significant effects [35] or differed from the general trend [35, 37]. These findings underscore the need for further research to better understand the factors influencing the efficacy of Huaier granule in different cancer types and patient populations.

Apart from its immunomodulatory effect, Huaier granule as adjuvant therapy also could improve patient quality of life in patients with various types of cancer [19, 27, 32, 33, 38]. More importantly, adjunctive treatment with Huaier granule could improve 3-year survival rate in patients with breast cancer [29, 39].

Significant heterogeneity existed in our overall meta-analyses and subgroup analyses. The existed heterogeneity may be attributed to different types of cancers, stages of cancer, or treatment duration. However, subgroup analyses based on the abovementioned factors only reduced heterogeneity to a certain degree. Moreover, demographic variations and anti-cancer treatments may also contribute to the significant heterogeneity. Unfortunately, we were unable to conduct such subgroup analyses due to insufficient data description in the original studies.

Whether adjunctive Huaier granule to the conventional treatment increases the side effects is a significant concern. The most frequently reported side effects induced by Huaier granule included nausea, vomiting, diarrhea, and rash [21, 27, 32, 38]. However, a well-designed meta-analysis have reported that Huaier granule as adjuvant therapy did not significantly increase gastrointestinal adverse events in patients with primary liver cancer [46]. Further studies are needed to evaluate the safety of Huaier granule as adjuvant therapy.

The findings of our meta-analysis may offer guidance for cancer management. Chemotherapy can damage the immune function of cancer patients, while the combination of Huaier and conventional treatment has the potential to enhance immune functional indexes. The underlying the anti-cancer mechanisms of Huaier may be partially explained by its immunomodulatory effects. For cancer patients with immune deficiency, Huaier granules may enhance their anti-cancer effect by regulating immune function. In addition, anti-inflammation, anti-angiogenic effect, apoptosis induction, inhibition of migration and invasion of cancer cells, enhancement of chemo- and radiotherapy are contributed to the anti-cancer mechanisms of Huaier [47]. However, further studies are needed to fully understand its mechanisms of action.

This meta-analysis has several potential limitations. Firstly, most of the included RCTs only mentioned the randomization but not provided a detailed method of random sequence generation. Additionally, blinding method and allocation concealment were not implemented, which may lead to selection and detection bias. Secondly, there is variability in the duration of Huaier granule treatment, which have affected the comparability and pooling of results. Thirdly, significant heterogeneity was observed in the pooled outcomes, which could not be completely explicated by the subgroup or sensitivity analysis. Fourthly, our poling effect sizes of CD4+, CD4+/CD8+, and NK cell may have overestimated the degree of treatment effects due to the potential impact of publication bias. Fifthly, another significant limitation is our meta-analysis only focused on the biomarkers of immune function but did not address patient-centered outcomes such as quality of life, symptom management, or survival rates. Finally, all the analyzed RCTs are predominantly from China, so caution should be exercised when generalizing these findings to the Western population.

Conclusions

Huaier granule, as an adjuvant therapy, has the potential to provide a beneficial immunomodulatory effect for cancer patients. However, it is premature to draw a definitive conclusion because of the methodological flaws found in the included trials. To confirm the current findings, additional well-designed RCTs with double-blind designs are necessary.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

RCTs:

Randomized controlled trials

MD:

Mean difference

SMD:

Standardized mean difference

CI:

Confidence intervals

NK:

Natural killer

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Funding

This work is supported by (1) Jiangsu 333 Talent Fund (BRA2020016); and (2) Zhenjiang Key Research and Development Fund (SH2021038, SH2022032, SH2022090).

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  1. Ye Zang and Yue Qiu have contributed equally to this work.

Authors and Affiliations

  1. Department of Oncology, The People’s Hospital of Danyang, Affiliated Danyang Hospital of Nantong University, Danyang, 212399, China

    Ye Zang

  2. Institute of Molecular Biology and Translational Medicine, Cancer Institute, The Affiliated People’s Hospital, Jiangsu University, No. 8 Dianli Road, Zhenjiang, 212002, Jiangsu, China

    Yue Qiu, Yimeng Sun & Yu Fan

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Contributions

Study conception/design and interpretation of data: Y Fan and YM Sun; Literature search, data extraction, quality assessment, statistical analysis: Y Zang and Y Qiu; Writing the manuscript: Y Qiu; Revising the manuscript: Y Fan. All authors read and approved the final manuscript.

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Correspondence to Yimeng Sun or Yu Fan.

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Zang, Y., Qiu, Y., Sun, Y. et al. Immunomodulatory effects of Huaier granule in cancer therapy: a meta-analysis of randomized controlled trials. Eur J Med Res 29, 467 (2024). https://doi.org/10.1186/s40001-024-02060-7

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  • DOI: https://doi.org/10.1186/s40001-024-02060-7

Keywords

European Journal of Medical Research

ISSN: 2047-783X

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