|Year : 2018 | Volume
| Issue : 12 | Page : 1012-1018
Xi huang pills enhance the tumor treatment efficacy when combined with chemotherapy: A meta-analysis and systematic review
Qiujun Guo, Xinyao Xu, Shulin He, Yuan Yuan, Shuntai Chen, Baojin Hua
Department of Faculty of Graduate Studies, Beijing University of Chinese Medicine, Chaoyang, Beijing 100029, China
|Date of Web Publication||11-Dec-2018|
Beijing University of Chinese Medicine, No. 11 North Third Ring Road East, Chaoyang, Beijing 100029 and Department of Oncology, Guang'anmen Hospital, China Academy of Chinese Medicine Sciences, No. 5 Beixiange, Xicheng District, Beijing 100053
Source of Support: None, Conflict of Interest: None
Objective: To evaluate Xi huang pill combined with chemotherapy for tumor treatment in a meta-analysis.
Materials and Methods: We searched PubMed, Excerpta Medica Database, the Cochrane Library, the China National Knowledge Infrastructure, and the Weipu database and Wanfang Databases for eligible studies. We manually searched for printed journals and relevant textbooks. Statistical analyses were performed with Review Manager 5.3 (Cochrane Community, London, United Kingdom) and STATA 12.0 software packages.
Results: Fifteen studies were included. Xi huang pill combined with chemotherapy could enhance response (risk ratio [RR] =1.35, 95% confidence interval [95% CI]: 1.14–1.60, P < 0.0004), improve disease control (RR = 1.13, 95% CI: 1.05–1.21, P = 0.0006), prolong overall survival (hazard ratio = 0.80, 95% CI: 0.08–0.98, P = 0.03), improve patient quality of life (RR = 1.35, 95% CI: 1.10–1.67, P < 0.004), reduce 2–4° leukocyte (white blood cell) and platelet count due to chemotherapy (pooled RR = 0.42, 95% CI = 0.30–0.60, pooled RR = 0.42, 95% CI = 0.25–0.72, respectively).
Conclusion: Xi huang pill combined with chemotherapy can enhance the short-term efficacy and overall survival, alleviate treatment-induced side effects, and serve as a suitable regimen for the treatment of patients with tumors. However, the findings of the current study require validation in further high-quality trials.
Keywords: Chemotherapy, tumor, Xi huang pills
|How to cite this article:|
Guo Q, Xu X, He S, Yuan Y, Chen S, Hua B. Xi huang pills enhance the tumor treatment efficacy when combined with chemotherapy: A meta-analysis and systematic review. J Can Res Ther 2018;14, Suppl S5:1012-8
|How to cite this URL:|
Guo Q, Xu X, He S, Yuan Y, Chen S, Hua B. Xi huang pills enhance the tumor treatment efficacy when combined with chemotherapy: A meta-analysis and systematic review. J Can Res Ther [serial online] 2018 [cited 2020 Apr 10];14:1012-8. Available from: http://www.cancerjournal.net/text.asp?2018/14/12/1012/192795
| > Introduction|| |
Cancer is a leading cause of death and a major public health problem, with increasing incidence and mortality. Chemotherapy, radical surgery, radiotherapy, immune, and target therapies have attained a certain therapeutic effect;,,, however, it is not possible to completely control the disease in a number of patients with cancer. Complementary and alternative medicine (CAM) is another tumor treatment approach that has been adopted for the use by an increasing number of physicians and patients,,, and is efficacious in the treatment of disease, controlling tumor related-pain, improving patient quality of life (QOL), and as palliative care.,, Traditional Chinese medicine (TCM) is an important part of CAM and has been reported to display a broad range of biological effects, including, reducing toxicity and enhancing the efficacy of chemo/radio-therapy and regulating tumor microenvironment and cancer cells when applied to the treatment of tumors.,
Xi huang pill (XH), also termed Xi huang Wan, is a CAM currently used for tumor treatment. We previously reported that XH and its ingredients could inhibit the growth of tumor cells and cancer stem cells, prevent tumor invasion and angiogenesis, and regulate the tumor microenvironment. However, the clinical effects of XH on tumor treatment have yet to be quantitatively evaluated. Thus, the present meta-analysis was conducted to evaluate the effects of XH combined with chemotherapy for the treatment of patients with tumors. The present study was performed in accordance with the PRISMA statement [Supplementary File 1] and will endeavor to provide further clinical evidence of the effects of XH.
| > Materials and Methods|| |
The studies were explored from databases including PubMed (from January 1975 to March 2016), the Cochrane Library (from January 2010 to March 2016), Excerpta Medica Database (from January 1990 to March 2016), China National Knowledge Infrastructure (from January 1979 to March 2016), Weipu database (from January 1990 to March 2016), and Wanfang database (from January 1989 to March 2016). Each of the studies was investigated regardless of its publication type and without language restriction. Key words, MESH terms, and search strategies for each database were as follows: (Xi huang Wan OR Xi huang Pill) AND (cancer OR tumor OR neoplasm OR carcinoma OR sarcoma).
In addition to electronic databases, printed journals and relevant textbooks were manually searched from the libraries of Beijing University of Chinese Medicine, Peking Union Medical College, and Guang'anmen Hospital. Specialized experts in particular fields were also consulted for necessary supplements.
The inclusion criteria were as follows: (1) Types of studies: Randomized clinical trials (RCTs). (2) Participants: Adult human populations (age > 18 years) who were pathologically diagnosed with malignant neoplasms. (3) Interventions: The control group was treated with chemotherapy while the study group was treated with the same chemotherapeutics as in the control group, in addition to XH. (4) Outcomes: Short-term chemotherapy response rate, long-term survival rate, Karnofsky's performance score (KPS), and chemotherapeutic side effects such as myelosuppression and gastrointestinal symptoms.
Exclusion criteria: (1) The studies such as reviews, animal research, observational studies without a control group, or other types of non-RCT studies. (2) Trials concerning other nonneoplastic diseases or benign tumors. (3) Trials involving participants who had a nonpathological diagnosis had been previously subjected to chemotherapy, radiotherapy, or surgery, had a concurrent infection, other malignancies, or other serious medical illnesses. (4) Participants in the control group were treated with other antitumor TCM drugs. (5) The outcomes did not include short-term chemotherapy response rate or long-term survival rate.
Literature selection and data extraction
Two independent reviewers (Y. Y. and S. H.) evaluated each title, abstract, and citation, and selected relevant studies according to the inclusion criteria. Disagreements were discussed with and resolved by the third reviewer (X. X.). Data from the included studies were extracted separately by Q. G. and S. C. using a specific form and checked by B. H. The data obtained included the name of the first author, year of publication, gender, number of cases and controls, methods of randomization, interventions, treatment periods, and outcomes. The hazard ratio (HR) was calculated according to the Kaplan–Meier survival curve and survival outcome events as reported by Tierney et al.
Quality assessment of studies
The methodological quality of each RCT was independently assessed by X. H. and S. H. using the Cochrane Risk of Bias tool. Disagreements were discussed with and resolved by B. H.
Data synthesis and analysis
Statistical analyses were performed using Review Manager (RevMan) 5.3.5 software (Cochrane Community, London, United Kingdom) and STATA 12 software (StataCorp LP, College Station, Texas, United States of America). The total effectiveness rates of dichotomous data were pooled using risk ratios (RRs) with 95% confidence interval (95% CI). P <0.05 was considered statistically significant. The heterogeneity of the included studies was evaluated by the χ2 and I2 tests, and P < 0.10 or I2 > 50% was defined as indicating heterogeneity. The fixed-effect model was used in homogeneity data merge, and the random-effects model was suitable for the merging of heterogeneous data. Publication bias was evaluated by the visual assessment of the asymmetry of funnel plots (RevMan 5.3.5) and by Egger's test (STATA 12), with P < 0.05 indicating a potential bias. Sensitivity analysis was evaluated by reanalyzing the data using different statistical approaches.
| > Results|| |
A total of 166 studies were found during the initial search, among which 49 duplicated studies were removed in addition to a further 93 studies that met one or more of the exclusion criteria. On reading of the full manuscripts, a further 9 studies were excluded because they did not have a control group or had insufficient outcomes. Ultimately, 15 studies were included in the final analysis [Supplementary File 2: Figure 1].
Nineteen studies with 815 patients were included in the present study, with 417 patients in the experimental groups and 398 in the control groups. Characteristics such as sample size, gender, age, interventions, and outcomes for each study are described in [Table 1].
All the included studies applied randomization; however, 11 of them did not describe the randomization method in detail. All the included studies had complete data, but none of the studies mentioned the details of allocation concealment. Two studies had a high risk of bias with regard to the blinding of participants and personnel and outcome assessment because they did not apply the blind method. Two studies had a high risk of reporting bias with regard to the data as a number of the outcomes were reported incompletely so they could not be incorporated into the meta-analysis. Five studies had high levels of bias resulting from other sources, including that the survival analysis was conducted based on the different types of tumors or the clinical staging of tumors [Table 2], [Supplementary File 2: Figure 2] and [Supplementary File 2: Figure 3].
Xi huang pill prolonged overall survival following chemotherapy
Five studies compared the long-term survival between the experimental (XH combined with chemotherapy) and control groups (chemotherapy only). The pooled HR was 0.80, 95% CI: 0.08–0.98, P = 0.03 obtained from the Z-test. The heterogeneity was not significant (P = 0.26, I2 = 24%) [Supplementary File 2: Figure 4].
HX may enhance the response rate to chemotherapy in patients with tumors
Thirteen studies evaluated the response rate to chemotherapy. The response rate in the experimental group was significantly higher compared with that of the control group (RR = 1.35, 95% CI: 1.14–1.60, P < 0.0004 in the Z-test). The result did not indicate heterogeneity with the χ2 = 3.72, P = 0.99, I2 = 0%. Subgroups were categorized depending on the evaluation criteria utilized: Nine studies followed the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines, and four studies followed WHO guidelines. In the WHO subgroup, the response rate in experimental group was significantly higher compared with that in control group (RR = 1.34, 95% CI: 1.11–1.62, P = 0.002). In the RECIST subgroup, the response rate in experimental group was higher compared with that in control group, but the difference was not significant (RR = 1.39, 95% CI: 0.96–2.00, P = 0.08). There was not a significant difference between two subgroups (P = 0.87), and the evaluations of the two showed the similar results [Supplementary File 2: Figure 5].
Xi huang pill may enhance the disease control rate when combined with chemotherapy
Thirteen studies evaluated the disease control rate of chemotherapy. The disease control rate in experimental group was significantly higher compared with that in control group (RR = 1.13, 95% CI: 1.05–1.21, P = 0.0006 in the Z-test). The results did not indicate a high level of heterogeneity based on the χ2 test = 4.26, P = 0.98, I2 = 0%. Subgroups were formed of the following: Nine studies utilized the WHO guidelines, and four studies followed RECIST guidelines. In the WHO subgroup, the disease control rate in the experimental group was significantly higher compared with that in the control group (RR = 1.13, 95% CI: 1.05–1.22, P = 0.002). In the RECIST subgroup, the response rate in the experimental group was higher compared with that in the control group; however, the difference was not significant (RR = 1.12, 95% CI: 0.96–1.31, P = 0.16). There was no significant difference between the two subgroups (P = 0.91), and the two showed the similar results with regard to the disease control rates [Supplementary File 2: Figure 6].
Xi huang pill improves the quality of life for patients with tumors
The improvement of KPS and QOL quality of life index score was pooled for evaluation, and the RR was 1.35, 95% CI: 1.10–1.67, P < 0.004. The results indicated a significant heterogeneity (χ2 = 25.01, df = 10, P = 0.005, I2 = 60%). Subgroups were comprised the following: Eight studies followed Karnofsky's (KPS) guidelines, and three studies followed QOL guidelines. In the KPS subgroup, the improvement in the experimental group was significantly higher compared with that in the control group (RR = 1.24, 95% CI: 1.02–1.50, P = 0.03). In the QOL subgroup, the improvement in the experimental group was higher in comparison to that in the control group (RR = 2.12, 95% CI: 1.27–3.53, P = 0.004). Although there was a difference between the two subgroups (P = 0.05, I2 = 72.9%), and the two subgroups produced the same conclusions [Supplementary File 2: Figure 7].
Xi huang pill reduces the decline of 2–4° leukocyte (white blood cell) and platelet count due to chemotherapy
Five articles evaluated the decline of 2–4° white blood cell (WBC) and platelet (PLT) count among patients with tumors in the experimental and control groups (pooled RR = 0.42, 95% CI = 0.30–0.60, pooled RR = 0.42, 95% CI = 0.25–0.72, respectively). There was no significant heterogeneity between the two groups. The declination of the number of erythrocytes, 1–4° WBC and PLT count, abnormal liver dysfunction, and nausea and vomiting were also evaluated; however, there was no significance difference between the experimental and control groups [Table 3], [Supplementary File 3].
The results of the sensitivity analysis indicated that changing the study effect model did not change the results of the pooled analysis [Table 3], [Supplementary File 3].
The Egger's test is based on a linear regression of the standard normal deviate against its precision. In our analysis, we used the inverse of the standard error as the independent variable and the standardized estimate of the size effect (log RR upon its standard error) as the dependent variable. The estimate of the effect is considered biased if the intercept is significantly different from zero. The test results are shown in [Supplementary File 4]. The Egger's tests suggested that there significant publication bias was not present within our evaluations.
| > Discussion|| |
XH is used for the treatment of tumors in TCM for patients with noxious heat with blood stasis syndrome. XH contains four TCM ingredients: Three blood-activating and stasis-eliminating compounds (Ru Xiang [olibanum], MoYao [Commiphora myrrha], and She Xiang [Moschus]) and a heat-clearing and a detoxifying compound (Niu Huang [Calculus bovis]). Research has indicated that ingredients in XH such as bile acids, 11-keto-boswellic acid, and guggulsterone had a significant effect on the suppression of tumor cell proliferation.,, Muscone, another ingredient in XH, was observed to inhibit the expression of vascular endothelial growth factor and basic fibroblast growth factor, which are important for tumor angiogenesis. The aforementioned findings may partly indicate the underlying mechanisms of XH in extending the long-term survival and enhancing the short-term response rate when combined with chemotherapy. However, the method by which XH can improve QOL and reduce the declination of 2–4° WBC and PLT count in patients with tumors requires further investigation.
Meta-analysis is the highest form of evidence in evidence-based medicine, permits the user to perform statistical synthesis, and can be used to enhance the statistical power and produce a more credible conclusion. To clarify the clinical effects of XH in the treatment of tumors, the current meta-analysis was conducted, and the result showed that XH could prolong overall survival, enhance the response rate and disease control rate, improve QOL, and reduce the declination of 2–4° WBC and PLT count, when combined with chemotherapy. However, the current evaluation had a number of limitations. First, the quantity of RCTs for the investigation of the effects of XH in the treatment of tumors was insufficient, which led to the failure to conduct subgroup analysis based on the different types of tumor. Second, the included trials were all first published in Chinese, resulting in low-quality papers, and publication bias was evident in certain results. The randomization and concealment allocation of the majority of the studies were not clear, resulting in possible bias, and an overestimation of efficacy. Finally, the study periods were generally short, and only a small number of the included trials included a long-term follow-up.
However, despite the persistent problems that hinder the drawing of a definitive conclusion regarding the efficacy of XH, the present results provide useful information for clinicians, indicating that XH can enhance drug efficacy and reduce drug-induced toxicity caused by chemotherapy. Well-designed clinical trials are warranted to clarify the precise role of XH in this treatment setting.
| > Conclusion|| |
Xi huang pill combined with chemotherapy can enhance the short-term efficacy and overall survival, alleviate treatment-induced side effects, and serve as a suitable regimen for the treatment of patients with tumors. However, the findings of the current study require validation in further high-quality trials.
Financial support and sponsorship
This work was supported by the National Twelfth Five-Year Plan for Science and Technology Support Program of China (number 2014BAI10B01) and the National Natural Science Foundation of China (numbers 81202656, 81273718, and 81403346). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]