Chen-Chen Zhao,Tong Wu,Xian-Bin Kong,Chuan-Xin Liu,Yang Luo,Jian-Hua Duan,Zhu-Ting Li*

1Departments of Oncology,Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine,Tianjin 300250,China.2Tianjin Traditional Chinese Medicine Rehabilitation Centre,Tianjin 300250,China.3Departments of Cardiology,Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine,Tianjin 300250,China.4College of Traditional Chinese Medicine,Tianjin University of Traditional Chinese Medicine,Tianjin 301617,China.5Department of Metabolism and Endocrinology,Endocrine and Metabolic Disease Center,Luoyang 471003,China.6The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology,Luoyang 471003,China.7Medical Key Laboratory of Hereditary Rare Diseases of Henan,Luoyang 471003,China.8Luoyang Sub-center of National Clinical Research Center for Metabolic Diseases,Luoyang 471003,China.

Abstract Objective:To compare the safety and efficacy of Kang’ai injection combined with chemotherapy and chemotherapy alone in the treatment of non-small cell lung cancer.Methods:The related control and randomized studies from 1966 to October 01,2022,were retrieved in the following databases:China National Knowledge Infrastructure,Wanfang databases,Value In Paper,SinoMed,PubMed,Embase and Cochrane Library.A comprehensive literature search was conducted in 7 electronic databases identifying all the relevant randomized controlled trials.Cochrane handbook 5.2.3 was applied to evaluate the quality of included trials,and the RevMan 5.3 software was used to analyze data and assess the publication bias.Results:From the 16 studies reviewed,a total of 1,398 patients were included.Compared with docetaxel+cis-platinum chemotherapy alone,Kang’ai injection combined with docetaxel+cis-platinum chemotherapy showed significant effects in improving clinical response rate(RR:1.40,95% confidence interval(CI)(1.25,1.58)),quality of life score(Karnofsky score)(RR:1.53,95% CI(1.32,1.78)),traditional Chinese medicine syndrome(RR:2.01,95% CI(1.43,2.83))and safety(RR:0.62,95% CI(0.54,0.71)),the differences were statistically significant.Conclusion:Kang’ai injection may increase the therapeutic effectiveness,improve the quality of life,and reduce the toxicity of chemotherapy in patients with non-small cell lung cancer.These results require confirmation by further rigorously designed randomized controlled trials(PROSPERO registration number:CRD42020176917).

Keywords:non-small cell lung cancer;Kang’ai injection;chemotherapy;meta-analysis

Introduction

80% of lung cancer is non-small cell lung cancer.Most are in the middle and late stages when they are found.According to the latest statistics,there were 19.29 million new tumor cases and 9.96 million deaths worldwide[1].There were nearly 820,000 new cases of lung cancer and 710,000 deaths in China,leading the way.The treatment of lung cancer varies by pathological type and molecular characteristics.However,platinum-based chemotherapy still plays an essential role in non-small cell lung cancer,but its toxic side effects limit its further application[2].Therefore,it is urgent to find a drug that can enhance chemotherapy’s efficacy and reduce its toxic side effects.

“Shennong’s Classic of Materia Medica”lists astragalus as“top grade”.“Medicinal Ge Jue”believes:“astragalus root is used as a medicine,it is a tonic,has the effects of invigorating vitality,strengthening the spleen and stomach,draining the pus and relieving pain,invigorating blood,and treating critical illness”,“compendium of Materia Medica”,“Famous Doctors Supplementary Records”also think its beneficial qi deficiency effect;“Materia medica of Southern Yunnan”thinks ginseng can“cure the deficiency of Yin and Yang,lung qi weakness”.That bitter ginseng can“cool blood,antipyretic poison...detumescent poison,phlegm poison”,and so on.Modern studies have shown that astragalus,ginseng,and matrin,as the main components of Kang’ai injection,have good anti-tumor activity and can protect and stimulate the hematopoietic function of human bone marrow with good safety,and have become more commonly used anti-tumor drugs in clinical practice[3–6].

In the basic and clinical research progress of Kang’ai injection in non-small cell lung cancer(NSCLC):Kang’ai injection is extracted and refined from ginseng,matrine,and astragalus by modern high-tech preparation technology.Ginseng contains a variety of saponins and ginseng polysaccharides,which can promote the proliferation and directional differentiation of hematopoietic stem cells and promote the expression of bone marrow stromal cells and hematopoietic colony-stimulating factors,which can improve immunity and increase white blood cells.Astragalus and astragalus polysaccharides protect and improve the bone marrow hematopoietic microenvironment,improve the contact between bone marrow stromal cells and hematopoietic stem cells,and promote the secretion of endogenous cytokines such as hematopoietic colony-stimulating factor.Matrine(oxymatrine)is an alkaloid aqueous solution extracted from the traditional Chinese medicine(TCM)Sophora fragrans.It has inhibitory effects on the proliferation of tumor cells and vascular endothelial cells and the proliferation of vascular endothelial cells induced by tumor cells.Sanjie analgesic effect.Concurrent use of Kang'ai injection and chemotherapy can obviously play an adjuvant and synergistic role.It can effectively improve patients’quality of life with advanced NSCLC,especially in reducing adverse reactions such as nausea,vomiting,decreased appetite,and fatigue caused by chemotherapy.In particular,it can reduce the inhibitory effect of chemotherapy drugs on bone marrow,effectively prevent leukopenia,improve tolerance to chemotherapy,and greatly improve patients’compliance with treatment.It is worthy of further clinical observation and promotion.

In the research field of TCM treatment of NSCLC,high-level randomized controlled clinical studies and meta-analysis results are urgently needed to provide evidence-based medical support for clinical practice.So we use the system evaluation on the meta-analysis method to confirm the joint docetaxel+cis-platinum(DP)Kang’ai injection chemotherapy can significantly improve the clinical curative effect of patients with NSCLC,to control the disease development,improve the patients’quality of life,provide relevant evidence to support for Chinese medicine treatment of NSCLC.

Methods

Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines are conformed to in this meta-analysis and system review.

Registration: PROSPERO registration number is CRD42020176917

Data sources

Through Chinese electronic databases:China National Knowledge Infrastructure,Value In Paper,and SinoMed;English electronic database:PubMed,Embase,and Cochrane Library searched for randomized controlled trials(RCTs)published from 1966 to October 01,2022.The search strategies in the electronic databases are listed in Table 1.

Comprehensive retrieval was carried out.Then,the literature mentioning“randomized controlled”and“randomized grouped”was screened.In addition,we manually searched our own personal literature files.After reading the full text of the included literature and related articles,we collected the documents together in hard copy format for preservation.

Inclusion criteria

1.Papers published in Chinese or English.2.All RCT studies of Kang’ai injection combined with DP chemotherapy in treating non-small cell lung cancer from 1966 to October 01,2022.3.The diagnosis of NSCLC is confirmed by pathology and conforms to National Comprehensive Cancer Network guidelines and relevant expert consensus[2,7].4.At baseline,the characteristics of the two groups were evenly comparable.5.In terms of intervention,the treatment group was treated with Kang’ai injection combined with DP chemotherapy,while the control group was treated with DP alone.The regiments of the two groups should be completely consistent,and the course of treatment and drug dosage was not required.6.Outcome indicators mainly include:(1)Clinical response rate:according to the Response Evaluation Criteria for Solid Tumors,the response indicators are divided into measurable lesions and unmeasurable lesions:complete remission,partial remission,stable disease or no change,progression disease[8].Effective rate=(complete remission+partial remission)/total number of cases×100%.(2)Quality of life score(Karnofsky score)according to the relevant content of“practical oncology internal medicine”,efficacy evaluation criteria were formulated[9].Total effective rate=(significant effect+effective)/total cases×100%.(3)TCM syndrome score:the efficacy of TCM syndrome was evaluated according to the Guiding Principles for Clinical Research of New TCM Drugs(2002 edition)[10].Firstly,the quantitative scale of TCM symptom grading and scoring was developed,and the severity of symptoms was scored according to the severity of symptoms.Then,the cumulative comparison before and after treatment was carried out,and the efficacy was evaluated according to the integral ratio method.The response rate=(number of cases with significant response+number of cases with partial response)/total number of cases×100%.(4)Safety:according to the World Health Organization classification standards for toxic side effects of anticancer drugs,it is divided into 0–Ⅳdegrees.For details,please see Table 2 in the Statement of participants,interventions,Procedures,outcomes,and study design.

Table 1 The search strategies

Table 2 Statement of participants,interventions,comparisons,outcomes,and study design

Exclusion criteria

1.Patients and studies with non-pathological diagnosis.2.Non-randomized controlled trial study.3.In the control group,DP was not used,or TCM or proprietary Chinese medicine was used simultaneously.4.Only the first published literature should be retained for the repeated or identical literature.5.The design description of the study was unclear,and the efficacy indicators did not include any one of the outcome indicators of the study.6.Animal or cell experiments,etc.7.Documents with incorrect or incomplete data.

Data extraction

Two researchers conducted literature screening and data extractionindependently.First,they read the title and abstract of each paper.According to the title and abstract,still not sure,need to download the full text to read and judge.Finally,cross-check was carried out.In case of disagreement between two people,it would be solved in the form of discussion.Combined with the full text,the general information of the literature was extracted.

Bias risk assessment

The quality of the included studies was evaluated by using the risk of bias assessment tool recommended by the Cochrane Systematic Reviewers’Manual 5.2.3[11].The quality of each included study was evaluated one by one according to seven aspects,including randomization method,allocation hiding,subject blindness,outcome evaluation blindness,data integrity,selective reporting and other biases.The literature is classified into low-risk,high-risk and uncertain.

Statistical analysis

Revman 5.3 software was used to analyze the collected information carefully,and response rate(RR)or odds ratio(OR)was selected as the observation index of the count data for comparison.Measurement data,after evaluation,should be compared by means difference or standardized mean difference,both of which are expressed as effect values with 95% confidence intervals(95% CI).χ2 test was used to analyze the heterogeneity.According to the heterogeneity of test results,whenP＞0.1 and I2≤50%,it was generally considered that the statistical homogeneity was good,and the fixed effect model should be used for merging.WhenP≤0.1 and I2＞50%,the statistical heterogeneity is large,and the source and cause of heterogeneity should be analyzed[11].Random-effect models should be used actively after excluding the influence of significant clinical heterogeneity.Significant clinical heterogeneity was treated by subgroup analysis or sensitivity analysis,or descriptive analysis only.The funnel plot was drawn to determine the potential publication bias of included studies when more than 8 articles were included in an outcome measure.

Results

Retrieval results

596 Chinese literature and 5 English literature were retrieved.Software Note Express 3.2 was used for duplicate checking,and 108 literature were obtained after eliminating the repeatedly published literature.57 literature were preliminarily screened by reading literature titles and abstracts,and 16 literatures were finally obtained after reading the full text for multiple screening(Figure 1)[12–27].

Figure 1 PRISMA flow diagram.PRISMA,Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Study characteristics

The included studies were all in Chinese and published between 2009 and 2019[12–27].16 studies included a total of 1,398 patients with NSCLC cancer.In 16 studies,the experimental group was treated with Kang’ai injection combined with DP chemotherapy,while the control group was treated with DP chemotherapy alone,with 1–6 cycles of treatment[12–27].The basic characteristics of the included studies are shown in Table 3.

Table 3 Characteristics of included studies

Risk of bias assessment

Among 16 studies[12–27],5 studies adopted the correct randomization method[13,14,22,24,26],which is low risk,and 7 studies only mentioned randomness without describing specific Random method[12,15,16,18,19,25,27],4 studies are classified as a risk because of randomized approaches[12,17,19,22].All 16 studies are classified as risky because of distribution hiding and blinding.16 studies are at risk of selective reporting because of the unavailability of experimental designs.Sixteen studies were classified as low risk due to complete data(Table 4,Figure 2,Figure 3).

Table 4 Risk of bias for included studies

Figure 2 Risk of bias graph

Figure 3 Risk of bias summary

Meta-analysis

Clinical response rate.15 studies[12–17,19–27]reported the clinical response rate and were analyzed by heterogeneity test:there was good homogeneity among the included studies(I2=0%,P=0.84),and the fixed-effect model was used.The results showed that Kang’ai injection combined with DP chemotherapy had better clinical efficacy than DP alone.The difference was statistically significant.As shown in Figure 4.

Quality of Life Score.8 studies[13,15,16,20,22,23,25,27]reported the quality of life and analyzed by heterogeneity test:there was good homogeneity among the included studies I2=0%,P=0.82),and the fixed-effect model was used.The results showed that Kang’ai injection combined with DP chemotherapy had a better quality of life than DP alone.The difference was statistically significant.As shown in Figure 5.

TCM syndrome score.3 studies[13,16,25]reported the TCM syndrome score.Heterogeneity test analysis showed that the included studies had good homogeneity(I2=0%,P=0.88),the fixed-effect model was used for meta-analysis,and the results showed(RR=2.01,95%CI(1.43,2.83),Z=4.03,P＜0.00001),indicating that the TCM syndrome score of Kang’ai injection combined with DP chemotherapy was better than that of DP chemotherapy alone,and the difference was statistically significant.As shown in Figure 6.

Adverse events.In total safety,14 studies[12–24,27]reported adverse events,and digestive tract reaction and bone marrow suppression were more common.Heterogeneity test analysis:there was good homogeneity among the included studies(I2=43%,P=0.05).The fixed-effect model was used,and the results showed that(RR=0.62,95%CI(0.54,0.71),Z=7.01,P＜0.00001),indicatingthat the incidence and degree of adverse reactions of combination therapy were lower.The difference was statistically significant,and there were few adverse reactions above grade III in the two groups,which were related to the use of DP chemotherapy,and were effectively alleviated after drug withdrawal or symptomatic treatment.Therefore,Kang’ai injection has good safety.As shown in Figure 7.

Figure 4 The meta-analysis outcome of clinical response rate.CI,confidence interval.

Figure 5 The meta-analysis outcome of quality of life score.CI,confidence interval.

Figure 6 The meta-analysis outcome of TCM syndrome score.TCM,traditional Chinese medicine;CI,confidence interval.

Table Bias Publication bias Evaluated the publication bias of the total effective rate in each included literature

An inverted funnel plot was drawn with logRR as the abscess and estimate of effect(logRR)as the ordinate.As can be seen from the figure,the funnel plot was not completely symmetric,indicating a certain publication bias.As shown in Figure 8.

Figure 7 The meta-analysis outcome of adverse events.CI,confidence interval.

Figure 8 Funnel plot of response rate for the publication bias.

Discussion

Malignant tumor poses a severe threat to human health and is a major global public health problem[28].There are 19.29 million new cancer cases and 9.96 million deaths worldwide.Cancer deaths are expected to exceed 13 million by 2030,with 70 percent of global cancer deaths occurring in low and middle-income countries.China is the largest developing country with 4.57 million new cancer cases and 3 million deaths,including nearly 820,000 new lung cancer cases and 710,000 deaths,accounting for first place in cancer.The medical burden related to cancer is increasing,and the situation is very grim.Chinese doctors need to pay attention to promoting people’s cancer prevention and treating cancer patients.With the quickening pace of modern life,serious environmental pollution,and increasing population aging,the incidence and mortality rate of cancer are increasing year by year.Whether cancer diseases can be effectively controlled has become a common concern in China and even the world.

NSCLC cancer accounts for about 80% of lung cancer.At present,platinum-based combination chemotherapy is limited due to severe toxic and side effects brought by chemotherapy.In recent years,practice shows,TCM is very effective in treating common cancers by various means[29–31].Through a large number of clinical studies and experimental research,fully confirmed for cancer treatment should be on the premise of grasping the overall,both the disease itself and the“mark”,according to patients’personal physical disease and pathology,distinguishes the stages and syndrome differentiation of TCM,can alleviate patients’clinical symptoms,reduce to a great extent from pure western medicine treatment side effects,prolonging survival time and improving patients’quality of life[32–34].In terms of basic research,TCM can effectively inhibit tumor cell invasion and metastasis,induce tumor cell apoptosis,promote autophagy,and reverse drug resistance,etc.[35–38].

Kang’ai injection has the function of invigorating qi and enhancing immune function.Clinical is commonly used in lung cancer,primary liver cancer,rectal cancer,malignant lymphoma,and gynecological malignant tumor.Various causes of leukopenia and hypoxia and chronic hepatitis B treatment.Its pharmacological effects include the following four aspects:(1)it directly kills cancer cells(reduces the mass);(2)it can cut off the synthesis of the DNA molecular chain of cancer cells and inhibit the growth of cancer cells(control and stabilize the disease);(3)enhance physical fitness,improve the erosion of cancer cells;(4)it has analgesic,antiemetic and antidiarrheal effects.In addition,studies have shown that it can increase the level of white blood cells in patients,so it is especially suitable for use during radiotherapy and chemotherapy without toxic side effects.In clinical application,Kang’ai injection not only has a therapeutic effect on a variety of tumors,but it is also safe and non-toxic and has side effects[39–46].

This study spent a lot of time and effort collecting all published RCTS and retrieving 16 clinical studies related to Kang’ai injection combined with DP chemotherapy in the treatment of non-small cell lung cancer.The study showed that Kang’ai injection combined with curative chemotherapy effect is distinct,can effectively control the disease process,and can improve the patients’quality of life,improve the patients’TCM syndrome,objective reduce the incidence of bone marrow suppression and gastrointestinal side effects,the tip can be in a certain extent can be attenuated synergistic impact,to ensure the smooth implementation of chemotherapy.

The relevant conditions in the study were clearly specified when the inclusion and exclusion criteria were formulated in this study,so some deviations can be controlled.However,there are still limitations in this study.Firstly,randomization is an important factor in ensuring RCT study.In future experimental design,attention should be paid to more scientific randomization of the study subjects to avoid all kinds of deviations that may be caused in clinical design and experimental implementation to the greatest extent and to improve the quality of the study.Correctly using the blinding method is also vital to reduce artificial bias[47].In the future,experimental designers can use the blinding method for relevant personnel in the experiment,which can further reduce the possible bias,increase the rigor and improve the accuracy of the study.

Conclusion

Kang’ai injection combined with chemotherapy can effectively improve the clinical efficacy of patients with non-small cell lung cancer,and it is safe and has the effect of attenuating toxicity and enhancing efficacy.At the same time,it is hoped that researchers will widely carry out multi-center clinical research on the treatment of lung cancer by combining traditional Chinese and western medicine so as to push the cause of TCM to a new height.