Compound Kushen injection combined with chemotherapy in the treatment of gastric cancer: a meta-analysis of randomized controlled trials

Su-Tong Liu , Kai-Qi Su , Wen-Xia Zhao*

1Department of Gastroenterology, the First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, 450008, China. 2 Department of Gastroenterology, Shanghai Municipal Hospital of Traditional Chinese Medicine Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200071, China.

Introduction

Gastric cancer (GC) is the most common malignant tumor of the digestive tract and the third cause of cancer mortality worldwide, which seriously endangers human health. In China, about 400,000 patients are diagnosed with GC each year, accounting for 42% of the world [1].On top of that, the majority of GC patients are not in a position to undergo surgery as they are founded to have been advanced stages, and it is estimated that approximately 300,000 GC patients lost their lives each year, according to the cancer statistics in China [2, 3].

Chemotherapy-based comprehensive therapy is currently considered to be one of the most commonly used treatments for those who cannot receive surgery or recurrence of GC patients [4]. Oxaliplatin or fluorouracil-based chemotherapy is currently one of the most commonly used chemotherapy regimens for the gastrointestinal tumor in China, and indeed achieved a certain effect [5, 6]. However, because chemotherapy drugs have a lack of targeting characteristics, while killing the tumor cells at the same time, normal cells are also affected by varying degrees of damage, resulting in many adverse drug reactions, such as gastrointestinal reactions, myelosuppression, liver, and kidney injury and a series of toxic side effects, these effects often lead to most patients cannot tolerate and have a lower quality of life, and even die [7-9]. Therefore, it is extremely urgent to find some drugs that can reduce the toxicity and improve the quality of life for GC patients during chemotherapy treatment.

Compound Kushen injection (CKI) has been widely used in the supplementary treatment of cancer patients in China since it was approved by the State Food and Drug Administration of China for two decades. Modern pharmacological studies found that CKI mainly contains matrine and oxymatrine [10], which have a significant impact on inhibiting tumors growth,relieving cancer pain, and reducing toxic side effects[11-13]. In view of the fact that more and more clinical researchers reported that CKI combined with chemotherapy in the treatment of GC patients, but not yet a systematic evidence-based analysis was published about the efficacy and safety of CKI for GC. Thus, in this study, clinical studies were extensively collected and meta-analysis was used to assess the clinical efficacy and safety of CKI in combination with chemotherapy in patients with GC.

Methods

Literature Search

Randomized controlled clinical studies of CKI in combination with chemotherapy in GC patients were searched in PubMed, EMBASE, Cochrane Library,Chinese Biological Medical disc, China National Knowledge Infrastructure, and Wanfang databases until January 20, 2018. The searching keywords contained:Compound Kushen, stomach neoplasms, randomized controlled trial and multiple synonyms for each term.Hand searching methods also applied to find additional eligible studies to avoid missing. The languages were confined to Chinese and English.

Inclusion and Exclusion Criteria

Articles that met the following requirements will be included: (1) the type of study was randomized controlled trials (RCTs); (2) all patients included were diagnosed and confirmed with GC; (3) the experimental group received CKI plus chemotherapy while the control group received chemotherapy alone; (4) on or more sufficient outcomes can be measured to evaluate efficacy and safety, such as effectiveness rates,performance status (the Karnofsky performance scale),and adverse drug reactions (ADRs).

The exclusion criteria were as follows: (1)non-intravenous injection of CKI or other dosage forms;(2) patients included with other malignant or non-malignant tumors; (3) review, case reports, animal experiments, and non-randomized controlled trials; (4)no enough outcome indicators can be extracted; (5)improper interventions, not combined with chemotherapy.

Data Extraction

Two investigators (Su-Tong Liu and Kai-Qi Su)independently reviewed all of the articles that met the inclusion criteria by reading titles and abstracts carefully. It was settled by the third investigator(Wen-Xia Zhao) if some disagreements were found.Extracted contents included the name of the first author,the time of publication, the number of patients, gender,clinical stage, the Karnofsky performance scale, details of the intervention, outcomes, adverse drug reactions and the Jadad score in each group. Corresponding authors were not contacted when the primary data were not available.

Methodological quality assessments

An open methodological quality assessment was carried out according to the seven-point Jadad scales [14]. The standard of evaluation included these followings: the generation of randomization, allocation concealment,blinding as well as the description of withdrawals and dropouts. After a rigorous scoring for each study, 0 to 3 points were considered to be low-quality studies and 4 to 7 were high-quality studies. In this study, only studies with a score of 3 or more were listed in this analysis.

Data Synthesis and Analysis

Review Manager 5.3 software was implemented to perform this analysis. The pooled odds ratio (OR) with 95% confidence interval (CI) was used to assess the efficacy and safety of CKI on patients with GC. The Cochran Q statistic and I2were implemented to evaluate the heterogeneity of included studies. If P ≤ 0.1 in the Q test or I2> 50%, we considered significant heterogeneity existed and the random effect model was used. If P > 0.1 or I2<50%, the fixed effect model was used [15], otherwise the fixed effect model was preferred. Meanwhile, a sensitivity analysis was performed to detect the sources of heterogeneity and assess the stability of those results by alternately eliminating each study. As for the publication bias, we performed Egger’s tests and Begg’s funnel plot to reveal it by STATA 14 software [16, 17], and P > 0.05 suggested that there was no significant publication bias.

Results

Search Results

Depending on the search strategy, a total of 354 related articles were collected. After removing duplications,155 articles were removed. Then titles and abstracts were screened, 86 studies were left. After further reading the full text, we excluded 77 studies according to the inclusion criteria. Finally, a total of nine published RCTs were included in this meta-analysis.The process of selection of the eligible studies was shown in Figure 1.

Characteristics of studies

Nine studies, with a total of 688 patients were enrolled,and 347 patients were treated with CKI plus chemotherapy, others were treated with chemotherapy alone. All studies included were randomized controlled trials published in China from 2010 to 2015. Six of these studies showed overall response rate [20, 21,23-26], five studies [19, 21, 24-26] reported the number of individuals who achieved increasing of KPS, and six studies [18, 19, 22, 23, 25, 26] showed the ADRs of patients. Only two studies had a Jadad score of 4 [18,19], and others scored 3 [20-26]. The baseline characteristics of the included articles were presented in Table 1.

Meta-analysis Results

Clinical efficacy of CKI plus chemotherapy

Six studies [20, 21, 23-26] that included 450 patients reported the overall response rate (ORR), there was no heterogeneity been found and the fixed effect model was implemented (I2= 0%, P = 0.61). The results showed that significant statistical difference was exited in patients who achieved ORR in CKI plus chemotherapy and chemotherapy alone groups. The OR for ORR was 1.69, 95% CI: 1.16-2.45, P = 0.006(Figure 2A). This result showed a higher ORR in the experimental group than that in the control group,which indicated that CKI combined with chemotherapy had a better clinical curative effect than chemotherapy alone in patients with GC.

Figure 1 The process of selection of the eligible studies

KPS score evaluation

Five studies’ outcome indicators included the number of patients with elevated KPS [19, 21, 24-26]. No significant difference in the heterogeneity test (I2= 0%,P = 0.81), so the fixed effect model was used and the value of OR for KPS was 2.24, 95% CI: 1.48-3.37, P =0.0001, which means that patients who underwent CKI plus chemotherapy treatment had a higher KPS score than those patients who underwent chemotherapy alone,so we can think that CKI combined with chemotherapy can improve the quality of life of GC patients when compared with chemotherapy alone (Figure 2B).

Safety evaluation

The results of meta-analysis of safety evaluation showed that CKI plus chemotherapy could reduce the incidence of adverse events for digestive tract reactions,leukopenia, thrombocytopenia, liver injury and renal injury. No significant heterogeneity was found in these data (all I2= 0%), then the fixed effect model was applied and the values of OR were: OR = 0.31, 95% CI:0.18-0.53, I2= 0%, P < 0.0001 (Figure 2C), OR = 0.38,95%CI: 0.22-0.65, I2 = 0%, P = 0.0003 (Figure 2D),OR = 0.51, 95% CI: 0.29-0.91, I2= 0%, P = 0.02(Figure 3A), OR = 0.34, 95% CI: 0.20-0.58, I2= 0%, P< 0.0001 (Figure 3B), OR = 0.51, 95% CI: 0.26-0.98, I2= 0%, P = 0.04 (Figure 3C), respectively. However,there was no any significant different in term of neurotoxicity between the two groups (OR = 0.59, 95%CI: 0.30-1.18, I2 = 0%, P = 0.14) (Figure 3D). This results suggested that CKI combined chemotherapy can reduce the risk of digestive adverse reactions,leukopenia, thrombocytopenia, liver injury and renal injury, but it can’t reduce the risk of neurotoxicity when compared with chemotherapy alone

Publication Bias and Sensitivity Analysis

Publication bias assessments were performed using Egger’s and Begg’s test based on the data for OR of ORR by STATA 14 software. No significant publication bias was discovered according to the Egger’s test (P =0.505) and Begg’s test (P = 0.851) (Figure 4). The sensitivity analysis showed similar results before and after exclusion of each study at a time, which demonstrated that the result was robust (Figure 5).

Table 1 Baseline characteristics of included studies

Figure 5 The sensitivity analysis based on the overall ORs for ORR

Discussion

Undoubtedly, as the main mean of tumor treatment,especially for advanced cancer, chemotherapy does benefit tumor patients. But the fact that it brings serious side effects constantly becomes a thorny problem for clinicians. Thus, how to reduce the toxic side effects of chemotherapy and improve clinical efficacy becomes an urgent clinical problem needs to be solved at present.

Traditional Chinese medicine injection has been extensively used in the adjuvant treatment of cancer patients in the course of chemotherapy for decades. It was confirmed that traditional Chinese medicine injection can improve the efficacy of chemotherapy,reduce the toxic side effects, improve the quality of life and achieve the optimization of treatment [25, 26].TCM believes that chemotherapy drugs can make human bodies be in weaknesses, disturb the coordination between the spleen and stomach, leading to Qi and Yin injuries and deficiency of Qi and blood.CKI is frequently used in patients with a malignant tumor for adjuvant therapy in China. CKI is mainly composed of matrine and oxymatrine, with the functions of heat removal, cooling blood,dehumidification, and detoxification. Matrine has a beneficial effect against tumor invasion and growth and distant metastasis in nude mice[27, 28]. Matrine and oxymatrine could inhibit the proliferation of tumor cells,and decrease the expression of iNOS, COX-2, and P53[29]. Several previous experimental studies have confirmed that CKI can reduce the production of cytokine, enhance the activation of adenyl cyclase and induction of liver microsomal enzymes so that CKI has better protection of liver function [30-35]. Furthermore,these assisted anti-tumor effects were confirmed in several studies by raising objective response rate,improving the karnofsky score and reducing the incidence of adverse events in combination with chemotherapy for liver cancer [36, 37] and lung cancer patients [38, 39].

In this study, we are the first using meta-analysis evaluated the clinical efficacy and safety of CKI combined chemotherapy in the treatment of GC. A total of nine RCTs with 688 patients were involved, and the pooled results showed that CKI plus chemotherapy could further benefit patients with gastric cancer when compared with chemotherapy alone. In the CKI plus chemotherapy group, the clinical efficacy and quality of life were significantly improved and the toxic and side effects were significantly reduced, such as digestive tract reactions, leukopenia, thrombocytopenia, liver injury, and renal injury. This comprehensive treatment of integrative could be a relatively superior treatment option for gastric cancer patients.

Several limitations exist in our study. First, though extensive search and strict screening were carried out,all of the trials included were retrieved in China, with low methodological quality, which might cause some bias. Secondly, although there was no heterogeneity in subgroup analysis, the dosage and duration of CKI and the chemotherapy regimen in each study was not completely unified, which increased the risk of heterogeneity. In addition, the sample size of 688 cases may result in a decline in our research persuasion,which may affect our results to some extent. Therefore,large-scale RCTs using strict methodology are needed in order to examine our findings. Nevertheless, our study still provides some reliable information for the clinical research of CKI adjuvant therapy for GC.

Conclusion

CKI combined with chemotherapy can improve the clinical efficacy and quality of life, and increase safety.However, our findings need to be confirmed further by high-quality studies.

Reference

1. McCracken M, Olsen M, Chen MS Jr., et al. Cancer incidence, mortality, and associated risk factors among asian americans of chinese, filipino,vietnamese, korean, and japanese ethnicities. CA Cancer J Clin 2007, 57: 190-205.

2. Chen W, Zheng R, Baade PD, et al. Cancer statistics in china, 2015. CA Cancer J Clin 2016,66: 115-132.

3. Nie Y, Wu K, Yu J, et al. A global burden of gastric cancer: The major impact of china. Expert Rev Gastroenterol Hepatol 2017, 11: 1.

4. Chi Y, Yang J, Yang S, et al. Phase i dose-finding study of sorafenib with folfox4 as first-line treatment in patients with unresectable locally advanced or metastatic gastric cancer. Chin J Cancer Res 2015, 27: 239-246.

5. Park SC, Chun HJ. Chemotherapy for advanced gastric cancer: Review and update of current practices. Gut Liver 2013, 7: 385-393.

6. Haghighi S, Kasbkar H, Esmaeilpour K, et al.Oxaliplatin, 5fluorouracil and leucovorin (folfox4)as first line chemotherapy in elderly patients with advanced gastric cancer. Asian Pac J Cancer Prev 2016, 17: 3277-3280.

7. Bano N, Najam R, Qazi F, et al. Gastrointestinal adverse effects in advanced colorectal carcinoma patients treated with different schedules of folfox.Asian Pac J Cancer Prev 2014, 15: 8089-8093.

8. Loree JM, Mulder KE, Ghosh S, et al.Retrospective comparison of capox and folfox dose intensity, toxicity, and clinical outcomes in the treatment of metastatic colon cancer. J Gastrointest Cancer 2014, 45: 154-160.

9. Carlomagno C, Matano E, Bianco R, et al.Adjuvant folfox-4 in patients with radically resected gastric cancer: Tolerability and prognostic factors. Exp Ther Med 2010, 1: 611-617.

10. He X, Fang J, Huang L, et al. Sophora flavescens ait.: Traditional usage, phytochemistry and pharmacology of an important traditional Chinese medicine. J Ethnopharmacol 2015, 172: 10-29.

11. Luo C, Zhong HJ, Zhu LM, et al. Inhibition of matrine against gastric cancer cell line mnk45 growth and its anti-tumor mechanism. Mol Biol Rep 2012, 39: 5459-6464.

12. Peng X, Zhou D, Wang X, et al. Matrine suppresses proliferation and invasion of sgc7901 cells through inactivation of pi3k/akt/upa pathway. Ann Clin Lab Sci 2016, 46: 457-462.

13. Wang ZY, Li GS, Huang HX. clinical observation on treatment of 75 mid-late stage cancer patients with yanshu injection. Zhongguo Zhong Xi Yi Jie He Za Zhi 2006, 26: 681-684.

15. Higgins JP, Thompson SG, Deeks JJ, et al.Measuring inconsistency in meta-analyses. Bmj 2003, 327: 557-560.

16. Zhang LQ, Tian SQ, Yu YH, et al. Compound Matrine Injection in Combination with FOLFOX-4 Regimen for Gastric Cancer: A Clinical Study.Evaluation and Analysis of Drug-use in Hospital of China 2010, 10: 1030-1031.

17. Liu YH. The clinical effect of "Yanshu" adjuvant therapy for elderly patients with gastric cancer. Jilin Tradit Med 2010, 31: 5332.

18. Han QL, Zhang LW, Li J, et al. Curative effect observation of Compound Matrine Injection combined with chemotherapy in treatment of gastric cancer. Chin Med Herald 2011, 8: 68-69.

19. Qin HB, Zhang J, Zhang JW. Treatment of Advanced Gastric Cancer with Composed Kushen Injection Combined with FOLFOX4 Adjuvant Chemotherapy. Med J Wuhan Univ 2012, 33:215-218.

20. Song SJ, Shen JH, Zhao HD, et al. To observe the curative effect of compound Kushen injection in combination with chemotherapy for patients with gastric cancer. World Health Digest 2013, 39:189-190.

21. Feng XM, Fu FX, Han WQ, et al. The curative effect of compound Kushen injection combined with chemotherapy in the treatment of advanced gastric cancer. National Medical Frontiers of China 2013, 8: 63+78.

22. Gao XP. A study of compound kushen injection combined with chemotherapy in the treatment of gastric cancer. Yiyao qianyan 2014, 8: 107-108.

(3)尽管氢气在主流中的扩散程度随进口Mach数和压强的增大而减弱, 但由于Mach数和压强的增大会导致截面空气质量流量大大增加, 最终使得沿流向截面上的氢气掺混效率和燃烧效率都增大.

23. Liu KH, Wang YZ. Clinical observation of compound Kushen injection combined with FOLFOX4 chemotherapy for advanced gastric cancer Asia-Pac Trad Med 2014, 10: 103-104.

24. Ning SQ, Xu HS, Yang C. Clinical study of Compound Kushen Injection combined with FOLFOX4 chemotherapy in treatment of advanced gastric cancer. Drugs & Clinic 2015, 30: 275-278.

25. Qi F, Zhao L, Zhou A, et al. The advantages of using traditional Chinese medicine as an adjunctive therapy in the whole course of cancer treatment instead of only terminal stage of cancer. Biosci Trends 2015, 9: 16-34.

26. Qi F, Li A, Inagaki Y, et al. Chinese herbal medicines as adjuvant treatment during chemo-or radio-therapy for cancer. Biosci Trends 2010, 4:297-307.

27. Zhao ML, Song LQ, Xia ZM, et al. Anti-tumor effect of matrine in the gastric cancer nude mice model. J Dalina Med Univ 2016, 38: 546-548.

28. Zhu DD, Yao Sk. Anti-tumor effect of matrine on human hepatocarcinoma cell HepG2 tumor in nude mice. Drugs & Clinic 2016, 31: 736-741.

29. Zhang Q, Ru QG, Liu Y, et al. Chemoprevention of matrine and oxymatrine on prevention of inflammation related colorectal cancer. Chin Tradit Herbal Drugs 2016, 47: 1548-1553.

30. Zhao Z, Fan H, Higgins T, et al. Fufang kushen injection inhibits sarcoma growth and tumor-induced hyperalgesia via trpv1 signaling pathways. Cancer Lett 2014, 355: 232-241.

31. Ou X, Chen Y, Cheng X, et al. Potentiation of resveratrol-induced apoptosis by matrine in human hepatoma hepg2 cells. Oncol Rep 2014, 32:2803-2809.

32. Xu W, Lin H, Zhang Y, et al. Compound kushen injection suppresses human breast cancer stem-like cells by down-regulating the canonical wnt/beta-catenin pathway. J Exp Clin Cancer Res 2011, 30: 103.

33. Fan CX, Lin CL, Liang L, et al. [enhancing effect of compound kusheng injection in combination with chemotherapy for patients with advanced non-small cell lung cancer]. Zhonghua Zhong Liu Za Zhi 2010, 32: 294-297.

34. Ueng YF, Tsai CC, Lo WS, et al. Induction of hepatic cytochrome p450s by the herbal medicine sophora flavescens extract in rats: Impact on the elimination of theophylline. Drug Metab Pharmacokinet 2010, 25: 560-567.

35. Lao Y. Clinical study on effect of matrine injection to protect the liver function for patients with primary hepatic carcinoma after trans-artery chemo-embolization (tae). Zhong Yao Cai 2005,28: 637-638.

36. Ma X, Li RS, Wang J, et al. The therapeutic efficacy and safety of compound kushen injection combined with transarterial chemoembolization in unresectable hepatocellular carcinoma: An update systematic review and meta-analysis. Front Pharmacol 2016, 7: 70.

37. Sun Q, Ma W, Gao Y, et al. Meta-analysis:Therapeutic effect of transcatheter arterial chemoembolization combined with compound kushen injection in hepatocellular carcinoma. Afr J Tradit Complement Altern Med 2012, 9: 178-188.

38. Zhao Z, Liao H, Ju Y. Effect of compound kushen injection on t-cell subgroups and natural killer cells in patients with locally advanced non-small-cell lung cancer treated with concomitant radiochemotherapy. J Tradit Chin Med 2016, 36:14-18.

39. Wang S, Lian X, Sun M, et al. Efficacy of compound kushen injection plus radiotherapy on nonsmall-cell lung cancer: A systematic review and meta-analysis. J Cancer Res Ther 2016, 12: 1298.