A Chinese medicine formula for treating advanced colorectal cancer and its application

Abstract

The present invention relates to a Chinese medicine formula for treating advanced colorectal cancer, which is made of the following raw materials in parts by weight: 8-12 parts of Cuscuta seeds, 3-7 parts of Rhizoma Euryale, 8-12 parts of Herba Mori, 1-5 parts of Euryale, 3-7 parts of Herba Hedyotis diffusae, 1-3 parts of Scorpio, and 3-7 parts of Herba Precoci. The present invention also provides the use of the Chinese medicine composition. Its advantages are: in the prescription, the Cuscuta seeds nourish the liver and kidney, strengthen the spleen and stop diarrhea, the Herba Mori clears away heat, detoxifies and removes dampness, and activates blood circulation and reduces swelling, which are all monarch drugs; the Herba Mori warms and nourishes the liver and kidney, the Herba Euryale strengthens the spleen and removes dampness and stops diarrhea, the Herba Hedyotis diffusae clears away heat, detoxifies and removes dampness, and the Herba Precoci is a minister drug for soothing the liver and regulating qi, activating blood circulation and removing blood stasis, and softening and dispersing nodules; the Herba Scorpio attacks toxins and dissipates nodules, dredges the meridians and relieves wind, and is an adjuvant drug, and all the drugs are used together to play the effect of strengthening the body and detoxifying.

Description

Technical Field

[0001] The invention relates to the technical field of traditional Chinese medicines, and in particular to a traditional Chinese medicine formula for treating advanced colorectal cancer and an application thereof. Background Art

[0002] Colorectal cancer (CRC) is a common malignant tumor in the gastrointestinal tract. The latest data show that the incidence and mortality of colorectal cancer are still among the top three in the world. A 2019 International Cancer Survey Report shows that in China, colorectal cancer is the second most common malignant tumor and its mortality rate ranks fifth. Nearly 50%-60% of patients have entered the advanced stage when diagnosed, which has become the main cause of related deaths.

[0003] In the past five years, fluorouracil drugs combined with oxaliplatin or irinotecan combined with bevacizumab, cetuximab or panitumumab have been widely used as the first-line treatment for advanced colorectal cancer and have been found to prolong the progression-free survival time by an average of 2.6 months. However, many clinical studies including CALGB 80405 and FIRE-3 have shown that the overall progression-free survival (PFS) is an average of 8.5 months, and the longest does not exceed 15 months. Chinese herbal medicine, as an important part of traditional Chinese medicine, has been found by many studies in recent years to have the effect of enhancing efficacy and reducing toxicity when combined with chemotherapy. Therefore, how to further prolong the survival of advanced colorectal cancer needs to be solved urgently.

[0004] Chinese patent document CN201610020840.3 discloses a Chinese medicine granule for treating colon cancer and a preparation method thereof. The Chinese medicine granule is composed of 25-30 parts of radix pear roots, 10-15 parts of hawthorn charcoal, 15-20 parts of liushenqu, 10-15 parts of astragalus, 10-15 parts of roasted licorice, 6-8 parts of radix aconiti lobatae, 8-10 parts of cat's claw, 8-10 parts of tongguangsan, 15-20 parts of red dates, 10-15 parts of poria, 10-15 parts of raspberry, 8-10 parts of dendrobium, 6-8 parts of codonopsis pilosula, 6-8 parts of ophiopogon japonicus, 10-15 parts of cypress seeds, 8-10 parts of dodder seeds, 10-15 parts of silkworm cocoons, 15-20 parts of psoralea corylifolia, and 10-15 parts of polyphylla. This traditional Chinese medicine can remove blood stasis and detoxify, reduce swelling and disperse nodules, replenish qi and nourish blood, reduce swelling and disperse nodules, thereby inhibiting tumor reproduction, controlling tumor spread and metastasis, and significantly improving the quality of life and prolonging survival.

[0005] At present, there is no report on the Chinese medicine formula for treating advanced colorectal cancer and its application. Summary of the invention

[0006] The purpose of the present invention is to provide a Chinese medicine composition for treating advanced colorectal cancer in view of the deficiencies in the prior art.

[0007] Another object of the present invention is to provide use of a Chinese medicine composition in the preparation of a drug for treating advanced colorectal cancer.

[0008] To achieve the above object, the technical solution adopted by the present invention is:

[0009] The invention provides a traditional Chinese medicine composition for treating advanced colorectal cancer. The traditional Chinese medicine composition is prepared from the following raw materials in proportion by weight: 8-12 parts of dodder seeds, 3-7 parts of iris root, 8-12 parts of parasitic plant, 1-5 parts of euryale fruit, 3-7 parts of oldenlandia diffusa, 1-3 parts of scorpion and 3-7 parts of cyperus rotundus.

[0010] Preferably, the Chinese medicine composition is made of the following raw materials in the following weight ratio: 9-11 parts of Cuscuta seeds, 4-6 parts of Pyrus truncatula roots, 9-11 parts of Viscum album, 2-4 parts of Euryale ferox, 4-6 parts of Hedyotis diffusa, 1-2 parts of Scorpio, and 4-6 parts of Fructus cyrtonemae.

[0011] More preferably, the Chinese medicine composition is made of the following raw materials in the following weight ratio: 10 parts of Cuscuta seeds, 5 parts of Pyrus truncatula roots, 10 parts of Viscum album, 3 parts of Euryale ferox, 5 parts of Hedyotis diffusa, 1 part of Scorpio, and 5 parts of Fructus cyrtonemae.

[0012] Preferably, the preparation method of the Chinese medicine composition comprises the following steps:

[0013] S1. Raw material selection: take any of the above-mentioned Chinese medicine raw materials in proportion;

[0014] S2. Raw material cleaning: put the Chinese medicine raw materials into the container and clean them for 5-20 minutes;

[0015] S3. Soaking raw materials: Soak the cleaned drugs for 1 hour;

[0016] S4. Hydration of raw materials: decoct the soaked medicine until the volume is reduced to 200ml.

[0017] Preferably, the dosage form of the Chinese medicine composition is granules, tablets, capsules, oral liquids, mixtures or syrups.

[0018] To achieve the above second purpose, the technical solution adopted by the present invention is:

[0019] The present invention provides use of any of the above-mentioned traditional Chinese medicine compositions in the preparation of a drug for treating advanced colorectal cancer.

[0020] The present invention has the advantages that:

[0021] In the formula, Cuscuta australis nourishes the liver and kidneys, strengthens the spleen and stops diarrhea, while Pyrus nobilis root clears away heat, detoxifies, promotes dampness, and promotes blood circulation and reduces swelling, all of which are the main medicines; Viscum album warms and nourishes the liver and kidneys, Euryale ferox strengthens the spleen, removes dampness and stops diarrhea, Herba Hedyotis diffusae clears away heat, detoxifies and removes dampness, while Semen Preparata soothes the liver and regulates qi, promotes blood circulation and removes blood stasis, softens and disperses nodules, all of which are the assistant medicines; Scorpion attacks toxins, disperses nodules, dredges meridians and calms wind, and is the adjuvant medicine. All the medicines are used together to achieve the effect of strengthening the body and detoxifying. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 is a flow chart;

[0023] Figure 2 shows the baseline characteristics of the patients (a is before PSM; b is after PSM);

[0024] Figure 3 This is the survival curve of patients with advanced colorectal cancer (control group vs. Chinese medicine group); P value comes from the Log-rank test;

[0025] Figure 4 This is the forest plot for subgroup analysis of the effects of the Chinese medicine group and the control group on overall survival of advanced colorectal cancer;

[0026] Figure 5 It is a single factor and multi-factor analysis chart;

[0027] Figure 6 To conduct a multivariate analysis of the effect of traditional Chinese medicine on overall survival of advanced colorectal cancer;

[0028] Figure 7 This is a high-frequency Chinese medicine chart;

[0029] Figure 8 This is the high-frequency Chinese medicine clustering dendrogram;

[0030] Fig. 9 This is the grouping diagram of Chinese medicine after high-frequency Chinese medicines are clustered;

[0031] Fig.10 The graph shows the correlation results between the first group and the second group;

[0032] Fig.11 This is a network diagram for the association analysis of traditional Chinese medicines, in which the frequency of use of traditional Chinese medicines is proportional to the color and font. The lines between traditional Chinese medicines represent the degree of association (the number of times when drug A appears, drug B also appears), and the color and thickness of the lines are proportional to the degree of association. A: the first group, B: the second group;

[0033] Fig.12Representative analysis of core drugs; A: The effect of different TCM treatments on the overall survival of advanced colorectal cancer. In mOS, only the difference between TTS (44.57) vs. Control (30.30) was statistically significant (P = 0.010). B: The effect of the kidney-tonifying and detoxifying group (TTS) and the overall TCM group on OS. The mOS were TTS (44.60) vs. TCM (39.10), P = 0.341, HR = 1.24 (95% CI: 0.79-1.96);

[0034] Fig.13 This is a multiple comparison chart of the effects of different treatments on patients’ overall survival;

[0035] Fig.14 It is a guided association analysis between the people who use Bushen Jiedu prescription and the remaining Chinese medicines in the first group;

[0036] Fig.15 This is a network diagram of Chinese medicine-oriented association analysis. The network centered on the Bushen Jiedu Recipe (Dodder Seed + Tengli Root + Hedyotis Diffusa + Morus Altissima + Precocious Seed + Euryale Fructus) and the remaining Chinese medicines, in which the frequency of use of Chinese medicines is proportional to the color and font, and the lines between Chinese medicines represent the degree of association (the number of times when Drug A appears, Drug B also appears), and the color and thickness of the lines are proportional to the degree of association. DETAILED DESCRIPTION

[0037] The specific implementation methods provided by the present invention are described in detail below in conjunction with examples.

[0038] Example 1 Preparation of a Chinese medicine composition for treating advanced colorectal cancer (I)

[0039] 10 parts of Cuscuta seeds, 5 parts of Rhizoma Cibotii, 10 parts of Herba Mori, 3 parts of Euryale ferox, 5 parts of Herba Hedyotis diffusae, 1 part of Scorpio, and 5 parts of Fructus Precocidi.

[0040] Example 2 Preparation of a Chinese medicine composition for treating advanced colorectal cancer (II)

[0041] 10 parts of Cuscuta seeds, 4 parts of Rhizoma Cibotii, 8 parts of Herba Mori, 3 parts of Euryale ferox, 5 parts of Herba Hedyotis diffusae, 1 part of Scorpio, and 6 parts of Fructus Precoci

[0042] Example 3 Preparation of a Chinese medicine composition for treating advanced colorectal cancer (III)

[0043] 9 parts of Cuscuta seeds, 6 parts of Rhizoma Cibotii, 12 parts of Herba Mori, 3 parts of Euryale ferox, 4 parts of Herba Hedyotis diffusae, 2 parts of Scorpio, and 3 parts of Fructus Precocidi.

[0044] Example 4 Preparation of a Chinese medicine composition for treating advanced colorectal cancer (IV)

[0045] 11 parts of Cuscuta seeds, 3 parts of Rhizoma Cibotii, 10 parts of Herba Mori, 3 parts of Euryale ferox, 5 parts of Herba Hedyotis diffusae, 1 part of Scorpio, and 5 parts of Fructus Precocidi.

[0046] Example 5 Preparation of a Chinese medicine composition for treating advanced colorectal cancer (V)

[0047] 8 parts of Cuscuta seeds, 7 parts of Rhizoma Cibotii, 9 parts of Herba Mori, 4 parts of Euryale ferox, 3 parts of Herba Hedyotis diffusae, 3 parts of Scorpio, and 5 parts of Fructus Precocidi.

[0048] Example 6 Preparation of a Chinese medicine composition for treating advanced colorectal cancer (VI)

[0049] 12 parts of Cuscuta seeds, 5 parts of Rhizoma Cibotii, 11 parts of Herba Mori, 1 part of Euryale ferox, 7 parts of Herba Hedyotis diffusae, 1 part of Scorpio, and 4 parts of Fructus Precoci

[0050] Example 7 Preparation of a Chinese medicine composition for treating advanced colorectal cancer (VII)

[0051] 10 parts of Cuscuta seeds, 6 parts of Rhizoma Cibotii, 8 parts of Atractylodes macrocephala, 12 parts of Herba Mori, 3 parts of Euryale ferox, 4 parts of Herba Hedyotis diffusae, 2 parts of Scorpio, and 3 parts of Fructus Precoci

[0052] Example 8 Preparation of a Chinese medicine composition for treating advanced colorectal cancer (VIII)

[0053] 9 parts of Cuscuta seeds, 5 parts of Rhizoma Cibotii, 10 parts of Herba Mori, 3 parts of Euryale ferox, 5 parts of Herba Hedyotis diffusae, 1 part of Scorpio, and 5 parts of Fructus Precocidi.

[0054] Example 9 Preparation of a Chinese medicine composition for treating advanced colorectal cancer (IX)

[0055] 11 parts of Cuscuta seeds, 7 parts of Rhizoma Cibotii, 9 parts of Herba Mori, 4 parts of Euryale ferox, 3 parts of Herba Hedyotis diffusae, 3 parts of Scorpio, and 5 parts of Fructus Precocidi.

[0056] Example 10 Preparation of a Chinese medicine composition for treating advanced colorectal cancer (X)

[0057] 8 parts of Cuscuta seeds, 5 parts of Rhizoma Cibotii, 11 parts of Herba Mori, 1 part of Euryale ferox, 7 parts of Herba Hedyotis diffusae, 1 part of Scorpio, and 4 parts of Fructus Precoci

[0058] Example 11 Preparation of a Chinese medicine composition for treating advanced colorectal cancer (XI)

[0059] 12 parts of Cuscuta seeds, 4 parts of Rhizoma Cibotii, 8 parts of Herba Mori, 3 parts of Euryale ferox, 5 parts of Herba Hedyotis diffusae, 1 part of Scorpio, and 6 parts of Fructus Precoci

[0060] Example 12 Preparation of Chinese medicine composition tablets / capsules for treating advanced colorectal cancer

[0061] Take any one of the Chinese medicine compositions described in Examples 1-11, add 9-11 times the amount of water, decoct for 2-3.5 hours, and filter out the medicinal juice. Add 9 times the amount of water again, decoct for 2.5 hours, filter out the medicinal juice, combine the two decoctions, let stand, filter out the supernatant, concentrate, cool, add 3 times the amount of alcohol of the concentrate, stir and precipitate overnight. Take the supernatant, concentrate to a thick extract; add pharmaceutical excipients, vacuum dry, crush and granulate, press into tablets or fill in capsules.

[0062] Example 13 Preparation of Chinese medicine composition granules for treating advanced colorectal cancer

[0063] Take the Chinese medicine composition described in any one of Examples 1-11, add 8-10 times the amount of water, decoct for 3 hours, and filter out the juice. Add 10 times the amount of water again, decoct for 2.5 hours, filter out the juice, combine the two decoctions, let stand, filter out the supernatant, concentrate, cool, add 2 times the amount of alcohol of the concentrate, stir and precipitate overnight. Take the supernatant, concentrate to a thick extract; add appropriate pharmaceutical excipients, granulate, dry, and granulate to obtain 20g granules, which are divided into 10g / bag.

[0064] Example 14 Preparation of Chinese medicine composition / oral liquid / syrup for treating advanced colorectal cancer

[0065] Take the Chinese medicine composition described in any one of Examples 1-11, add 8-11 times the amount of water, decoct for 3 hours, and filter out the juice. Add 8 times the amount of water again, decoct for 3 hours, filter out the juice, combine the two decoctions, let stand, filter out the supernatant, concentrate, cool, add 3.5 times the amount of alcohol of the concentrate, stir and precipitate overnight. Take the supernatant, concentrate to a thick extract; add appropriate pharmaceutical excipients to prepare a mixture, oral liquid or syrup.

[0066] Example 15 Clinical Trial

[0067] 1. Clinical data

[0068] 1.1 Case source

[0069] This study collected data from patients diagnosed with advanced colorectal cancer from January 1, 2010 to May 1, 2020 from Shanghai Hospital of Traditional Chinese Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai Yangpu District Hospital of Traditional Chinese Medicine, Shanghai Jiading District Hospital of Traditional Chinese Medicine, Shanghai Putuo District Central Hospital, Shandong Cancer Hospital, Baoshan Hospital of Integrated Traditional Chinese and Western Medicine, and Shanghai Pulmonary Hospital. The ethics approval number of this study is: 2021SHL-KY-04-02.

[0070] 1.2 Diagnostic criteria

[0071] Refer to the "Chinese Colorectal Cancer Diagnosis and Treatment Guidelines (2017 Edition)" of the Ministry of Health of the People's Republic of China, and the patient is diagnosed with advanced colorectal cancer based on surgery or colonoscopy, with a clear pathological diagnosis; the colorectal cancer staging standard adopts the TNM staging of the 2020 third edition of the NCCN guidelines.

[0072] 1.3 Inclusion criteria

[0073] (1) Meet the above diagnostic criteria;

[0074] (2) TNM staging: stage IV;

[0075] (3) Aged ≥18 years;

[0076] (4) The patient gave informed consent and accepted follow-up;

[0077] (5) Those who meet all of the above requirements.

[0078] 1.4 Exclusion criteria

[0079] (1) Incomplete clinical case materials;

[0080] (2) pregnant women or patients with a history of mental illness;

[0081] (3) Expected survival time < 3 months;

[0082] (4) combined cancer (combined with other primary malignant tumors within 1 year);

[0083] (5) Applicants who meet any of the above criteria will not be selected. Applicants who meet any of the above criteria will not be selected.

[0084] 1.5 Elimination criteria

[0085] (1) Patients who were not successfully followed up after enrollment and whose survival period could not be obtained;

[0086] (2) patients with non-tumor related deaths;

[0087] (3) The patient himself requests to withdraw from the program;

[0088] (4) Those who meet any of the above conditions.

[0089] 1.6 Dropout Cases

[0090] The number of patients experiencing adverse events or lost to follow-up after inclusion in the program should be controlled within 15%.

[0091] 2. Research Methods

[0092] 2.1 Experimental design

[0093] This study is a bidirectional multicenter cohort clinical study. The effect of traditional Chinese medicine on the overall survival of patients was analyzed, subgroup analysis was used to explore the potential advantage population of traditional Chinese medicine, and multivariate analysis was used to explore whether traditional Chinese medicine is an independent prognostic factor for advanced colorectal cancer. Based on the traditional Chinese medicine prescription, data mining was used to find the core prescription for the treatment of advanced disease and determine whether the prescription is representative.

[0094] 2.2 Data Collection

[0095] For eligible patients, after obtaining informed consent from the patients, the patient's gender, date of birth, primary site of colorectal cancer, whether the primary site was surgically removed, pathological report, date of recurrence and metastasis, site of recurrence and metastasis, whether metastasis resection was performed, chemotherapy regimen after recurrence and metastasis, which was divided into oxaliplatin-containing regimen, irinotecan-containing regimen, other regimens (single-agent chemotherapy such as Xeloda, S-1, and 5-fu), and unknown specific chemotherapy regimen were recorded through telephone, outpatient or inpatient system electronic medical record query, etc.

[0096] 2.3 Follow-up plan

[0097] A follow-up plan will be developed and training for follow-up personnel will be conducted before each follow-up. Patients will be followed up once every three months by telephone or outpatient reception from the date of entry into the study until the outcome event (death) occurs. Patients who are not followed up will go to the Shanghai Center for Disease Control and Prevention to inquire about supplementary survival data. As of August 31, 2020, if no outcome event has occurred, or if contact is lost for various reasons, and the endpoint event cannot be known, it will be classified as censored.

[0098] 2.4 Grouping method

[0099] All patients were divided into two cohorts according to whether they took Chinese medicine systematically, namely the control group and the Chinese medicine group. Taking Chinese medicine systematically refers to taking Chinese medicine decoction (including Chinese medicine granules) continuously for ≥ 3 months from the diagnosis of late stage to the end of the outcome or the end of follow-up.

[0100] 2.5 Main outcome measures

[0101] Outcome indicators: Overall survival (OS), that is, the date of diagnosis of late stage (date of recurrence and metastasis) to the date of death.

[0102] 2.6 Sample size estimation

[0103] The Lakatos method (PASS software) was used to estimate the sample size of survival data in this study. According to previous studies, the expected median survival time of the Chinese medicine group was 35 months, the expected median survival time of the control group was 22 months, the enrollment time was 10 months, the follow-up time was 72 months, the ratio of the experimental group to the control group was 1:1, the test power was 1-β=0.80, the test level α=0.05, and the sample size calculation formula was: n=2d / (PE+PC), where PE and PC were the mortality rates of the experimental group and the control group at the end of the trial. Considering a 5% loss to follow-up rate. After calculation, it can be seen that a total sample size of 448 cases is required. Among them, 224 cases were included as the control group and 224 research subjects were included as the Chinese medicine group.

[0104] 2.7 TCM prescription processing

[0105] Standardization of Chinese medicine: According to the Pharmacopoeia of the People's Republic of China Clinical Drug Use Instructions for Chinese Medicine Pieces Volume 2015 Edition, Chinese medicine pieces are standardized in naming. Among them, insect medicines such as scorpions, centipedes, dragons and earthworms are classified in the category of attacking poison and dispersing nodules because they have the effect of attacking poison and dispersing nodules in actual clinical applications in oncology. Chinese medicine database management: (1) Determine the patient's personal representative prescription: 1) Eliminate licorice, rice sprouts, malt, and hawthorn; 2) Superimpose all prescriptions for each patient and calculate the frequency of Chinese medicine; 3) Calculate the patient's personal Chinese medicine use frequency: patient's personal Chinese medicine use frequency = patient's Chinese medicine frequency / patient's number of prescriptions; 4) Personal representative prescription: Take the Chinese medicine with a patient's Chinese medicine use frequency of >50% as the patient's personal representative prescription. (2) Establish a high-frequency Chinese medicine database: 1) Integrate all personal representative prescriptions and calculate the use frequency of Chinese medicine: Chinese medicine use frequency = single Chinese medicine use frequency / total number of people; 2) Determine high-frequency Chinese medicine: define Chinese medicine with a frequency of ≥10% as high-frequency Chinese medicine, and establish a high-frequency Chinese medicine database.

[0106] 2.8 Statistical analysis

[0107] All statistical analyses and plots were performed using SPSS 24.0, STATA 14.0, Cytoscape 3.8.0, R 3.6.0, and SPSS modeler 14.0. The significance level was α = 0.05, and P < 0.05 was considered statistically significant. Categorical variables were compared using X 2 or Fisher's exact test, and Wilcoxon rank sum test was used for graded data. The Kaplan-Meier method was used for univariate analysis, and the Log-rank test was used to test whether the difference was statistically significant; the Cox proportional hazard model was used for multivariate analysis; propensity score matching (PSM) analysis was used to stabilize baseline characteristics, with a caliper value of 0.05; forest plots were drawn using R software; cluster analysis used systematic clustering and was displayed through a dendrogram; association analysis used the Apriori algorithm (SPSS modeler), with support and confidence as the criteria, and was displayed as a network diagram through Cytoscape, with support set to "20%" and "confidence" set to 80%.

[0108] 3. Research Results

[0109] 3.1 General Information

[0110] This study finally included 434 cases, including 203 in the control group and 231 in the Chinese medicine group. Figure 1. Comparison of baseline characteristics between the two groups revealed statistically significant differences in the age, primary site, and chemotherapy regimens at diagnosis of recurrence and metastasis between the two groups. In the control group, 39% were aged ≥65 years and 61% were aged <65 years. In the TCM group, 50% were aged ≥65 years and 50% were aged <65 years. The patients in the TCM group were older than those in the control group (P=0.030). In the control group, the primary site was the colon (32%) and the rectum (68%). In the TCM group, the colon (57%) and the rectum (43%) were more likely to be in the rectum (P<0.001). The chemotherapy regimens were divided into unknown, irinotecan-containing regimens, oxaliplatin-containing regimens, and others, of which the control group accounted for 26%, 25%, 37%, and 12%, and the TCM group accounted for 57%, 11%, 24%, and 8%, respectively. The chemotherapy regimens in the TCM group were more likely to be unknown than those in the control group (P<0.001). There were no significant differences in other factors between the two groups, see Figure 2A After the propensity matching (PSM) stabilized the baseline between the groups, there was no statistically significant difference between the TCM group and the control group in each factor (P>0.05). Figure 2B .

[0111] 3.2 Univariate analysis

[0112] The median survival (mOS) of the control group before PSM was 30.30 months, and the mOS of the Chinese medicine group was 39.10 months. Survival analysis showed that compared with the control group, the mortality rate of the Chinese medicine group was reduced by 29% (HR=0.71, 95%CI: 0.54-0.93, P=0.013), see Figure 3 A. After PSM, the mOS of the control group was 26.10 months, and that of the TCM group was 39.10 months, indicating that the mortality rate of the TCM group was reduced by 40% compared with that of the control group (HR=0.60, 95%CI: 0.42-0.86, P=0.005). Figure 3 B.

[0113] 3.3 Subgroup analysis

[0114] To further explore the potential advantage population of TCM, this study conducted a subgroup analysis. The specific results are shown in Figure 4. The results showed that in different genders, the difference between the Chinese medicine group and the control group was statistically significant in male patients, HR = 0.67 (95% CI: 0.48-0.94). Male patients with advanced colorectal cancer who used Chinese medicine had a 33% lower risk of death compared with the control group. In different ages, there was a statistical difference between the two groups of patients aged ≥ 65 years, HR = 0.57 (95% CI: 0.39-0.82). After using Chinese medicine, patients aged ≥ 65 years could reduce the risk of death by 43% compared with the control group. For patients with primary sites of colon, the difference between the Chinese medicine group and the control group was statistically significant. The risk of death in patients with colon cancer who used Chinese medicine was lower than that in the control group, HR = 0.38 (95% CI: 0.26-0.57). For patients who underwent primary surgical resection, the risk of death in the Chinese medicine group was lower than that in the control group, HR = 0.69 (95% CI: 0.52-0.91). For patients with adenocarcinoma as the pathological type, the risk of death in the Chinese medicine group was lower, HR = 0.63 (95% CI: 0.47-0.85), that is, the risk of death in patients with adenocarcinoma who used Chinese medicine was 37% lower than that without Chinese medicine treatment. In patients with mCRC with liver metastasis, the risk of death in the Chinese medicine group was reduced by 57%, compared with the control group, HR = 0.43 (95% CI: 0.26-0.73). In patients who had undergone metastatic resection, the risk of death in the Chinese medicine group was lower than that in the control group, HR = 0.38 (95% CI: 0.19-0.77). In patients whose chemotherapy status was unknown, the risk of death in the Chinese medicine group was lower than that in the control group, HR = 0.50 (95% CI: 0.34-0.74). In patients without other comorbidities, the difference between the Chinese medicine group and the control group was statistically significant, HR = 0.63 (95% CI: 0.41-0.96).

[0115] 3.4 Multivariate analysis

[0116] Univariate analysis was performed on the factors of gender, age, primary site of cancer and primary site resection, pathology, differentiation, recurrence and metastasis, resection of metastases, chemotherapy regimen and comorbidities. The results showed that the mOS of patients of different ages was 41.33mo vs. 25.60mo (P<0.001), that is, the survival of patients ≥65 years old was lower than that of patients <65 years old. The mOS of patients who underwent primary site resection was longer than that of patients who did not undergo surgery, and the difference was statistically significant (37.60movs.19.37mo, P=0.009). The mOS of patients with adenocarcinoma, non-adenocarcinoma and unknown pathological type were 37.57, 11.23 and 28.47mo, respectively (P=0.036). Among patients with different recurrence and metastasis sites, the mOS of liver metastasis was 29.4mo, the mOS of lung metastasis was 62.40mo, the mOS of other sites was 54.33mo, and the mOS of multiple metastases was 28.03mo, P<0.001. The mOS of patients who did not undergo resection was 28.47mo, and the median survival of patients who underwent resection was not obtained, P<0.001. The mOS of patients without comorbidities was 46.67vs.32.67, P=0.003. There was no statistically significant difference between the other groups (P>0.05), see Figure 5 All factors were included in the COX multivariate analysis, and the results showed that age, site of recurrence and metastasis, metastatic resection, chemotherapy regimen and traditional Chinese medicine were independent factors affecting advanced colorectal cancer, with P values ​​all less than 0.05. For specific results, see Figure 5 . The risk of death in patients with advanced colorectal cancer aged 65 years and above was higher than that in patients under 65 years old, HR = 1.91 (95% CI: 1.41-2.60). Compared with liver metastasis, the risk of death in patients with lung metastasis and other metastasis was lower than that in liver metastasis, HR was 0.48 (95% CI: 0.30-0.78) and 0.47 (95% CI: 0.30-0.74), respectively. Compared with patients who did not undergo metastasectomy, the risk of death in patients who underwent metastasectomy was reduced by 56%, HR = 0.44 (95% CI: 0.29-0.64). Compared with unknown chemotherapy regimen, the risk of death in patients with oxaliplatin-containing regimens and other chemotherapy regimens was lower than that in patients with unknown chemotherapy regimen, HR were 0.60 (95% CI: 0.42-0.87) and 0.45 (95% CI: 0.26-0.78), respectively. Compared with the control group, the risk of death in patients with advanced colorectal cancer who systematically used Chinese medicine was reduced by 43%, HR = 0.57 (95% CI: 0.41-0.78), and a survival curve of the effect of Chinese medicine on advanced colorectal cancer after factor adjustment was drawn. Figure 6 .

[0117] 3.5 High-frequency Chinese medicine

[0118] This study collected a total of 781 prescriptions involving 118 patients. The personal representative prescriptions of the 118 patients involved a total of 284 Chinese medicines. The single Chinese medicines with higher frequency of use were Hedyotis diffusa, Atractylodes macrocephala, Rhizoma Coptidis, Cuscuta australis, and Astragalus membranaceus, with a frequency of more than 50%. A total of 60 Chinese medicines were used more than 10% of the time, which were defined as high-frequency Chinese medicines. For details, see Figure 7 .

[0119] 3.6 Cluster analysis

[0120] The high-frequency Chinese medicines were systematically clustered and displayed in a tree diagram. Figure 8 . In order to ensure the difference between the clustering result groups, the final cluster number was defined as "2". The results showed that the first group included 35 high-frequency Chinese medicines, of which 4 had the effects of nourishing yin and promoting blood circulation and removing blood stasis, 9 had the effects of clearing away heat, 3 had the effects of regulating qi, 3 had the effects of attacking toxins and dispersing knots and tonifying qi, 2 each had the effects of astringency and tonifying yang, 1 each had the effects of warming the interior, resolving phlegm, nourishing blood, removing rheumatism, calming the liver and calming wind. The second group included 25 Chinese medicines, of which 4 had the effect of tonifying qi, 3 had the effects of regulating qi and removing dampness, 2 each had the effects of nourishing yin, replenishing blood, digesting food, clearing heat, promoting diuresis and removing dampness, and tonifying yang, and 1 each had the effects of resolving phlegm, warming the interior and calming the nerves. For specific drug groupings, see Fig. 9 .

[0121] 3.7 Association analysis

[0122] The drugs in the first and second groups were analyzed for association respectively. Strong associations from the second to sixth order were extracted according to the support > 20% and the confidence > 80%. The association results were arranged in descending order according to the support. The top 10 results were displayed for each order. All results were displayed for less than 10 items. The specific results of the association analysis are shown in Fig.10 The results showed that in the first group, the second-order strong association was vine pear root + Hedyotis diffusa, with a support of 72.03% and a confidence of 80.00%; the third-order strong association was dodder + vine pear root + Hedyotis diffusa, with a support of 57.63% and a confidence of 91.18%; the fourth-order strong association was dodder + euryale + vine pear root + Hedyotis diffusa, with a support of 40.68 and a confidence of 95.83%; the fifth-order strong association was Hedyotis diffusa + Euryale + dodder + vine pear root + Hedyotis diffusa, with a support of 36.44% and a confidence of 100.00%; the sixth-order strong association was mistletoe + Euryale + euryale + dodder + vine pear root + Hedyotis diffusa, with a support of 29.66% and a confidence of 80.00%. In the second group, the second-order strong association is Atractylodes macrocephala + Poria cocos, with a support of 47.46% and a confidence of 83.93%; the third-order strong association is Atractylodes macrocephala + Poria cocos + Astragalus membranaceus, with a support of 27.97% and a confidence of 93.94%. The association results are displayed in the form of a network diagram through Cytoscape, see Fig.11The results showed that the core drugs of the first group were Cuscuta australis + Phellodendron chinense + Herba Hedyotis diffusae. Combined with the correlation analysis, the medication idea of ​​the first group was to tonify the kidney and detoxify. The core drugs of the second group were Atractylodes macrocephala + Poria cocos + Astragalus membranaceus. The medication idea of ​​the second group was to strengthen the spleen and eliminate dampness.

[0123] 3.8 Representative Analysis of Core Drugs

[0124] Among the 118 patients, those who used Cuscuta australis + Rhizoma Cibotii + Herba Hedyotis diffusae were included in the tonifying kidney and detoxifying group (TTS), N = 54, and those who used Atractylodes macrocephala + Poria cocos + Astragalus membranaceus were included in the strengthening spleen and removing dampness group (BBH), N = 31. They were compared with the control group and patients with unknown Chinese medicine prescriptions. The specific results are shown in Fig.12 A and Fig.13 The results showed that the mOS of the control group was 30.30 months, TTS was 44.57 months, BBH was 43.63 months, and other treatments were 34.17 months. The survival time distribution of colorectal cancer patients under different treatments was compared pairwise. The results showed that there was a statistically significant difference between TTS and the control group (P=0.010), and the P values ​​of the differences between the other groups were all greater than 0.05. Fig.12 B shows that the overall survival of the tonifying kidney and detoxifying group (TTS) is not worse than that of the overall Chinese medicine group, which are TTS (44.60) vs. TCM (39.10), P = 0.341, HR = 1.24 (95% CI: 0.79-1.96), suggesting that TTS is representative.

[0125] 3.9 Determine the core

[0126] According to the results of association analysis and drug representativeness analysis, the method of tonifying the kidney and detoxifying has more advantages in prolonging the survival of advanced patients than the method of strengthening the spleen and eliminating dampness and other treatments. Fig.11 A shows that in the Chinese medicine association network, Cuscuta australis + Hedyotis diffusa + Rhizoma Cibotii have the strongest association, among which Cuscuta australis is mainly used to nourish the kidney and is proposed to be one of the main medicines. Fig.10 ) showed that Cuscuta + Rhizoma Cibotii (support: 61.86%) had higher support than Cuscuta + Herba Hedyotis Diffusae (support 59.32%), so another monarch drug was proposed to be Rhizoma Cibotii. Herba Hedyotis Diffusae, Herba Mori, Herba Euryale and Herba Precociliae were proposed as assistant drugs according to the sixth-order association results in the association analysis. A total of 28 patients out of 118 used the drug pair combination of Cuscuta + Rhizoma Cibotii + Herba Hedyotis Diffusae + Herba Mori + Herba Precociliae. This drug pair combination was named Kidney-Nourishing and Detoxifying Recipe, and it was associated with the remaining Chinese medicines. Only the top 10 results with the highest support were shown. See details for details. Fig.14 Among them, the strong correlation is Bushen Jiedu Recipe + Scorpion, with a support of 44.83% and a confidence of 100%, and is represented by cytoscape drawing. Fig.15Therefore, it was planned to be an adjuvant drug. Finally, the core formula was determined to be Cuscuta, Rhizoma Cibotii, Herba Hedyotis Diffusae, Herba Mori, Herba Euryale, Herba Preparata, and Herba Scorpio, and was named Cuscuta Fragrance (TTF).

[0127] 4. Conclusion

[0128] The Chinese medicine of the present invention has the potential advantage of reducing the risk of death in patients with advanced colorectal cancer; clinical research has discovered a dodder prescription with kidney-tonifying and detoxifying treatment as the main method, the prescription composition: monarch medicine (dodder seed, vine pear root), minister medicine (hedyotis diffusa, mistletoe, Euryale ferox, euryale ferox), adjuvant medicine (scorpion).

[0129] The above is only a preferred embodiment of the present invention. It should be pointed out that ordinary technicians in this technical field can make several improvements and supplements without departing from the method of the present invention. These improvements and supplements should also be regarded as the scope of protection of the present invention.

Claims

1. A Chinese medicine composition for treating advanced colorectal cancer, characterized in that: The drug is prepared from the following raw materials in proportion by weight: 8-12 parts of Cuscuta seeds, 3-7 parts of Rhizoma Cibotii roots, 8-12 parts of Herba Mori, 1-5 parts of Euryale ferox, 3-7 parts of Herba Hedyotis diffusae, 1-3 parts of Scorpio and 3-7 parts of Fructus Precocidiellae.

2. The Chinese medicine composition according to claim 1, characterized in that: The drug is prepared from the following raw materials in proportion by weight: 9-11 parts of Cuscuta seeds, 4-6 parts of Rhizoma Cibotii roots, 9-11 parts of Herba Mori, 2-4 parts of Euryale ferox, 4-6 parts of Herba Hedyotis diffusae, 1-2 parts of Scorpio and 4-6 parts of Fructus Precocidiellae.

3. The Chinese medicine composition according to claim 2, characterized in that: The medicine is prepared from the following raw materials in proportion by weight: 10 parts of Cuscuta seeds, 5 parts of Rhizoma Cibotii roots, 10 parts of Morus alba, 3 parts of Euryale ferox, 5 parts of Hedyotis diffusa, 1 part of Scorpio and 5 parts of Fructus Precoci 4. The Chinese medicine composition according to any one of claims 1 to 3, characterized in that: The dosage form of the Chinese medicine composition is granules, tablets, capsules, oral liquids, mixtures or syrups.

5. Use of the Chinese medicine composition according to any one of claims 1 to 3 in the preparation of a drug for treating advanced colorectal cancer.

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