Meng-Qi Cheng, Yu-Wei Zhao,2, Ju-Ling Jiang, Hong-Gang Zheng, Bao-Jin Hua?

1. Guang' anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China

2. Beijing University of Chinese Medicine, Beijing 100029, China

Keywords:Hua Baojin Colorectal cancer Data mining Medication rule

ABSTRACT Objective: To study the prescription and medication rule of Professor Hua Baojin in the treatment of colorectal cancer through data mining, so as to provide reference for clinical treatment of colorectal cancer. Methods: The outpatient medical records of Professor Hua Baojin from June 2015 to October 2020 in Guang'anmen Hospital, China Academy of Chinese Medical Sciences were collected. TCM Inheritance Support Platform (V2.5) was used to analyze high-frequency drugs, drug properties, flavors, belonging meridians, common drug combinations, core combinations and new prescriptions. Results: A total of 500 prescriptions were included, involving 222 traditional Chinese medicines and 38 high-frequency (≥ 100)medicines, including Atractylodes, Poria cocos, Ginger, etc. The most common medicinal properties of drugs were warm, cold and mild, flavors were sweet, bitter and pungent,belonging meridians were spleen, stomach, liver and lung meridians. 36 groups of common drug combinations and 20 association rules were obtained by data mining, and 18 core combinations and 9 new prescriptions were evolved. Conclusion: Professor Hua Baojin takes recuperating spleen and stomach as the core in the treatment of colorectal cancer, attaching importance to regulating the rise and fall of qi, adding and subtracting on the basis of Xiangsha Liujunzi Decoction, flexibly selecting the drugs of dispelling blood stasis, resolving phlegm,detoxification and loose knots, and using both cold and warm in the prescription, tonifying and reducing at the same time.

1. Introduction

Global cancer statistics in 2018 show that colorectal cancer, as a common clinical malignant tumor of digestive system, ranks third and second in morbidity and mortality respectively [1]. In China,its incidence occupies the third place of malignant tumor, and the mortality occupies the fifth place [2]. Traditional Chinese medicine(TCM) has accumulated rich clinical experience in the treatment of colorectal cancer, and its advantages are mainly reflected in the prevention and treatment of postoperative recurrence and metastasis,reducing the adverse reactions of radiotherapy and chemotherapy,improving the quality of life, prolonging survival and so on.Professor Hua Baojin has been engaged in the clinical work of TCM oncology for nearly 30 years. He is the academic leader of the key disciplines of TCM oncology in Guang’anmen Hospital,the national outstanding clinical talent of TCM, and the honorary chairman of the Oncology Branch of China Association of Chinese Medicine. In this study, 500 prescriptions for colorectal cancer were selected by Professor Hua in the past 5 years, and data mining was carried out by using TCM Inheritance Support Platform (V2.5) to analyze the medication rules of the prescription for the treatment of colorectal cancer. with a view to providing reference for clinical treatment of colorectal cancer.

2. Materials and methods

2.1 Sources of prescriptions

This study is based on the outpatient medical record prescription of Professor Hua Baojin of Guang’anmen Hospital, China Academy of Chinese Medical Sciences, from June 2015 to October 2020.

2.2 Diagnostic criteria

The diagnosis of colorectal cancer was diagnosed by imaging examination and histopathology with reference to the relevant standards in the New Standard for diagnosis and treatment of Common malignant tumors (Colorectal Cancer Volume) [3].

2.3 Inclusion criteria

(1) The effective medical record prescription that meets the diagnostic criteria of colorectal cancer; (2) The age of the patient 18 years old; (3) The prescription form is TCM decoction or decoctionfree granule; (4) The selected prescription is aimed at the treatment of colorectal cancer in the main syndrome. The prescription for the treatment of fever and other concurrent syndromes (symptoms) shall not be included.

2.4 Exclusion criteria

(1) Tumors of the colon and rectum metastasized from other sites;(2) Patients with other serious primary diseases such as heart, liver,kidney and hematopoietic system; (3) Incomplete diagnostic data.

2.5 Data specification

Refer to the textbook of Chinese Material Medica [4] and the Great Dictionary of Chinese Medicine [5] to standardize the name of traditional Chinese medicine, such as Yunling is amended to Poria cocos and Huai Rhizoma Dioscoreae is amended to Rhizoma Dioscoreae and so on. For the processed Chinese herbs with special curative effect, the terms after processing should be retained, such as Millet Sprout is amended to Fried sprout, and Malt is modified to Fried malt.

2.6 Analysis software

The software of TCM Inheritance Support Platform (V2.5) is provided by the Institute of Chinese Materia Medica China Academy of Chinese Medical Sciences.

2.7 Prescription entry and verification

The above selected prescriptions were entered into the TCM Inheritance Support Platform (V2.5). After the input is completed,two reviewers independently review the data to ensure the accuracy of the data.

2.8 Data analysis

2.8.1 Extract prescription

Select the data source, enter "colorectal cancer" in the "Western Medicine Disease" option, and extract all the prescriptions for the treatment of colorectal cancer.

2.8.2 Statistics of drug use frequency

Click the "frequency statistics" button, show all the drugs in all prescriptions, arrange them in descending order according to the occurrence frequency of drugs, and then click the "Drug Frequency Export" button to generate CSV data files.

2.8.3 Analysis of the Law of Formula

Click the "prescription rule" button, set the "support number"to 150 and the "confidence" to 0.95. Through the three options of "medication mode", "law analysis" and "network display", the prescription law of the combination was analyzed, and the obtained core TCM was displayed in a visual view on the network.

2.8.4 Get new prescriptionsSet correlation degree as 7, penalty degree as 4, carry on the cluster analysis to the data, click the "extract combination" button, get the new prescriptions, and carry on the visual network display.

3. Results

3.1 Frequency of drug use

A total of 500 prescriptions for colorectal cancer were recorded in the system database, and 222 Chinese herbs were used, arranged in descending order from high to low, and 38 herbs were used more than 100 times, as shown in Table 1. The top 20 are Atractylodes,Poria cocos, Ginger, Jujube, Fried grain malt, Coloured malt,Tangerine peel, Astragalus, Crataegi fructus, Medicated leaven,Yangtao Actinidia Root, Indian strawberry, Rhizoma Pinelliae,Raw licorice, Radix cyathulae, Cortex eucommiae, Rhodiola rosea,Fructus Amomi, Raw Coix seed, Radix Aucklandiae.

3.2 Herb properties, flavors and belonging meridians

According to the analysis of herb properties and flavors of 500 prescriptions, the use frequency of warm, cold and mild herbs is the highest, while that of hot herbs is the lowest. As shown in Table 2, sweetness, bitterness and spice are used most frequently. The belonging meridian of herbs is ranked from high to low, and the top five are spleen meridian, stomach meridian, liver meridian, lungmeridian and kidney meridian, which is shown in Table 3.

Table 1 Herbs used more than 100 times in prescriptions

Table 2 The use frequency of herb properties, flavors in prescriptions

Table 3 The use frequency of herb belonging meridians in prescriptions

3.3 The rule of prescription based on association rules

By using the method of association rule mining, the support degree was set to 150 and the confidence was set to 0.95. The top three drug combinations in the prescription are Poria cocos - Atractylodes,Ginger - Jujube, Fried malt - Fried grain malt. The herbs with frequency ≥ 300 are shown in Table 4. The association rules for drug pairs are shown in Table 5. The association rules of prescription drugs are displayed on the network, as shown in figure 1.

Figure 1 Network display of drugs with support of 150 and confidence of 0.95

3.4 Analysis of prescription composition Law based on Entropy method

Based on the correlation degree analysis between drugs based on the improved mutual information method, as well as the number of selected prescriptions, different parameters were set to extract data for pre-reading, and then combined with empirical judgment, the correlation degree was set to 7 and the punishment degree was set to 4. Based on the entropy hierarchical clustering method based on software integration, 18 groups of drug core combinations can be evolved (see Table 6, core combinations for new party clustering).Nine new combinations of colorectal cancer are obtained by clustering (see Table 7), and the potential new prescriptions for colorectal cancer are shown in figure 2.

Table 4 Herb pairs with a frequency of ≥ 300 in the prescription

Table 5 Analysis of Drug Association rules in the Top 20 confidence level of prescription

Table 6 Herb combination based on complex system Entropy clustering

Table 7 New prescription based on unsupervised entropy hierarchical clustering

Figure 2 Correlation analysis of new prescription network based on entropy hierarchical clustering

4. Discussion

4.1 Etiology and pathogenesis

Colorectal cancer belongs to the category of "intestinal mushroom","visceral poison", "locked anal hemorrhoids", "accumulation",etc. in TCM. Deficiency of vital qi and stagnation of evil qi are the main factors in the pathogenesis of colorectal cancer. Professor Hua Baojin believes that the incidence of colorectal cancer is based on spleen deficiency. The deficiency of spleen and stomach,coupled with the influence of factors such as improper diet, feeling evil poison and emotional discomfort, lead to obstruction of qi,imbalance of ascending and descending of qi, abnormal transfusion and distribution of essence, blood and body fluid, accumulation of pathological products such as phlegm-dampness, blood stasis and evil poison in the large intestine, and obstruction of intestinal viscera, which aggravates the imbalance of qi operation and leads to the occurrence of colorectal cancer for a long time. It is emphasized that the imbalance of qi rise and fall is the basic pathological process and internal mechanism of the disease [6].

4.2 Treatment principles and methods

Through the analysis of herb belonging meridians, it is found that Professor Hua most likely use herbs which belonging to spleen meridian, stomach meridian, liver meridian and lung meridian in the treatment of colorectal cancer, which embodies the treatment method of regulating spleen and stomach and regulating qi.Through the herb properties, flavors, Professor Hua mainly uses sweet and warm herbs in the treatment of colorectal cancer. Sweet and warm herbs are used to tonify the spleen and stomach. Bitter and pungent herbs are the second and third in the herb flavors,respectively, which regulating the rise and fall of qi. Professor Hua takes Fuzheng Peiben as the basis, recuperating the spleen and stomach as the core, and believes that the spleen and stomach is located in the center, which is the acquired foundation, the hub of qi ascending and descending, the source of qi and blood, and the method of regulating spleen and stomach is the basis of regulating ascending and descending of qi[8]. It is the foundation to dispel the pathological products of tumor. He pays more attention to regulating the qi of the whole body and local intestinal organs, supplemented by removing dampness and resolving phlegm, removing blood stasis and detoxification to remove pathological products, so as to achieve the purpose of tonifying. He also adopts different treatment methods according to different stages of colorectal cancer [9]. The patients were mainly treated with Fuzheng Peiben in the early stage after operation, paying attention to restoring the circulation of spleen and stomach, and adding anti-cancer and detoxification products to prevent the recurrence of colorectal cancer after the gradual recovery of vital qi. During chemotherapy, patients were mainly treated by invigorating the spleen, tonifying the kidney and nourishing blood,supplemented by regulating qi, relieving gastrointestinal adverse reactions such as nausea, vomiting and diarrhea, and preventing and treating myelosuppression. In the late stage, we should pay attention to symptomatic treatment and use more products for relieving pain and regulating qi, so as to improve pain, fatigue and other symptoms,reduce patients' pain and improve the quality of life.

4.3 Prescription

In this study, the association rules obtained under the conditions of support of 150 and confidence of 0.95 well demonstrate Professor Hua Baojin's prescription for the treatment of colorectal cancer. As shown in figure 1, a total of 20 medicines are shown in the drug association network display map, which are Atractylodes, Poria cocos, Ginger, Jujube, Fried grain malt, Coloured malt, Tangerine peel, Astragalus, Crataegi fructus, Medicated leaven, Yangtao Actinidia Root, Indian strawberry, Rhizoma Pinelliae, Raw licorice,Radix cyathulae, Cortex eucommiae, Rhodiola rosea, Fructus Amomi, Raw Coix seed, Radix Aucklandiae. The following analysis of these high-frequency drugs is based on the results.First of all, Atractylodes, Poria cocos, Astragalus, licorice, Rhizoma Pinelliae, tangerine peel, Radix Aucklandiae and Amomum villosum constitute Xiangsha Liujunzi Decoction, invigorating the spleen and replenishing qi, resolving phlegm and removing dampness. Professor Hua likes to replace ginseng with astragalus to tonify Zhongqi and ascend spleen yang, often reused to 80g / 120g, Atractylodes and Poria cocos to invigorate the spleen and remove dampness to help spleen, licorice Yiqi Buzhong, Rhizoma Pinelliae dry dampness and phlegm, reducing adverse reaction and stopping vomiting,Tangerine peel, Radix Aucklandiae, Fructus Amomi, awaken spleen and stomach, smooth intestinal viscera qi, the above 8 medicines are combined, ascending and lowering, and make Zhongqi turn,clear turbid reset. Related studies have shown that [10-12] Xiangsha Liujunzi decoction can effectively improve the immune function and nutritional status of postoperative patients with colon cancer,improve the quality of life, resist adverse reactions of chemotherapy,prevent postoperative recurrence and metastasis, and significantly improve the postoperative survival time of patients. The combination of ginger and jujube means that ginger and jujube coincide with each other just like in Guizhi Decoction, on the one hand, to protect the spleen and stomach and prevent cold injury caused by drugs such as heat-clearing and detoxification, promoting blood circulation and removing blood stasis, and on the other hand, to raise stomach qi in order to "protect stomach qi and store body fluid" [13]. Fried grain malt, Coloured malt, Crataegi fructus, Medicated leaven to promote the movement of the spleen and stomach, which bring the source of qi and blood. Modern pharmacological studies have shown that Raw Coix seed has the effects of anti-tumor, enhancing immunity,antioxidation and so on. Experiments have shown that [15] Raw Coix seed can directly inhibit the proliferation and induce apoptosis of colon cancer SW480 cells in vitro. The above drugs fully reflect Professor Hua Baojin's academic idea of recuperating the spleen and stomach as the core and attaching importance to the rise and fall of qi in the treatment of colorectal cancer.

Yangtao Actinidia Root and Indian strawberry are commonly used anti-cancer and detoxification drugs by Professor Hua Baojin [16]. Rattan pear root taste sweet, astringent, cool, with the function of heat-clearing and detoxification, dispelling wind and dehumidification. Snake berries are first recorded in the Records of famous doctors, with sweet and bitter taste, cold nature and small poison, which belong to the meridians of lung, liver and large intestine. it has the effect of clearing away heat and detoxification,cooling blood and dissipating blood stasis. Modern studies have shown that [17-18] rattan pear root and snake berry have good antitumor activity, which can inhibit cell proliferation, stimulate cell apoptosis, block cell cycle, inhibit metastasis and so on, which are widely used in the treatment of digestive system tumors such as esophageal cancer, colorectal cancer, gastric cancer, liver cancer and so on. Professor Hua often uses 15-30g each of the two drugs to enhance the power of anti-cancer and detoxification, detumescence and removing blood stasis, not only to control the growth of solid tumor, but also to prevent recurrence and metastasis of postoperative patients. Rhodiola rosea has the laudatory name of "snow-covered ginseng", which was first included in the Four Medical Classics of Tibetan medicine. It plays an active role in the prevention and treatment of tumor by regulating immunity, inhibiting tumor cell proliferation, inducing apoptosis, reducing migration and inhibiting angiogenesis [19].

Cortex eucommiae, sweet and warm, tonifies the liver and kidney;Radix cyathulae, which tastes sweet and slightly bitter, is flat,belongs to the meridian of the liver and kidney, removes blood stasis and dredges the joints. The combination of the two drugs can not only benefit the liver and kidney, but also promote blood circulation and dredge menstruation, tonify but not stagnate, and live without injury. it is suitable for patients with colorectal cancer with deficiency and blood stasis, and improve their symptoms such as waist and knee pain, lower limb weakness and so on [20]. All kinds of drugs are used in the treatment of colorectal cancer, including invigorating the spleen, tonifying qi, resolving phlegm and removing dampness, detoxification and dispersing blood stasis.

4.4 Analysis of new prescriptions

Based on the unsupervised entropy hierarchical clustering, there are 18 core combinations and 9 new prescriptions for the treatment of colorectal cancer, reflecting the law of recessive drug use by Professor Hua Baojin. ①New prescription 1: Radix Rehmanniae,Asini Corii Colla, Cornu Cervi Degelatinatum nourishing yin and blood, warming kidney to help yang, Salvia miltiorrhiza, Chuanxiong Rhizoma, Notoginseng radix to remove blood stasis and activating blood. It is suitable for patients with colorectal cancer who have myelosuppression with deficiency of both yin and yang and blood stasis after chemotherapy.②New prescription 2: Tangerine peel,Astragalus, Radix Glehniae, Mori Folium replenishing qi, nourishing yin and clearing lung, which is suitable for patients with colorectal cancer who have cough due to deficiency of both qi and yin after lung metastasis. ③Tumor patients are often accompanied by sleep disorders. New prescription 3: Longan Arillus, Concha Margaritifera,Semen Ziziphi Spinosae, Polygoni Multiflori Caulis tonifying liver and nourishing blood, calming the liver-yang, nourishing the heart and mind, which is a common prescription for Professor Hua Baojin to improve sleep disorders in patients with colorectal cancer. ④New prescription 4: Uncaria calming liver extinguishing wind, Platycodon grandiflorum, Acorus tatarinowii, Perilla stem, lotus petiole can improve the liver wind, phlegm dampness disturbing the orifices and other symptoms of dizziness caused by dizziness.⑤New prescription 5: Baicalensis, Artemisia scopariae herb, Fructus gardenia, Radix Bupleuri, Mint clearing liver and purging fire, promoting dampness and removing heat, combined with new prescription 6: Cortex Phellodendri, Sophora, Herba Patriniae, Rhizoma smilacis glabrae can be regarded as Yinchenhao decoction and Longdan Xiegan decoction. It is suitable for the symptoms of dampness-heat accumulation in patients with colorectal cancer, such as acute weight,burning anus, dry mouth, bitter mouth, red tongue, yellow tongue and so on.⑥ New prescription 7: Aconite, Schisandra Chinensis,Cinnamon, Coptis, Mume Fructus, Rhizoma zingiberis using both cold and heat, including Wumei pill and Jiaotai pill, suitable for colorectal cancer patients with upper heat and lower cold, mixed cold and heat, dysphoria caused by poor sleep, abdominal distension,aversion to cold, diarrhea and other symptoms.⑦New prescription 8:the combination of Pseudobulbus Cremastrae seu Pleiones, Yangtao Actinidia Root, Indian strawberry and Prunella vulgaris to enhance the effect of anti-cancer and detoxification, clearing away heat and dispersing knots. ⑧New prescription 9: Suberect Spatholobus Stem,Curcuma Rhizoma, Angelica dahurica radix, Turtle Shell, Persicae Semen, activating blood circulation and softening, eliminating accumulation and removing dysentery, combined with all kinds of medicine, it is suitable for patients with obvious signs of blood stasis block in patients with liver metastasis of colorectal cancer. From the above new prescription multi-angle, multi-faceted medication can be seen, colorectal cancer as a local manifestation of the overall disease, its clinical signs are complex, when combined with the specific situation to be carefully analyzed. These new prescriptions provide new ideas for clinical drug selection, but they need to be used flexibly in combination with clinical practice.To sum up, Professor Hua Baojin, centering on the pathogenesis of spleen deficiency and qi imbalance, treats colorectal cancer under the guidance of invigorating the spleen, regulating qi, expelling pathogen and guiding stagnation, and adopts a stage-by-stage treatment strategy to constantly adjust the internal environment of the patient. to achieve balance and homeostasis with the tumor,in order to improve the quality of life and prolong the life span of patients. This study collates and excavates the medication rules of the prescription obtained by Professor Hua, which is consistent with Professor Hua's thinking on clinical differentiation and treatment,verifies and complements the experience summed up by individuals and teachers in the past, and obtains new information that can not be obtained in the arrangement of previous medical records. It provides data support for the in-depth excavation and inheritance of Professor Hua Baojin's clinical experience, and provides ideas for clinical treatment of colorectal cancer.

Author’s contribution

Professor Hua Baojin put forward the idea of the article, Cheng Mengqi, Zhao Yuwei and Jiang Juling collected outpatient medical records, Zhao Yuwei completed data entry, Cheng Mengqi and Jiang Juling checked the data, Cheng Mengqi completed the first draft of the article, and Professor Zheng Honggang and Professor Hua Baojin gave suggestions for revision.