The Traditional Chinese Medicine Kangai Injection as an Adjuvant Method in Combination with Chemotherapy for the Treatment of Breast Cancer in Chinese Patients: A Meta-Analysis

Objective The traditional Chinese medicine Kangai injection as an adjuvant method in combination with chemotherapy has been widely used for treating breast cancer in clinical practice in China. This study systematically reviewed the clinical effect and safety of traditional Chinese medicine Kangai injection as an adjuvant method in combination with chemotherapy for treating Chinese patients with breast cancer. Methods Seven databases were searched in this study, namely, PubMed, the Cochrane Library, Embase, CNKI, Sino Med, VIP, and Wanfang Data. The timeframe of retrieval was set from the founding date of each database to November 1, 2017. Results Fifteen papers were included in this study. The quality of all the studies included was low. All the studies were carried out among the Chinese population. Meta-analyses showed that, compared with single-use chemotherapy, using a Kangai injection combined with chemotherapy to treat Chinese breast cancer patient can increase the total effective rate [RR = 1.15, 95% CI (1.01, 1.32), and P = 0.033], improve the quality of life [RR = 1.30, 95% CI (1.14, 1.48), and P ≤ 0.001], decrease the incidence of weight loss [RR = 0.49, 95% CI (0.32, 0.77), and P = 0.002], decrease WBC count [RR = 0.78, 95% CI (0.68, 0.89), and P ≤ 0.001], decrease incidence of renal and liver dysfunction [RR = 0.58, 95% CI (0.46, 0.73), and P ≤ 0.001], and decrease cardiac dysfunction [RR = 0.41, 95% CI (0.18, 0.94), and P = 0.035]. For the incidence of gastrointestinal adverse reactions [RR = 0.89, 95% CI (0.65, 1.21), and P = 0.452], decreased platelet count [RR=0.49, 95% CI (0.18, 1.30), and P = 0.150], and alopecia [RR = 1.01, 95% CI (0.89, 1.14), and P = 0.879], these two groups showed no statistically significant differences. Conclusion Kangai injection as an adjuvant method in combination with chemotherapy for treating Chinese breast cancer patients can improve their life quality and physical conditions and reduce the adverse reactions that result from chemotherapy. However, the present conclusion is only suitable for the Chinese population. The long-term, high-quality researches are required to further verify the above conclusions.


Introduction
The number of breast cancer patients has been growing in recent years.Breast cancer has become a major disease threatening women's health.Malignant tumors with high heterogeneity account for one-third of female malignant tumor patients.Over 1.5 million females in this world are newly diagnosed with breast cancer each year [1].In 2012, GLOBO-CAN evaluated 12.7 million cancer cases and 7.6 million cancer deaths and found that the incidence and mortality of breast cancer ranked number 1 among female malignant tumors [2].China is a country with low breast cancer incidence, but its incidence has experienced a sharp rise in recent years and is particularly significant in Shanghai, Tianjin, Beijing, and other large cities [3].It is estimated that breast cancer will take 20 years to become the malignant tumor with the highest incidence in Chinese females and the largest threat to women's health.For this reason, finding effective treatment methods is a top priority [4].and it is often combined with many chemotherapy drugs to treat tumors in clinical practice.(1) The major effective constituent of Astragalus is the dried root of the Leguminous Plant Astragalus, which has an antitumor effect.It is sweet in taste and warm in nature, with a meridian tropism in lung and spleen.With the highest immunological competence in Astragalus, Astragalus Polysaccharide can inhibit tumor cell proliferation and induce apoptosis.Some scholars have used Astragalus Polysaccharide in adjuvant chemotherapy for breast cancer and have found that Astragalus Polysaccharide causes fewer adverse effects, improves gastrointestinal reactions resulting from chemotherapy, and prevents the reduction of white blood cells.(2) The major effective constituents of Ginseng are Ginsenoside and Ginseng Polysaccharide, which are the major effective antitumor constituents extracted from Ginseng.To date, more than 80 monomer components have been separated from Ginseng to exert different antitumor effects via respective channels.(3) Kushenin, also known as oxymatrine, refers to a type of alkaloid that is extracted from the TCM Sophora alopecuroides.Recent studies have found that Kushenin can selectively kill tumor cells and inhibit tumor growth by changing the molecular sequence of the nucleic acids in cells, and such influence will be intensive and occur in many sites [5].The mechanism of action of Kang Ai injection to resist tumor may include improvement of immune function, direct inhibition of tumor growth, and inhibition of angiogenesis [6].However, whether this medicine can enhance the treatment effect and reduce the serious adverse reactions caused by chemotherapy is still debatable.Therefore, this article conducts meta-analyses to systematically review the safety and efficacy of Kangai injection as an adjuvant method in combination with chemotherapy for treating breast cancer and offers a theoretical basis for the integration of Chinese and Western medicine treatment for breast cancer as an evidence-based medicine.

Methods and Analysis
2.1.Search Strategy.Electronic network databases were searched via computer.Foreign databases included PubMed, Embase, and the Cochrane Library.Chinese databases included China National Knowledge Infrastructure (CNKI), China Biology Medicine Disc (Sino Med), the VIP information resource integration service platform (VIP), and Wanfang Data knowledge service platform (Wanfang Data).The retrieval scheme was mainly based on a combination of subject words and free words.The searched Chinese words were "Kangai zhusheye", "Ruxianai", "Ruxianzhongliu", "Ruai", "Ruxianzhongwu", "Ruxianzhongkuai", "Rufangzhongkuai", "Rufangai", "Rufangzhongliu" and "Xiongbuzhongliu", while the searched English words were "Kangai injection", "Kang'ai injection", "Breast Neoplasms", "Breast Tumors", "Cancer of Breast", and so on.The retrieval language was not limited, and the timeframe of the retrieval was from the founding date of each database to November 1, 2017.Nonelectronic papers and journals after 2010 were manually searched, and additional references were searched when needed to improve the recall ratio.See Supplementary Table 1 for the search strategy.

Type of Study.
Randomized controlled trials (RCTs) that use Kangai injection as an adjuvant method in combination with chemotherapy to treat Chinese breast cancer patients, regardless of blinding, were used in this study.The language was also not restricted to minimize publication bias.

Subject Investigated.
(1) Diagnostic criteria were as follows: patient diagnosed by a postoperative pathology slice; (2) patient whose life quality was assessed by the Karnofsky score and heart, liver, and kidney functions were normal before treatment, with no obvious complications; and (3) studies that did not use breast cancer drugs unrelated to this study  3) systematic review, important data report, and case report; the author not receiving a reply by contact article, so all data cannot be obtained; (4) therapeutic measures failing to meet the predetermined inclusion criteria; and (5) study on the type of animal test.

Intervention.
Experimental group: the chemotherapy regimen included a Kangai injection combined with conventional cytotoxic drugs [cyclophosphamide (CTX), pirarubicin (THP), fluorouracil (5-Fu), epirubicin, Adriamycin (ADM), etc. (medication dose, medication time and frequency, and treatment course)].Control group: the chemotherapy regimen included conventional cytotoxic drugs (medication dose, medication time and frequency, and treatment course).The age, gender, and other baseline conditions of the research objects were well-matched.

Outcome Indicators.
Statistical analysis was performed on the following measures after treatment: A total effective rate; B improvement of the quality of life; C incidence of weight loss; D incidence of decreased WBC count; E incidence of gastrointestinal adverse reactions; F incidence of renal and liver dysfunction; G incidence of cardiac dysfunction; H incidence of decreased platelet count; and 0 incidence of alopecia.
The evaluation of the short-term effect was based on the Evaluation Criteria for Solid Tumor [7].Complete remission (CR): carcinoma completely disappears for more than one month, with no recurrence or metastasis.Partial remission (PR): tumor maximum diameter * maximum vertical diameter decreases by over 50% for more than one month, with no enlargement of the other lesions.Stable disease (SD): lesion maximum diameter * maximum vertical diameter decreases by less than 50% or increases by less than 25% for more than one month.Progressive disease (PD): lesion maximum diameter * maximum vertical diameter increases by more than 25%, or there are new lesions.
Weight Changes.Weight gain: weight increased after treatment more than before treatment by ≥1 kg.Weight remained stable: there is increase <1 kg.Weight loss: weight decreased after treatment more than before treatment by ≥1 kg.
Quality of life was evaluated in accordance with Karnofsky Performance Status (KPS) [8].An increase of more than 10 points in the KPS is considered an improvement, while an increase of less than 10 points in the KPS is considered stable, and a decrease of more than 10 points in the KPS is regarded as a decrease.
We use NNT (the number of patients who must be treated in order to prevent one adverse event) when RR or OR > 1 or RD < 0; we use NNH (the number of patients who need to be treated over a specific period of time before one adverse side effect of the treatment will occur) when RR or OR > 1 or RD > 0.
2.2.6.Data Extraction.Two evaluators independently performed a search according to the search strategy, and preliminary screening was based on independent topics and abstracts of the search results, excluding obviously unqualified documents.A full-text methodology screening was conducted on the literature that may meet the inclusion criteria, and the authors were contacted when there was incomplete information.Then, the studies were cross-checked by two evaluators.Any disagreement on the conclusion of two evaluators was solved by a discussion.If such disagreement could not be solved through discussion, final judgment and arbitration may be made by a third party.Extracted contents included author's name, year of publication, number of samples, TNM staging, intervention, course of treatment, and observed indicators.

Quality Evaluation.
The selected investigators simultaneously evaluated the bias risk of the included studies based on the "risk of bias" evaluation tool in the Cochrane Handbook for Systematic Reviews of Interventions and relevant assessment guideline regulations [9].This risk evaluation tool contains 7 items: (1) random sequence generation; (2) allocation concealment; (3) blinding of the participants and personnel; (4) blinding of the outcome data; (5) incomplete outcome data; (6) selective reporting; and (7) other bias.The 7 items were evaluated as having a "high risk of bias," "low risk of bias," or "unclear risk of bias" according to the assessment criteria.

Data Analysis.
(1) Stata 12.0 software was used to perform the statistical analysis for the meta-analyses.(2) Select effect size: if an index of the included documents is a binary variable, the curative effect analysis statistics can be represented by relative risk (RR) and expressed by its confidence interval (CI); mean difference (MD) and 95% CI were used to represent continuous changes.(3) Homogeneity test: the steps for the statistical result of the homogeneity test: test the variation degree of various original research results and clearly include the degree of homogeneity of the experiment.(4) Meta-analyses: according to the result of the heterogeneous test,  ≥ 0.05 and  2 < 50 indicate that the results have good agreement and that the fixed effect model (FEM) may be used. < 0.05 and  2 ≥ 50 suggest that the heterogeneity of the results cannot be ignored.If the included studies still have clinical significance, the random effects model (REM) may be used.( 5) Sensitivity analysis: in those meta-analyses of the comprehensive factors combined with multiple outcomes, possible anomalous studies were ruled out before reevaluation.The results were compared with those of meta-analyses before the exclusion to figure out to what extent the excluded studies would influence the combined effect size and whether those meta-analyses are stable.If there is little difference between the two results, then the sensitivity of the results is relatively low, and the results are stable, indicating high credibility.( 6) Subgroup analysis: subgroup analysis was conducted on some indexes with high heterogeneity.For events in which quantitative synthesis was impossible and events with very low incidence, qualitative evaluation may be based on the description.In this study, Stata 12.0 software was used to conduct sensitivity analysis and subgroup analysis and draw a sensitivity analysis chart.

Publication Bias.
Publication bias occurs when positive data in similar research papers with statistical significance are more likely to be published on journals.This situation is hard to control.The funnel plot method is often used to detect publication bias.Stata 12.0 software was used in this study.Egger's test was performed to detect the publication bias in the outcome measures with ≥6 included studies or  2 ≥ 30%, and a funnel plot was drawn.If a large publication bias was found in a certain research index, the exact reason should be identified.If we were unable to find the cause of the bias, the stability of the current results should be tested by the trim and filling method.
After reviewing the titles and abstracts, irrelevant studies ( = 6), reviews ( = 2), and conference papers that did not provide data ( = 1) were eliminated.Again, documents not meeting the predetermined inclusion criteria ( = 6), redundant publications ( = 1), and other documents ( = 1) were ruled out by reading the full content.Finally, 15 randomized controlled trials were included (see Figure 1).

Improvement of the Quality of Life.
Seven studies [10,11,13,[15][16][17]20] reported the improvement of the quality of life, involving 438 patients (the experimental group included 221 patients; the control group included 217 patients).A heterogeneity test showed heterogeneity in these studies ( = 0.162,  2 = 34.8%).The random effects model was used for data analysis.Meta-analyses suggested that the improvement of the quality of life of the Kangai injection combined with chemotherapy in treating breast cancer was higher than that in the control group, which showed a statistically significant difference [ = 7, RR = 1.30, 95% CI (1.14, 1.48), and  ≤ 0.001] [RD = 0.21 > 0, CI (0.12, 0.30), and NNH = 5] (see Figure 5).Supplementary Figure S2 showed the results of the sensitivity analysis.

Publication Bias
Publication Bias.Stata 12.0 software was used to check the publication bias for the measures with  2 ≥ 30 and the number of studies ≥ 6 among the outcome measures. ≤ 0.05 suggested publication bias.Egger's test was carried out.If any large publication bias was found, the trim and fill method would be employed to check the stability of the result.
The specific results are showed in Supplementary Figure S6.Incidence of Decreased WBC Count.Egger's test suggested publication bias ( ≤ 0.001, 95% CI (−2.446743, 0.9831339)).The result of the trim and fill method with Stata 12.0 software showed that the data was unchanged.The specific results are showed in Supplementary Figure S7.
Incidence of Gastrointestinal Adverse Reactions.Egger's test revealed no publication bias ( = 0.553, 95% CI (−4.422824, 2.670058)).The specific results could be found in Supplementary Figure S8.The research results above suggested that the heterogeneity of the incidence of decreased leukocyte count was high, and there might be certain publication biases.This may be associated with the small quantity of included studies.

Discussion
Breast cancer is the most common tumor among modern females.Its incidence across the world in on the rise, ranking number 1 in all female malignant tumors in Western countries.At present, major breast cancer treatment involves chemotherapy and radiotherapy following surgical treatment.Chemotherapy is the most active and effective therapeutic measure during various periods of treating breast cancer [25].However, the adverse effects caused by chemotherapy are also cumbersome.As a result, reducing these adverse effects and improving the patient's quality of life are particularly important [26].
The occurrence and development of breast cancer are the result of the interactions among multiple factors and multiple mechanisms.A single therapeutic approach cannot address this complicated problem.As a traditional treatment means for breast cancer, traditional Chinese medicine (TCM) treatment is a promising approach for the research and treatment of breast cancer.In recent years, TCM treatment has become part of modern comprehensive therapy.More and more reports have proven its unique effect and its role in compensating for deficiencies in Western medicine treatment.Both the internal treatment and external treatment of TCM show good effects in treating postoperative complications, promoting postoperative recovery, enhancing the body's immunity, reducing chemotherapy and radiotherapy toxicity, and improving efficacy.Traditional Chinese medicine tumor treatment involves such methods as strengthening healthy Qi to eliminate pathogens, clearing heat and removing toxicity, promoting blood circulation to remove blood stasis, dispelling phlegm and eliminating dampness, and softening hardness to dissipate stagnation [27].In the present research,  cardiac dysfunction; however, there were no statistically significant differences between the two therapeutic methods in the incidence of gastrointestinal adverse reactions, decreased platelet count, and alopecia.The immune system related indicators of the patients in the combined treatment group were significantly improved after the treatment.Description of Kangai injection had played a positive role in improving the immune function of patients with tumor.The patients' immune function was improved and the patients' ability to resist the adverse effects of chemotherapy was also enhanced [28].In a word, Kangai injection was effective in the treatment of breast cancer.

Limitations and Advantages
Multidrug resistance of tumor cells is a major barrier in tumor chemotherapy and can promote tumor cells to generate resistance to various structures and types of drugs with different mechanisms of action, thus compromising the antitumor effect and leading to chemotherapy failure.The major effect of TCM in tumor treatment is not achieved by acting on only one target.Instead, such an effect is realized by strengthening the immune function [28], downregulating the expression of vascular endothelial growth factor (VEGF), regulating the expression of apoptosis-related genes, reversing multidrug resistance of the tumor cells, or directly killing the tumor cells.The effective constituents of many traditional Chinese medicines demonstrate good effects for inhibiting tumor cell proliferation and inducing differentiation with fewer or even no adverse reactions.The limitation of this research primarily lies in publication bias [29,30].The possible reasons are as follows: (1) Most of the clinical studies included in this research were carried out in China, and all the subjects were Chinese people.The current findings fail to prove that this combination therapy also has the same effect among other populations.(2) All the documents obtained are written in Chinese, and most of them do not report allocation concealment, blinding, and specific allocation principles.
Consequently, the quality of the documents included is relatively low.Additionally, these documents lack further follow-ups and fail to study the relapse rate and total survival time.Thus, the long-term effect of this combination therapy in this research remains unclear.(3) Researchers and periodical offices prefer to publish clinical research papers with positive results, leading to publication bias due to the lack of documents with negative results and thus resulting in an overestimation of the real therapeutic effect.

Conclusion
Kangai injection as an adjuvant method in combination with chemotherapy for treating Chinese breast cancer patients can improve their life quality and physical conditions and reduce the adverse reactions that result from chemotherapy.However, the present conclusion is only suitable for the Chinese population.The long-term, high-quality researches with a large sample size in different populations are required to further verify the above conclusions.
Random sequence generation (selection bias) Allocation concealment (selection bias) Blinding of participants and personnel (performance bias) Blinding of outcome assessment (detection bias) Incomplete outcome data (attrition bias) Selective reporting (reporting bias)

Figure 3 :
Figure 3: The summary of subgroup analysis for the risk of bias is based on the selection bias.

Figure 4 :
Figure 4: Meta-analyses results of Kangai injection combined with chemotherapy versus chemotherapy alone in terms of the total effective rate for breast cancer.

Figure 5 :
Figure 5: Meta-analyses results of Kangai injection combined with chemotherapy versus chemotherapy alone in terms of the improvement of quality of life for breast cancer.

Figure 6 :
Figure 6: Meta-analyses results of Kangai injection combined with chemotherapy versus chemotherapy alone in terms of the incidence of weight loss for breast cancer.

QiuFigure 7 :
Figure 7: Meta-analyses results of Kangai injection combined with chemotherapy versus chemotherapy alone in terms of the incidence of decreased WBC count for breast cancer.

Figure 12 :
Figure 12: Meta-analyses results of Kangai injection combined with chemotherapy versus chemotherapy alone in terms of incidence of alopecia for breast cancer.

Table 1 :
The basic characteristics of the 15 included studies.

Table 1 :
Continued.incidence of alopecia.EG: experimental group; CG: control group.Cyclophosphamide: CTX.THP.Fluorouracil: 5-Fu.Intravenous drip: ivgtt.Kangai injection: KAI.EPI.Adriamycin: ADM.Evidence-Based Complementary and Alternative Medicine 5 recently.The age, gender, case source, disease course, tumor classification, and chemotherapy cycle were not limited.2.2.3.Exclusion Criteria.Exclusion criteria include the following: (1) non-RCTs study; (2) inconsistent baseline information (the age, gender, case source, disease course, tumor classification, and chemotherapy cycle); ( reported the incidence of renal and liver dysfunction involving 728 patients (the experimental group included 402 patients; the control group included 326 Figure 8: Meta-analyses results of Kangai injection combined with chemotherapy versus chemotherapy alone in terms of incidence of gastrointestinal adverse reactions for breast cancer.Figure 9: Meta-analyses results of Kangai injection combined with chemotherapy versus chemotherapy alone in terms of the incidence of renal and liver dysfunction for breast cancer.Figure 10: Meta-analyses results of Kangai injection combined with chemotherapy versus chemotherapy alone in terms of incidence of cardiac dysfunction for breast cancer.Figure 11: Meta-analyses results of Kangai injection combined with chemotherapy versus chemotherapy alone in terms of incidence of decreased platelet count for breast cancer.theselectedTCM, the Kangai injection, is a TCM compound that aims to treat the tumor by strengthening the healthy Qi to eliminate pathogens under the guidance of the basic theory of traditional Chinese medicine.It has been widely used to treat various tumors of different types in China as an adjuvant treatment.Therefore, this research systematically evaluates the clinical effectiveness and safety of the TCM Kangai injection as an adjuvant means in combination with chemotherapy for treating Chinese breast cancer patients, thus providing theoretical evidence, in terms of evidencebased medicine, for the integration of Chinese and Western medicine in the treatment of breast cancer.The results of the present research indicated that, compared with chemotherapy alone, Kangai injection as an adjuvant method in combination with chemotherapy could increase the total effective rate and improve the quality of life, as well as decreasing the incidence of weight loss, decreased WBC count, liver and renal dysfunction, and abnormal Evidence-Based Complementary and Alternative Medicine