Gastric cancer is a significant contributor to the worldwide incidence of cancer and cancer-related deaths. The high incidence and mortality of gastric cancer make it one of the most deadly of cancers. The primary clinical treatment is surgery, which increases the survival rate of patients within five years after treatment [
Some reports have shown that gastric cancer patients that underwent resection or radical surgery subsequently suffered from residual tumor metastasis, malnutrition, and other complications, due to the effects of surgical trauma on the immune function, making surgery a less preferred option for patients with compromised immunity [
In China, the proportion of patients receiving adjuvant chemotherapy is about 60% [
In China, many clinical randomized controlled trials have demonstrated that Chinese herbal compounds can be beneficial as a part of adjuvant chemotherapy and can improve immunity, reduce adverse reactions, and reduce the possibility of cancer recurrence and metastasis [
Jianpi Bushen (JPBS) is a Chinese medicine mixture of several compounds designed to invigorate the spleen and kidney (this is the meaning of Jianpi Bushen). JPBS is widely used in combination with chemotherapy in China for the clinical treatment of gastric cancer. In this study, a meta-analysis is performed to evaluate the clinical efficacy and safety of JPBS used together with chemotherapy for gastric cancer treatment to determine whether it can improve the clinical efficacy of treatment of gastric cancer, enhance immune function, reverse drug resistance, and reduce adverse reactions.
Clinical efficacy was evaluated using the WHO evaluation criteria for the recent treatment of solid tumors [
We performed literature retrieval electronically in the following databases: PubMed, EMBASE, MEDLINE, Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), Wanfang Data Information Site, and Chinese Science and Technique Journals Database (VIP). All of the searches were conducted in October 2017 and included all articles in those databases prior to that time. The search terms used are as follows: (“Jianpi Bushen” OR “bushenjianpi” OR “Jianpi Bushen and chemotherapy” OR “bushenjianpi and chemotherapy”) AND (“gastric cancer” OR “cancer of the stomach” OR “gastric carcinoma”). These terms were translated into Chinese when searching the Chinese databases. In the process of screening the literature, we identified two articles describing studies with compound E Jiao Jiang (compound donkey-hide gelatin slurry, abbreviated as FEJ) combined with chemotherapy for gastric cancer. Because FEJ contains JPBS, these studies were also included in the meta-analysis.
Two researchers (Xiaoqian Hao and Naijun Yuan) independently identified the relevant studies by reading the titles and abstracts and excluded documents that did not meet the inclusion criteria. The full text of the remaining studies was then read, and studies were assessed for inclusion in the meta-analysis based on the inclusion and exclusion criteria. To ensure accuracy and reliability, all the data and other clinical findings about the patients’ characteristics, treatment details, and other clinical outcomes were extracted independently using standardized data collection tables from two investigators (Fengjie Bie and Yurong Wang). To avoid subjective bias, the author’s name, the year and country of the paper published in the journal, and the titles were omitted in the data extraction. Two collaborators (Guijuan Zhang and Min Ma) jointly resolved disagreements about research content or data extraction. The other researchers (Xuefeng Jiang and Xiaoping Chen) independently extracted the data as follows: (1) the study design summary, including demographic characteristics, randomized methods, and implementation of blind methods, and (2) the sample size, short-term clinical effects, KPS scores, adverse reactions, and immunological expression in the treatment group and control group.
We assessed the risk of bias of the included studies according to the Cochrane Handbook for Systematic Reviews of Interventions (Chapter 8.5; Higgins, 2011). This assessment included seven aspects: random sequence generation, allocation concealment, blinding of participants and investigators, blindness of outcome assessments, incomplete outcome data, selective outcome reporting, and other biases. We judged each aspect as having low, unclear, or high bias based on the Cochrane criteria.
We used Review Manager 5.3 (RevMan 5.3) for data analysis. We analyzed the statistics by means of the mean difference (MD), with 95% confidence interval (CI). The heterogeneity of the included studies was assessed by
We identified 178 potentially relevant articles. After screening titles and abstracts, 80 articles were excluded as nonclinical studies, expert experience, or case reports. We reviewed the remaining 64 studies in depth, and 38 studies were excluded because they did not meet our inclusion criteria, 11 of which were not RCTs, 19 articles reported treatment performed in combination with other traditional Chinese medicine therapies, and 4 were excluded because the outcome index did not meet the demand. Therefore, a total of 26 articles [
Characteristics of included studies.
Included trials | Sample size (T/C) | Age (T/C) | Cancer stage | Intervention | Treatment course (C/W/D) | KPS | ||
---|---|---|---|---|---|---|---|---|
Gu et al., 2012 | 46 | 48 | 51.7 | 58.4 | - | FEJ + TCF, DC, FOLFOX4, DCF | 1 C, 4 W/C | >60 |
Nan and Yang, 2007 | 130 | 86 | 18–75 | III-IV | BJD + MFV | 1 C, 6 W/C | ≥60 | |
Zhang et al., 2010 | 30 | 30 | 45.2 ± 12.1 | 46.3 ± 11.8 | - | BJD + PTX, OXA, CF, 5-FU | 2–4 C, 14 D/C | - |
Li, 2008 | 16 | 16 | 53.2 | 53.6 | - | JBD + TF | 2 C, 3 W/C | ≥70 |
G. Q. Zhao and J. Z. Zhao, 2008 | 38 | 32 | 59.1 ± 9.4 | 57.8 ± 8.2 | I–III | JBD + MFP | 4 C, 28 D/C | - |
Le et al., 2015 | 45 | 45 | 62.5 ± 5.5 | 61.7 ± 5.8 | II–IV | JBD + FOLFOX4 | 4 C, 14 D/C | ≥60 |
Zhang et al., 2012 | 46 | 46 | 45.35 ± 6.7 | 48.35 ± 7.2 | I–IV | JBD + PTX, CF, 5-FU | 4 C, 2 W/C | ≥60 |
Zhang et al., 2016 | 30 | 30 | 48.52 ± 4.58 | 45.52 ± 5.58 | II-III | JBD + FOLFOX4 | 6 C, 1 W/C | - |
Du et al., 2011 | 120 | 120 | 55.2 | IV | JBD + FOLFOX4 | 2 C, 21 D/C | ≥60 | |
Wang and Liu, 2015 | 30 | 30 | 70.2 ± 2.3 | 72.6 ± 2.1 | III-IV | JBD + EPI, DDP, CAP | 4 C, 10 D/C | ≥60 |
Zheng et al., 2012 | 35 | 30 | 64 | 63 | IIIB-IV | JBD + L-OHP, 5-FU/CF | 2 C, 21 D/C | ≥60 |
Guo et al., 2015 | 121 | 118 | 73.1 ± 4.4 | 74.1 ± 4.0 | III-IV | JBD + XELOX | 6 C, 3 W/C | ≥60 |
Huang et al., 2010 | 20 | 20 | 46.7 ± 11.9 | 45.3 ± 12.5 | - | JBD + 5-FU, CF, DDP/PTX | 2–4 C, 2 W/C | - |
Mo and Xiao, 2008 | 32 | 32 | 47.5 ± 8.6 | 48.3 ± 7.9 | I–IV | JBD + FLP | 4 C, 28 D/C | >60 |
Lin and Wu, 2007 | 30 | 20 | 24~65 | - | JBD + PTX, CF, FU | 4 C, 2 W/C | - | |
Tian and Han, 2011 | 42 | 39 | 56.83 ± 8.74 | 55.72 ± 7.32 | - | JBD + DOC, DDP | 2 C, 21 D/C | ≥60 |
Lai et al., 2010 | 25 | 30 | 44 | 48 | - | JBD + TAX, 5-FU, CF | 4 C, 10 D/C | ≥50 |
Huang and Xu, 2015 | 45 | 45 | 62.5 ± 5.5 | 61.7 ± 5.8 | - | JBD + tegafur | 1 C, 4 W/C | ≥60 |
Sun et al., 2009 | 414 | 255 | - | - | JBD + CTX | 6 C, 4 W/C | - | |
Bu et al., 2013 | 30 | 30 | 48 | 49 | III A-IV | FEJ + XELOX | 3 C, 3 W/C | ≥60 |
Cui et al., 2015 | 30 | 30 | 61 | 57.5 | - | JBD + TAX, DDP | 6 C, 3 W/C | - |
Zhao and Zhang, 2012 | 38 | 32 | 69.7 | 71.3 | III-IV | JBD + L-OHP, 5-FU | 3 C, 2 W/C | >50 |
Ning et al., 1985 | 180 | 146 | 51 | III-IV | JBD + MMC, 5-FU, VCR | 1 C, 6 W/C | - | |
Wang et al., 2016 | 40 | 38 | 32–75 | 35–73 | II-IIIA | JBD + FOLFOX4 | 12 C, 4 W/C | ≥80 |
Liu, 2010 | 69 | 34 | 25–84 | 32–82 | II-III | JBD + FOLFOX4 | 6–8 C, 2 W/C | >60 |
Chen and Wang, 1996 | 40 | 20 | 58 | 60 | II-III | JBD + 5-FU, MMC, ADM | 1 C, 6 W/C | - |
Study selection flow diagram.
Eight trials [
Forest plot of improved clinical curative efficiency.
Ten studies [
Forest plot of improved KPS.
The expression level of CD3+, a marker of immune function, was measured and reported in 6 of the 26 included trials [
Forest plot of immune function.
Six trials [
Six trials [
The expression of CD4+/CD8+ was also reported by the same 6 trials [
NK+ levels were reported in six trials [
Three studies [
Finally, data were extracted from two studies [
Fifteen trials [
Forest plot of the blood system.
The rate of platelet (PLT) decrease was reported by nine studies [
Seven trials [
The change of gastrointestinal reaction was reported by twelve trials [
Forest plot of the nonhematologic system.
Five trials [
Five trials [
The incidence of myelosuppression was reported by three studies [
We utilized the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions (Chapter 8.5; Higgins, 2011) to evaluate the risk of bias for each included article. The included studies all claimed randomization, but the methods used for random sequence generation were reported by only 13 of the 26 trials [
Risk of bias summary of included studies.
Risk of bias graph: review authors’ judgments about each risk of bias item presented as percentages for all included studies.
Figures
Funnel plot of KPS score evaluation.
Funnel plot of immune function.
Funnel plot of safety evaluation of the blood system.
Funnel plot of nonhematologic safety evaluation.
Table
Chinese medicine composition table.
JPBS Chinese herbal medicine components (sorted by frequency) | Daily dose |
---|---|
Chinese medicine for invigorating the spleen | |
Dangshen [ | 0.01~0.03 kg |
Baizhu [ | 0.01~0.02 kg |
Fuling [ | 0.01~0.02 kg |
Huangqi [ | 0.01~0.03 kg |
Gancao [ | 0.01 kg |
Danggui [ | 0.01 kg |
Chenpi [ | 0.01 kg |
Banxia [ | 0.01 kg |
Baishao [ | 0.01~0.02 kg |
Shanzha [ | 0.01~0.02 kg |
Jineijin [ | 0.01~0.02 kg |
| |
Chinese medicine for tonifying the kidney | |
Gouqi [ | 0.01~0.02 kg |
Nvzhenzi [ | 0.01~0.02 kg |
Buguzhi [ | 0.01~0.02 kg |
Tusizi [ | 0.01~0.02 kg |
Yiyiren [ | 0.02 kg |
Ejiao [ | 0.01 kg |
Shudihuang [ | 0.01~0.02 kg |
Shanzhuyu [ | 0.01~0.02 kg |
Jixueteng [ | 0.02~0.03 kg |
Huangjing [ | 0.01~0.02 kg |
According to Chinese medicine, spleen and kidney deficiency is the basis of the incidence of gastric cancer [
Many studies have shown that the drugs contained in JPBS show antitumor properties and can improve immune function [
This meta-analysis suggested that JPBS intervention indeed improves the clinical effect and the quality of survival (KPS) and strengthens the immune function (CD3+, CD4+, CD8+, CD4+/CD8+, NK+, and macrophages). Additionally, JPBS reduced the adverse effects of chemotherapy such as blood toxicity (WBC, PLT, and Hb effects), gastrointestinal reaction, neurotoxicity adverse reaction, hand-foot syndrome, and bone marrow suppression. However, little effects on E-rosette were seen, possibly due to the small sample size. Future large-scale studies can address the details of these effects more comprehensively.
Overall, this analysis revealed the effectiveness and safety of the use of the traditional Chinese medicine Jianpi Bushen combined with chemotherapy for the treatment of gastric cancer. The effects are striking, and these results should serve as the scientific basis for worldwide use of this powerful treatment.
There are some limitations of this study that preclude us from reaching definite conclusions. First, according to the statement published by the members of the International Committee of Medical Journal Editors in September 2004, all clinical trials are required to be registered in a clinical trial registry before enrolling subjects in the study [
Traditional Chinese medicine Jianpi Bushen therapy combined with chemotherapy in the treatment of gastric cancer may really enhance the immunity of patients to improve the clinical efficacy and safety. However, the detailed mechanism of how JPBS works together with chemotherapy remains unclear and the quality of the included studies was relatively inadequate. Hence, it is necessary to carry out more high-quality, large sample, multicenter, prospective, randomized, double-blind clinical trials to further evaluate the efficacy of JPBS and chemotherapy treatment for gastric cancer.
All the authors declare that they have no conflicts of interest.
Yunbo Chen and Guijuan Zhang contributed equally to this paper.
This study was financially supported by the National Natural Science Foundation of China (nos. 81673979, 81473688, 81373314, and 81173265); Education Program of China for New Century Excellent Talents (no. NCET-13-0827); Traditional Chinese Medicine Administration Project of Guangdong Province, China (no. 20141070); Science and Technology Program of Guangzhou, China (no. 2014J4100104); Science and Technology Program of Guangdong, China (nos. 2014A020212672 and 2014A020210015); Natural Science Foundation of Guangdong Province, China (nos. 2016A030313114 and 2015A030313333); National Undergraduate Training Programs for Innovation and Entrepreneurship in 2015 (no. 201510559046); Guangzhou Municipal Enterprise Research and Development Institutions Construction Project (no. 201503010064); Fundamental Research Funds for the Central Universities/Research and Cultivation and Innovation Fund of Jinan University, Guangzhou, China (nos. 21615412, 21615464, and 21617467); Guangzhou Municipal Science and Technology Program in 2018 (Project Leader: Min Ma).