Analysis of the law of traditional Chinese medicine in prevention and treatment of gastrointestinal reaction caused by lung cancer chemotherapy

Yue-Jie Lin, Yue Luo, Lu-Yao Wang, Pei-Tong Zhang

Guang'anmen Hospital,China Academy of Chinese Medicine Sciences,Beijing 100053,China

Keywords:Lung cancer Chemotherapy Ggastrointestinal reaction Traditional Chinese medicine Medication rules

ABSTRACT Objective: To explore the law of traditional Chinese medicine in prevention and treatment of gastrointestinal reaction after chemotherapy for lung cancer. Methods: The literatures on prevention and treatment of gastrointestinal reaction after chemotherapy with Chinese medicine were searched from CNKI, Wanfang and VIP databases from the establishment of the database to September 2020. After screening, the database was established, and data mining was conducted by using IBM SPSS statistics 20.0 and IBM SPSS modeler 18.0 to summarize the medication rules of traditional Chinese medicine in the prevention and treatment of gastrointestinal reaction after chemotherapy for lung cancer. Results: (1) A total of 131 literatures involving 245 traditional Chinese medicines were included for data mining; (2)High frequency drugs include Astragalus membranaceus, liquorice, Poria cocos, Atractylodes macrocephala, Pinellia ternata, Codonopsis pilosula, Ophiopogon japonicus, coix seed,Pericarpium Citri Reticulatae, Radix Glehniae and so on; (3)The traditional Chinese medicine used is mainly tonifying deficiency medicine, resolving phlegm and relieving cough and asthma medicine, diuresis and dampness medicine, heat clearing medicine and antiphlogistic medicine. The medicine tastes bitter and sweet, and has cold and warm properties. The meridian tropism involves liver, lung, stomach, spleen and kidney;(4) Seven core TCM combinations were obtained by cluster analysis, and 24 drug pairs (groups) were obtained by association rule analysis. Conclusion: Through the data mining of traditional Chinese medicine for the prevention and treatment of gastrointestinal reaction after chemotherapy for lung cancer, we can find out the potential rules of traditional Chinese medicine prescription,and clarify the core Chinese medicine, which is helpful to provide certain reference for the development and research of drugs for the treatment of gastrointestinal reaction and modern clinical practice.

1. Introduction

Among all cancer types, the incidence and mortality of lung cancer are in the first place[1]. At present, chemotherapy is still the main treatment method for patients with advanced lung cancer or those who are unwilling to accept surgical treatment. However, adverse drug reactions caused by chemotherapy drugs often perplex both doctors and patients. Among them, gastrointestinal reaction are the most common side effects of chemotherapy, The incidence rate is 77.5%～97.4%[2,3]. Most patients with lung cancer chemotherapy have poor tolerance to gastrointestinal reactions, and are often prone to fear of chemotherapy, and even require the termination of chemotherapy, which seriously affects the evaluation of efficacy and tumor control. Nowadays, how to eliminate the adverse gastrointestinal reactions of patients with lung cancer chemotherapy is still a clinical research hotspot. A large number of clinical studies have shown that traditional Chinese medicine has definite clinical effects in preventing and treating gastrointestinal reactions in patients with lung cancer after chemotherapy. However, different doctors have different treatment ideas, prescription ideas are flexible and changeable, and the rules of medication are not yet clear, so indepth research is urgently needed. In order to explore and summarize the rules of using traditional Chinese medicine to prevent and treat digestive tract reactions after chemotherapy for lung cancer, the author collected and screened the Chinese Journal Full-text Database(CNKI), Wanfang Database, and VIP Database (VIP) literature in order to explore and summarize the rules of Chinese medicine for preventing lung cancer chemotherapy Regarding the prescriptions for the prevention and treatment of gastrointestinal reactions after lung cancer chemotherapy, using IBM SPSS Statistics 20.0, IBM SPSS Modeler 18.0 software, using statistical methods such as frequency analysis, cluster analysis, and association rules to analyze the rules of drug use, and to dig deeper into the rules of compatibility of prescriptions. Provide reference for clinical prevention and treatment of digestive tract reaction after chemotherapy.

2. Data and methods

2.1 Data source

With "chemotherapy", "digestive tract reaction", "gastrointestinal reaction", "traditional Chinese medicine" and "Chinese herbal medicine" as the key words, the literatures included in CNKI,Wanfang database and VIP database from the establishment of the database to September 24, 2020 were searched.

2.2 Literature inclusion and exclusion criteria

Inclusion criteria: ①Randomized controlled clinical research literature, the research object is clearly lung cancer patients, and the sample size of the treatment group is 20; ②There are clear indications for gastrointestinal reactions after chemotherapy; ③the observation group was treated with oral administration of traditional Chinese medicine compound (including decoction, granule, powder,pill), use clinical literature with clear prescriptions and records of curative effect;④ TCM compound prescriptions for different syndrome types in the same literature are selected according to different prescriptions. Exclusion criteria: ①Expert experience,individual cases, animal experiment research and review literature;②The main drug used in the observation group is the literature of traditional Chinese medicine injection; ③Lack of literature in the control group; ④Repeated publication of the same compound. Take only one of them.

2.3 Selection of literature data

According to the retrieval rules, 3381 literatures about gastrointestinal reaction after chemotherapy treated by traditional Chinese medicine were retrieved and imported into Noteexpress to remove duplicate literatures, and then two researchers manually screened the literature by reading the original text, and finally 131 literatures were included according to the inclusion and exclusion criteria.

2.4 Data standardization processing

Standardize the entered names, tastes, and meridians of traditional Chinese medicines based on the "Pharmacopeia of the People's Republic of China" [4], supplemented by "Chinese Materia Medica"[5] and "Dictionary of Chinese Materia Medica" [6] deal with.For example: "Raw dried ginseng" is standardized to "Ginseng","Yirenmi" is standardized to "Coix seed", "Hanliancao" is standardized to "Eclipta prostrata", and some drug names containing names of origin are standardized to generic drug names. For example, "Chuan Achyranthes" is standardized as "Achyranthes"and "Huai yam" is standardized as "Yam".

2.5 Data entry and analysis

The binary variable data conversion method is used to process, and a researcher enters the standardized data through the 2010 version of the Excel sheet, and records the Chinese medicine that appears in the prescription as "1", and if it does not appear, it is recorded as " 0",after completion, another researcher will check the data to ensure the accuracy and completeness of the data, and finally import IBM SPSS Statistics 20.0 and IBM SPSS Modeler 18.0 for statistical analysis.

3. Results

131 literatures involved 10906 patients with lung cancer. A total of 157 Chinese medicine prescriptions appeared, including 47 prescriptions (29.94%) of classic prescriptions and their additions and subtractions, such as Sijunzi Decoction, Shenlingbaizhu Powder,Bazhen Decoction, Banxia Xiexin Decoction plus Decrease,110 self-made prescriptions (70.06%). This may be because the gastrointestinal reaction after lung cancer chemotherapy is different from ordinary gastrointestinal diseases. It is caused by chemical treatment and the history of lung cancer. Therefore, in the application of traditional Chinese medicine, it is necessary to further summarize the etiology and pathogenesis of gastrointestinal reaction, and to further optimize the prescription of traditional Chinese medicine on the basis of classic prescriptions in order to achieve better curative effects.

3.1 Drug frequency and efficacy classification

IBM SPSS statistics 20.0 was used to describe the data.The 131 articles contained 245 single medicines, and the total frequency of medications reached 2276 times. Among them, 18 kinds of traditional Chinese medicine were used more than 20%, accounting for 41.52% of the total frequency. The top five herbs were Astragalus membranaceus, liquorice, Poria cocos, Atractylodes macrocephala and Pinellia ternata. See Figure 1 for details. Among them, 66 kinds(75.35% of the total frequency) were used more than 10 times.According to the "Chinese Materia Medica" [5] Chinese medicine efficacy classification standard, the Chinese medicines with a frequency of 10 times are classified. The highest total frequency of medication is tonic drugs.Among them, qi medicine is the main one. See Figure 2 for the specific efficacy classification of Chinese medicine.

Figure 1 Traditional Chinese medicine with a frequency of＞ 20% in the prescription of digestive tract response after chemotherapy for lung cancer

Figure 2 Efficacy classification of commonly used Chinese medicines

3.2 Analysis of channel tropism, medicine taste and drug property

The channel tropism, medicinal taste and drug properties of all Chinese medicines involved in the included literatures were statistically analyzed. If the same traditional Chinese medicine has different meridian tropism and medicinal taste, it will be counted separately. In 245 kinds of traditional Chinese medicine, there were 604 times of meridian tropism, 390 times of medicinal taste and 245 times of drug property. The descending order of meridian tropism frequency is liver meridian, lung meridian, stomach meridian, spleen meridian, kidney meridian, etc. the medicine tastes are mainly bitter,sweet and spicy, and the drug properties are mainly cold and warm.See Table 1 for details. The radar chart of meridian tropism, taste and property of traditional Chinese medicine are shown in Fig. 3, 4 and 5.

Figure 3 Radar map of drug distribution

Figure 4 Radar map of Chinese medicine flavor distribution

Table 1 Statistics of channel tropism, taste, property frequency and frequency of traditional Chinese Medicine

Figure 5 Radar chart of the medicinal properties of traditional Chinese medicine

3.3 Core Chinese medicine combination based on systematic clustering

Using IBM SPSS Statistics 20.0 software to systematically cluster the top 21 core Chinese medicines with the frequency of use,taking prescription as a case, single Chinese medicine as a variable,measuring the squared Euclidean distance of the binary variable,and obtaining a cluster analysis dendrogram (Figure 6) ), the vertical axis represents the corresponding Chinese medicine variables,and the horizontal axis represents the "distance" between Chinese medicines. The graphical rule indicates that the shorter the distance between the Chinese medicines, the higher the homogeneity. The traditional Chinese medicine with smaller "distance" is classified into one category, while the traditional Chinese medicine with larger"distance" is classified into different categories. At the same time,the distance of "distance" can be used to evaluate the consistency and correlation of the drug set, that is, the shorter the "distance",indicating that the relationship between the two is closer. Based on this, the rules obtained from the tree diagram are classified, as shown in Table 2.

Figure 6 Dendrogram of cluster analysis of core traditional Chinese medicine for digestive tract response after chemotherapy for lung cancer

3.4 Analysis of core Chinese medicine association rules

Use the Apriori algorithm in IBM SPSS Modeler 18.0 to discover the compatibility relationship of core Chinese medicines (21 flavors before the frequency) for the treatment of gastrointestinal response after chemotherapy, set the support to 15%, the confidence to 80%, and the maximum number of antecedents to 5, improve ≧1,ranked in descending order of support, and explored its potential TCM combinations, and a total of 16 core drug pairs were obtained.Among them, the rule with higher support for the 2 TCM drug pair is Hedyotis diffusa Astragalus, and the 3 TCM drug group The rules with higher support are Atractylodes, Licorice Poria cocos, Poria cocos, licorice Atractylodes, Codonopsis, Po Poria cocos ria Atractylodes, and the commonly used rules with higher support in the 4 traditional Chinese medicine group are Codonopsis,Licorice, Atractylodes Poria cocos. The detailed statistical results are shown in Table 3.

4. Discussion

Western medicine believes that the gastrointestinal reaction after chemotherapy is a group of gastrointestinal dysfunction symptoms caused by the damage of the gastrointestinal mucosa by chemotherapy drugs. According to the specific symptoms of thegastrointestinal reaction, traditional Chinese medicine classifies it as "vomiting", "diarrhea", and "fullness",and other categories. The chemotherapeutic drugs are foreign poisonous pathogens, which are easy to damage the spleen and stomach and affect the transport function of the spleen and stomach. If the spleen does not rise, it will not be able to transport, and if the stomach qi does not drop, it becomes nausea, vomiting, abdominal distension, diarrhea, loss of appetite, constipation and so on. According to traditional Chinese medicine, lung cancer is a disease caused by deficiency, excess due to deficiency, deficiency of the whole body and local reality.Deficiency of positive Qi and internal deficiency is the root cause of the occurrence and development of lung cancer [7]. With the progress of chemotherapy and other treatments, the pathogenesis of digestive tract reaction after chemotherapy is also complex. With the continuation of chemotherapy, the spleen and stomach qi deficiency affects the generation and operation of Qi and blood, involving the five viscera and six Fu organs, resulting in deficiency of liver and kidney essence and blood, deficiency of heart and lung qi and other viscera symptoms.

Table 2 Cluster analysis combination of core Chinese medicines for digestive tract response after treatment chemotherapy

Table 3 Association rule analysis of core Chinese medicines for digestive tract response after treatment of chemotherapy (21 flavors before frequency)

A statistical analysis of 245 traditional Chinese medicines in the retrieved literature shows that the top ten Chinese medicines used are Astragalus, Licorice, Poria cocos, Atractylodes, Pinellia,Codonopsis, Ophiopogon, Coix Seed, Tangerine Peel, and Adenophora Radix. According to "Chinese Materia Medica" [5]the efficacy classification standard of traditional Chinese medicine classifies the efficacy of 66 traditional Chinese medicines with a frequency of use 10 times. It is found that the most frequently used are the tonic drugs, and the Qi tonic drugs (astragalus, licorice,atractylodes, dangshen, yam, and Radix Pseudostellariae Etc.), yin tonic drugs (Ophiopogon japonicus, Adenophora, lily, Ligustrum lucidum, etc.); in addition, phlegm, cough and asthmatic drugs(pinellia, bamboo, inula, etc.), diuretic and dampening drugs (Poria cocos) , Coix Seed, etc.), heat-clearing medicines (oldenlandia diffusa, Habitat, Scutellaria barbata, etc.), and digestive medicines(malt, Shenqu, Gallus gallus domesticus, etc.) are also used in the forefront. On the basis of the lack of righteousness and the severe impact of chemotherapy drugs, lung cancer patients suffer from even more loss of righteousness, severe damage to the spleen and stomach, and a series of gastrointestinal symptoms. Qi can produce body fluid, and body fluid can carry qi. Qi deficiency can affect the production of body fluid, resulting in insufficient body fluid, large loss of body fluid, and loss of qi along with body fluid. In addition,harsh chemotherapeutic drugs are not only easy to damage yin,but also "strengthening fire and eating qi" as a result, both qi and yin are weak. Therefore, when treating lung cancer patients with gastrointestinal reactions after chemotherapy, attention should be paid to tonic deficiency, and to replenish qi and yin at the same time. And Gujin. Modern pharmacological studies have shown that a variety of tonic Chinese medicines can enhance the body's immune function and anti-tumor effect, and achieve the effect of strengthening the body and eliminating evil [8, 9, 10]. It is said in"Suwen Meridians": Drinking into the stomach, overflowing essence and qi, uplifting into the spleen, spleen qi to disperse essence,upflowing to the lungs, regulating the waterway, and down into the bladder. The spleen and stomach are damaged in patients with lung cancer after chemotherapy, and the function of transporting and analysing is ineffective, and the function of promoting clearing and reducing turbidity is ineffective, resulting in accumulation of food,phlegm, dampness, and heat toxin in the body. Therefore, clinically,on the basis of replenishing deficiency, commonly used to relieve phlegm, relieve cough and relieve asthma Medicine, diuresis and dampness medicine, heat-clearing medicine, and antiseptic medicine to achieve the effect of taking into account the specimen, dispelling evil and strengthening the body.

According to the meridian tropism analysis of traditional Chinese medicine, the liver, lung, stomach, spleen and kidney meridians are the main meridians, accounting for 78.31% of the frequency of all drugs. It is suggested that the lesion site of the disease involves upper coke lung, middle coke spleen, stomach and lower coke liver and kidney. It can be seen that the damage caused by chemotherapeutic drugs is a disease involving multiple systems. The treatment should not be limited to the spleen and stomach. From the perspective of the use of traditional Chinese medicines, they are mostly bitter,sweet, and pungent, accounting for 84.36% of the frequency of all medicines. Bitterness can clear diarrhea, dry dampness, purify fire and preserve yin, which indicates that phlegm, dampness and heat are the important pathogenesis of digestive tract reaction after chemotherapy;Sweet can nourish and invigorate the body, nourish and invigorate deficiency, eliminate food and stomach, strengthen the body to eliminate evil; pungent can be scattered, it can be moved. which indicates the important role of promoting qi and promoting blood circulation in the treatment. The analysis of the four-qi of traditional Chinese medicine shows that cold and warm drugs are used most frequently (72.24% of the total), suggesting that chemotherapy damages have two pathogenic mechanisms: cold and heat, which is in line with the complex and changeable pathogenesis of malignant tumors and chemotherapy drugs. The coexisting characteristics require clinical treatment based on syndrome differentiation, cold and warm treatment.

A systematic cluster analysis of core Chinese medicines found that core Chinese medicines can be grouped into 7 groups. C1:Astragalus membranaceus, an essential medicine for replenishing the spleen. As a commonly used medicine for TCM tumors, Astragalus membranaceus has been proven to regulate tumor immunity and inhibit tumors cell proliferation, inhibition of tumor cell migration and invasion, induction of tumor cell apoptosis, anti-vascular and lymphangiogenesis, and synergistic and attenuating effects of combined chemotherapy drugs [11]; C2: Pinellia ternata, Glycyrrhiza uralensis, Radix Codonopsis, Atractylodes Macrocephalae, Poria cocos, Sijunzi Decoction plus Pinellia ternata, play the role of Tonifying Qi, strengthening spleen, drying dampness and resolving phlegm. Studies have shown that Sijunzi Decoction can effectively reduce a series of gastrointestinal reactions after chemotherapy[12,13]; C3: single-drug Coix seed can strengthen the spleen and stop diarrhea. Studies have shown that Coix seed has an inhibitory effect on a variety of tumor cells. In addition, it also has a broadspectrum antibacterial effect and improves the body’s immunity [14];C4: Tangerine peel, ginger, angelica, yam, Amomum villosum, malt,are the addition and subtraction of Jianpi pill. Studies have shown that Jianpi pill can effectively reduce the digestive tract reaction caused by chemotherapy [15]. Animal experiments have shown that ginger can reduce the toxicity of chemotherapeutic drugs maintains the normal function of the gastrointestinal tract [16]; C5: Single-drug Oldenlandia diffusa. Oldenlandia diffusa is a very widely used drug in modern Chinese medicine for oncology. It can clear heat, remove dampness, detoxify and reduce swelling. The extract of Oldenlandia diffusa has anti-cancer and antibacterial properties,curb the growth and reproduction of tumor cells, induce tumor cell apoptosis,alleviate adverse drug reactions, etc. [17], C6: Fritillaria thunbergii,Platycodon grandiflorum and Trichosanthes kirilowii are composed of beimu gualou powder. Modern research shows that Fritillaria thunbergii and Trichosanthes kirilowii have anti-tumor, anti ulcer,anti-inflammatory and anti diarrhea effects [18,19]; C7: Schisandra chinensis, radix rehmanniae, Radix Adenophorae, and Ophiopogon japonicus, is the Nourishing the Stomach Decoction minus Polygonatum odoratum and rock sugar, adding Schisandra chinensis to play the role of clearing heat, generating fluid, nourishing yin and benefiting stomach.

Through the analysis of the association rules of the core drugs, it is found that the rule with higher support for the 2 traditional Chinese medicines is Hedyotis diffusa → Astragalus, and the higher support rules for the 3 traditional Chinese medicine group are Atractylodes,Licorice → Poria cocos, Poria cocos , Licorice Atractylodes,Codonopsis, Poria cocos Atractylodes, the commonly used rules with higher support among the four traditional Chinese medicine groups are Codonopsis, Licorice, Atractylodes macrocephala Poria cocos. Astragalus and Oldenlandia diffusa are compatible with qi, nourishing energy, detoxifying and dispelling masses. They are high-frequency medicine pairs for TCM tumors; Codonopsis,Atractylodes, Poria cocos, and Licorice are the composition of Sijunzi Decoction (Ginseng is replaced by Codonopsis), from"Taiping Huimin Heji Jufang", they are mainly used to treat"Rongwei Qi deficiency, visceral timidity, heart and abdominal distension, no appetite, bowel sounds, diarrhea, vomit, etc.Modern studies have shown that Sijunzi Decoction can effectively improve the body's resistance to tumor and the body's self-healing ability,and reduce the side effects of chemotherapy such as gastrointestinal reactions [20, 21].

To sum up, the traditional Chinese medicine for prevention and treatment of gastrointestinal reaction after lung cancer chemotherapy is mainly composed of tonifying deficiency medicine, resolving phlegm, relieving cough and asthma medicine, diuresis and dampness medicine, clearing heat medicine, and eliminating food medicine. The medicine tastes bitter and sweet, and its properties are cold and warm. Its meridian tropism involves liver,lung, stomach, spleen and kidney. Through cluster analysis and association rule analysis, the core combination of traditional Chinese medicine reflects the core treatment of digestive tract reaction after chemotherapy of lung cancer, that is to strengthen the spleen and replenish qi, dry dampness to dissipate phlegm, reduce adverse reactions and digestion and stomach, which can provide certain reference for clinical practice.