Evidence-Based Complementary and Alternative Medicine
Volume 2018 (2018), Article ID 4579801, 10 pages
https://doi.org/10.1155/2018/4579801

Research Article

Association Rule Analysis for Validating Interrelationships of Combined Medication of Compound Kushen Injection in Treating Colon Carcinoma: A Hospital Information System-Based Real-World Study

Huisheng Yang,1,2 Yanming Xie,¹ Jisheng Ni,³ Yue Liu,⁴ Rui Song,⁵ Cen Chen,⁶ Yan Zhuang,⁷ and Yin Zhang1,4

¹Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Dongcheng District, Beijing 100700, China
²Institute of Acupuncture and Moxibustion, China Academy of Chinese Medical Sciences, Dongcheng District, Beijing 100700, China
³Southeast University-Monash University Joint Research Institute, Wuzhong District, Southeast University, Suzhou 215123, China
⁴School of Chinese Medicine, Beijing University of Chinese Medicine, Chaoyang District, Beijing 100029, China
⁵Longwood Translation Medicine China Initiative, Boston, MA 02115, USA
⁶School of Statistics, Renmin University of China, Haidian District, Beijing 100872, China
⁷Center of Computer Management, Navy General Hospital of PLA, Haidian District, Beijing 100048, China

Correspondence should be addressed to Yin Zhang; drzhangyin@163.com

Received 26 April 2018; Accepted 29 July 2018; Published 30 August 2018

Academic Editor: Massimo Nabissi

Copyright © 2018 Huisheng Yang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Background. Real world evidence is important for informing healthcare practice and developing medical products and has gained broad interest in healthcare. Compound Kushen Injection (CKI) has been widely applied into treatment of colon carcinoma (CC) in China. Postapproval drug assessment related retrospective studies using electrical medical record (EMR) collected from hospital information system (HIS) is one of the most important categories of real-world study (RWS). Based on HIS EMR, interrelationships of combined medication of CKI in treating CC can be validated in real world settings. Methods. This study was conducted based on a large-scale integrated database of EMR derived from HIS. EMR of 3328 patients initially diagnosed with CC among 49,597 patients treated with CKI were included in the study. Descriptive statistical analyses and apriori algorithm based association rule analyses were performed, respectively, to validate frequency distribution and interrelationships of combined medication of CKI in treating CC. Results. The pharmacological mechanisms of TCMs that have been commonly used in conjunction with CKI include heat-clearing and detoxifying, qi-reinforcing, blood circulation-promoting and stasis-removing, blood-stanching, and qi-regulating. For modern medicines, antibiotics, antineoplastic chemotherapeutic drugs, immunomodulator, 5-HT receptor antagonist drugs, and corticosteroids are most often combined with CKI. The association rules of medication combinations of CKI in treating CC in real world manifest certain laws for both TCMs and modern medicines. They are generally in line with CC treatment guidelines. Conclusions. It is a common practice for CKI to be integrated with both modern medicines and TCMs when treating CC in China. The associations of medication combinations of CKI in treating CC manifest certain laws for both TCMs and modern medicines. The RWS for validating interrelationships of combined medication may provide evidence for rational use of CKI. Further explorations are needed to verify and expand the conclusions.

1. Background

Compound Kushen Injection (CKI), is a pure TCM extracted from two herbs, Radix Sophorae Flavescentis and Rhizoma Hterosmilacis. In TCM theory, CKI has the effect of clearing heat, promoting diuresis, removing pathogenic and toxic material from the body [1]. With the effective components of oxymatrine, oxysophocarpine, and matrine [2], it has been widely applied into treatment of various kinds of malignant tumors in China, including colon carcinoma (CC) [3]. CKI has been listed in the Drug Directory for National Medical Insurance, Employment Injury Insurance, and Maternity Insurance [4]. It is also listed as therapeutic medication for CC according to Guideline for Diagnosis and Treatment of Tumor in TCM [5] published by China Association of Chinese Medicine in 2008 and Clinical Practice Guidelines of Chinese Medicine in Oncology [6] issued by China Academy of Chinese Medical Sciences in 2014.

Trails have showed that CKI can improve overall efficiency of the treatment for multiple malignant tumors, relieve clinical symptoms such as cancer pain, fever, and fatigue, and potentiate the efficacy of chemotherapy and radiotherapy for CC with additional toxicity reduction effect [3, 7, 8]. The mechanisms of CKI comprise inhibiting the proliferation and metastasis of tumor cells [9–11], inducing the differentiation and apoptosis of tumor cells [12, 13], restraining the formation of tumor neovascularization [14], suppressing tumors’ drug resistance [15], and inducing the autophagy of tumor cells [16, 17]. Previous studies show that compared with pure chemotherapy treatment, CKI combined with chemotherapy can improve clinical effects and patients’ life quality, extend lifetime, and reduce the toxicity of chemotherapy [18–20]. The mechanism of which includes improving the immunity of patients with CC [21], restraining the proliferation of colon cancer cells and inducing their apoptosis [22, 23], suppressing the formation of tumor neovascularization [24], and curbing the activation of NF-κB inside macrophage [25].

Real-world studies (RWS) include a spectrum of studies that apply various methods to data collected from real world settings [26]. Real world evidence is important for informing healthcare practice and developing medical products and has gained broad interest in healthcare [27]. In China, the term “real world evidence” was not explicitly used until 2010, when researchers from our group in Institute of Basic Research in Clinical Medicine (IBRCM), China Academy of Traditional Chinese Medical Sciences (CACMS), carried out the first RWS to evaluate traditional Chinese medicine interventions [28]. Retrospective studies using electrical medical record (EMR) collected from hospital information system (HIS) are one of the most important categories of RWS [27] and are important for postapproval drug assessment [29], healthcare quality improvement [30], and new indications of medical products [31].

EMR stored in HIS have inherent strengths of high reliability of sources, large scale of samples, accuracy of recording, reasonable framework, and abundance in dimensions. Particularly, it records detailed medication orders throughout the whole treatment process at the time of hospitalization [32]. The laws of combined medication can thus be found through the large quantity of data provided by HIS. Considering CKI has been widely applied into treatment of CC in China, our present study aimed to validate the interrelationships of combined medication of CKI in the treatment of CC by using HIS EMR and thus provide evidence for rational use of CKI in real world settings.

2. Methods

2.1. Data Sources

This study was conducted based on a large-scale integrated data warehouse of EMR from HIS of 39 Class A tertiary hospitals in China, that was built by IBRCM of CACMS [26, 33, 34]. EMR of patients whose first-listed diagnoses were CC and were treated with CKI were extracted from 22 hospitals among the above-mentioned medical centers.

2.2. Standardization of Database Structure

Due to the difference in data structure of HIS of varied hospitals, IBRCM, by standardizing original data structure, built an integrated database with the same structure of variables that contained general information, diagnosis information, medication orders, and laboratory test results. Patient’s ID is the only index that links different data subsets.

2.3. Data Standardization

All analyses were made on account of standardized modern medicine diagnosis information and medication orders. Disease names were standardized with reference to ICD-10 [35]. Chinese patent medicines with the same ingredients but in different drug forms were standardized and merged, while their TCM theory based pharmacological mechanisms were classified in accordance with their major functions. Modern medicines were standardized by translating their trade name into chemical name (if applicable), and their pharmacological effects were normalized and categorized with reference to Pharmacopoeia of the People’s Republic of China (2010) [36].

2.4. Exclusion Criteria

Exclusion criteria of combined medicines are as follows: (1) solvents, including glucose injection, sodium chloride injection, and glucose and sodium chloride injection, were excluded; (2) potassium chloride and vitamins (except for Vitamin C) were excluded; (3) insulin when combined with glucose injection or glucose and sodium chloride injection was excluded; (4) heparin only when administrated through intravenous drip, intravenous injection, pumping, or subcutaneous injection was excluded; (5) combined drugs the medication administration time of which did not fall into that of CKI were excluded.

2.5. Data Analysis

Descriptive statistical analyses in this study were carried out using SAS software (version 9.3, SAS Institute Inc., Cary, NC, U.S.A). Considering the complexity of drug combination, only the medicines that have been frequently used in conjunction with CKI (top 20 excerpted) were included for data mining analyses. Apriori algorithm based association rule analysis (ARA) and plotting in this study were processed by SPSS Clementine software (version 12.0, SPSS Inc., Chicago, IL, U.S.A).

3. Results

3.1. Characteristics of General Information

EMR of 3328 patients first diagnosed with CC among 49597 patients who were treated with CKI at the time of hospitalization were included in the study. The earliest record of case was August 2002, while the latest one was December 2014. The characteristics are as follows: gender: male: 1953 cases, female: 1353 cases, and missing: 22 cases; age: 61.85±13.68 years old; length of hospital stays: 11.96±6.43 days; course of CKI treatment: 9.32±6.28 days; single dosage of CKI: 16.73±5.63 ml; daily dosage of CKI: 15.84±4.17 ml.

3.2. Distribution Characteristics of Combined TCMs

227 traditional Chinese medicines were used in conjunction with CKI. Top 20 were tabulated based on the frequency of use (Table 1).

Table 1: Frequency of TCMs combined with CKI (Top 20, N=3328).

Frequency sequence
Medication
Distribution frequency (%)
Frequency sequence
Medication
Distribution frequency (%)

1
Yadanzi Youru injection
443 (13.31)
11
Lianqi capsules
110 (3.31)

2
Zhenqi Fuzheng granules
345 (10.37)
12
Kangfuxin liquid
109 (3.28)

3
Shenqi Fuzheng injection
317 (9.53)
13
Shengmai injection
91 (2.73)

4
Aidi injection
297 (8.92)
14
Tongbianling capsules
84 (2.52)

5
Ganmao Qingre granules
295 (8.86)
15
Qirong Runchang oral liquid
78 (2.34)

6
Yunnan Baiyao capsules
261 (7.84)
16
Tanreqing injection
77 (2.31)

7
Simotang oral liquid
214 (6.43)
17
Shengmai II oral liquid
74 (2.22)

8
Kangai injection
182 (5.47)
18
Shenfu injection
73 (2.19)

9
Xiaoaiping injection
170 (5.11)
19
Qingkailing injection
71 (2.13)

10
Jianpi Yishen granules
138 (4.15)
20
Xihuang capsules
69 (2.07)

3.3. Distribution Characteristics of Combined Modern Medicines

760 modern medicines were used in conjunction with CKI. Top 20 were tabulated based on the frequency of use (Table 2).

Table 2: Frequency of modern medicines combined with CKI (Top 20, N=3328).

Frequency sequence
Medication
Distribution frequency (%)
Frequency sequence
Medication
Distribution frequency (%)

1
Tropisetron
1599 (48.05)
11
Ornidazole
660 (19.83)

2
Thymosin
1554 (46.69)
12
Lidocaine
651 (19.56)

3
Oxaliplatin
1509 (45.34)
13
Recombinant human Interleukin 2
636 (19.11)

4
Fluorouracil
1361 (40.90)
14
Reduced glutathione
629 (18.90)

5
Leucovorin
1271 (38.19)
15
Alanyl-glutamine
623 (18.72)

6
Dexamethasone
1250 (37.56)
16
Furosemide
590 (17.73)

7
Metoclopramide
1018 (30.59)
17
Cinobufagin
569 (17.10)

8
Amino acid
964 (28.97)
18
Ambroxol
550 (16.53)

9
Medium- and long-chain fat emulsion
794 (23.86)
19
Omeprazole
550 (16.53)

10
Pantoprazole sodium
794 (23.86)
20
Human serum albumin
527 (15.84)

3.4. TCM Pharmacological Mechanism Distribution Characteristics of Combined TCMs

Frequency order of pharmacological mechanism of combined TCMs (top 20) is shown in Table 3.

Table 3: Frequency of TCM pharmacological mechanisms of TCMs combined with CKI (Top 20, N=3328).

Frequency sequence
TCM Pharmacological mechanism
Distribution frequency (%)
Frequency sequence
TCM Pharmacological mechanism
Distribution frequency (%)

1
Heat-clearing and detoxifying
1535 (46.12)
11
Reviving yang to save from collapse
73 (2.19)

2
Qi-reinforcing
1159 (34.83)
12
Qi-reinforcing and blood-nourishing
52 (1.56)

3
Blood circulation-promoting and stasis-removing
312 (9.38)
13
Warming interior
49 (1.47)

4
Blood-stanching
294 (8.83)
14
Promoting circulation of qi and blood to relieve pain
49 (1.47)

5
Qi-regulating
273 (8.20)
15
Cough-relieving
39 (1.17)

6
Bowel-relaxing
260 (7.81)
16
Cough-preventing
33 (0.99)

7
Spleen-invigorating and stomach-harmonizing
163 (4.90)
17
Digestion-promoting
32 (0.96)

8
Swelling-reducing and mass-resolving
103 (3.09)
18
Phlegm-eliminating
31 (0.93)

9
Blood-regulating
94 (2.82)
19
Blood-nourishing and tranquilization
25 (0.75)

10
Yin-tonifying
75 (2.25)
20
Yang-tonifying
23 (0.69)

3.5. Pharmacological Mechanism Distribution Characteristics of Combined Modern Medicines

Frequency order of pharmacological mechanism of combined modern medicines (top 20) is shown in Table 4.

Table 4: Frequency of pharmacological mechanisms of modern medicines combined with CKI (Top 20, N=3328).

Frequency sequence
Pharmacological mechanism
Distribution frequency (%)
Frequency sequence
Pharmacological mechanism
Distribution frequency (%)

1
Antineoplastic chemotherapeutic drugs
2760 (82.93)
11
Painkiller
1030 (30.95)

2
Immunomodulator
2308 (69.35)
12
Tranquilizer
947 (28.46)

3
Antibiotics
1676 (50.36)
13
Medicine for electrolyte balance adjustment
851 (25.57)

4
5-HT receptor antagonist drugs
1658 (49.82)
14
Anesthetic
799 (24.01)

5
Nutritious drugs
1386 (41.65)
15
Diuretics
786 (23.62)

6
Hepatic protector
1303 (39.15)
16
H2 receptor antagonist drugs
755 (22.69)

7
Proton pump inhibitor
1243 (37.35)
17
Analgesic and anti-inflammatory drugs
668 (20.07)

8
Antifolate
1211 (36.39)
18
Cell differentiation drugs
607 (18.24)

9
Corticosteroids
1152 (34.62)
19
Antianemics
603 (18.12)

10
Dopamine receptor antagonist
1063 (31.94)
20
Expectorant
557 (16.74)

3.6. ARA of Combined TCMs

TCMs are used in conjunction with CKI. The association rules between different medicines obtained by ARA are ordered by Support. Top 10 are listed in Table 5. The features are visually presented based on network of associations in Figure 1.

Table 5: Association rules of TCM combined with CKI.

No.
Association rules
Support
Confidence

1
Zhenqi Fuzheng granules =>Ganmao Qingre granules
1.472
14.2

2
Ganmao Qingre granules =>Zhenqi Fuzheng granules
1.472
16.6

3
Aidi injection =>Yunnan Baiyao capsules
1.322
14.8

4
Yunnan Baiyao capsules =>Aidi injection
1.322
16.9

5
Aidi injection =>Yadanzi Youru injection
1.322
14.8

6
Yunnan Baiyao capsules =>Shenqi Fuzheng injection
1.292
16.5

7
Ganmao Qingre granules =>Yadanzi Youru injection
1.292
14.6

8
Simotang oral liquid =>Ganmao Qingre granules
1.262
19.6

9
Ganmao Qingre granules =>Simotang oral liquid
1.262
14.2

10
Yunnan Baiyao capsules =>Yadanzi Youru injection
1.262
16.1

Figure 1: Network diagram of association rules of TCM combined with CKI. (1) Shenqi Fuzheng injection; (2) Yadanzi Youru injection; (3) Aidi injection; (4) Ganmao Qingre granules; (5) Kangai injection; (6) Simotang oral liquid; (7) Jianpi Yishen granules; (8) Xiaoaiping injection; (9) Yunnan Baiyao capsules; (10) Zhenqi Fuzheng granules.

In Figure 1, in order to show the difference of correlation between combined drugs, use frequency≧1.06% is represented by bold line; use frequency≦0.5% is represented by dotted line; use frequency between 0.5% and 1.06% is represented by fine line.

3.7. ARA of Combined Modern Medicines and Merged Analysis

Modern medicines are used in conjunction with CKI. The association rules between different medicines obtained by ARA are ordered by Support. Top 10 are listed in Table 6. The features are visually presented based on network of associations in Figure 2. In merged analysis, the network of associations is shown in Figure 3.

Table 6: Association rules of modern medicines combined with CKI.

No.
Association rules
Support
Confidence

1
Leucovorin =>Oxaliplatin
33.4
87.3

2
Oxaliplatin =>Leucovorin
33.4
73.6

3
Oxaliplatin =>Tropisetron
30.3
66.8

4
Tropisetron =>Oxaliplatin
30.3
63.0

5
Leucovorin =>Fluorouracil
28.9
75.6

6
Fluorouracil =>Leucovorin
28.9
70.6

7
Fluorouracil =>Tropisetron
28.2
68.9

8
Tropisetron =>Fluorouracil
28.2
58.7

9
Leucovorin =>Tropisetron
27.7
72.5

10
Tropisetron =>Leucovorin
27.7
57.6

Figure 2: Network diagram of association rules of modern medicines combined with CKI. (1) Oxaliplatin; (2) Dexamethasone; (3) Fluorouracil; (4) Amino acid; (5) Metoclopramide; (6) Tropisetron; (7) Thymosin; (8) Leucovorin; (9) Medium- and long-chain fat emulsion; (10) Pantoprazole sodium.

Figure 3: Network diagram of association rules of CKI combined with both TCM and modern medicines. (1) Shenqi Fuzheng injection; (2) Yadanzi Youru injection; (3) Aidi injection; (4) Ganmao Qingre granules; (5) Zhenqi Fuzheng granules; (6) Oxaliplatin; (7) Fluorouracil; (8) Tropisetron; (9) Thymosin; (10) Leucovorin.

In Figure 2, use frequency≧20.3% is represented by bold line; use frequency≦12% is represented by dotted line; use frequency between 12% and 20.3% is represented by fine line.

In Figure 3, use frequency≧7.49% is represented by bold line; use frequency≦2.87% is represented by dotted line; use frequency between 2.87% and 7.49% is represented by fine line.

3.8. ARA of Pharmacological Mechanisms of Combined TCMs

The association rules between different pharmacological mechanisms of combined TCMs obtained by ARA are ordered by Support. Top 10 are listed in Table 7. The features are visually presented based on network of associations in Figure 4.

Table 7: Association rules of pharmacological mechanism of TCMs combined with CKI.

No.
Association rules
Support
Confidence

1
Qi-reinforcing =>Heat-clearing and detoxifying
16.23
46.6

2
Heat-clearing and detoxifying =>Qi-reinforcing
16.23
35.2

3
Blood circulation-promoting and stasis-removing=>Heat-clearing and detoxifying
5.89
62.8

4
Heat-clearing and detoxifying =>Blood circulation-promoting and stasis-removing
5.89
12.8

5
Blood-stanching =>Heat-clearing and detoxifying
5.32
60.2

6
Heat-clearing and detoxifying =>Blood-stanching
5.32
11.5

7
blood circulation-promoting and stasis-removing=>Qi-reinforcing
5.02
53.5

8
Qi-reinforcing =>Blood circulation-promoting and stasis-removing
5.02
14.4

9
Qi-regulating =>Heat-clearing and detoxifying
4.78
58.2

10
Heat-clearing and detoxifying =>Qi-regulating
4.78
10.4

Figure 4: Network diagram of pharmacological mechanism association rules of TCMs combined with CKI. (1) Qi-reinforcing; (2) heat-clearing and detoxifying; (3) blood circulation-promoting and stasis-removing; (4) spleen-invigorating and stomach-harmonizing; (5) Qi-regulating; (6) bowel-relaxing; (7) blood-regulating; (8) Blood stasis-removing; (9) blood-stanching; (10) swelling-reducing and mass-resolving.

In Figure 4, in order to show the difference of correlation of pharmacological mechanism between combined drugs, use frequency≧2.08% is represented by bold line; use frequency≦0.42% is represented by dotted line; use frequency between 0.42% and 2.08% is represented by fine line.

3.9. ARA of Pharmacological Mechanism of Combined Modern Medicines, and Merged Analysis

Modern medicines are used in conjunction with CKI. The association rules between different pharmacological mechanisms of combined modern medicines obtained by ARA are ordered by Support. Top 10 are listed in Table 8. The features are visually presented based on network of associations in Figure 5. In merged analysis, the network of associations is shown in Figure 6.

Table 8: Association rules of pharmacological mechanisms of modern medicines combined with CKI.

No.
Association rules
Support
Confidence

1
Immunomodulator =>Antineoplastic chemotherapeutic drugs
57.8
83.4

2
Antineoplastic chemotherapeutic drugs =>Immunomodulator
57.8
69.7

3
5-HT receptor antagonist drugs =>Antineoplastic chemotherapeutic drugs
48.1
96.6

4
Antineoplastic chemotherapeutic drugs =>5-HT receptor antagonist drugs
48.1
58.0

5
Antibiotics =>Antineoplastic chemotherapeutic drugs
40.3
80.0

6
Antineoplastic chemotherapeutic drugs =>Antibiotics
40.3
48.6

7
5-HT receptor antagonist drugs =>Immunomodulator
37.5
75.3

8
Immunomodulator =>5-HT receptor antagonist drugs
37.5
54.1

9
Antibiotics =>Immunomodulator
36.9
73.3

10
Immunomodulator =>Antibiotics
36.9
53.2

Figure 5: Network diagram of pharmacological mechanism association rules of modern medicines combined with CKI. (1) 5-HT receptor antagonist; (2) hepatic protector; (3) dopamine receptor antagonist; (4) antibiotics; (5) antineoplastic chemotherapeutic drugs; (6) immunomodulator; (7) corticosteroids; (8) antifolate; (9) nutritious drugs; (10) proton pump inhibitor.

Figure 6: Network diagram of pharmacological mechanism association rules of CKI combined with both TCM and modern medicines. (1) Qi-reinforcing; (2) heat-clearing and detoxifying; (3) blood circulation-promoting and stasis-removing; (4) Qi-regulating; (5) blood-stanching; (6) 5-HT receptor antagonist drugs; (7) antibiotics; (8) antineoplastic chemotherapeutic drugs; (9) immunomodulator; (10) nutritious drugs.

In Figure 5, use frequency≧30.4% is represented by bold line; use frequency≦17.4% is represented by dotted line; use frequency between 17.4% and 30.4% is represented by fine line.

In Figure 6, use frequency≧28.1% is represented by bold line; use frequency≦5.15% is represented by dotted line; use frequency between 5.15% and 28.1% is represented by fine line.

4. Discussion

ARA is widely used to analyze internal connections hidden in item sets of multidimensional data [37–39]. In this study, ARA is performed to generate candidate item sets under a threshold control of support and confidence and finally identify association rules that highlight general trends in the database of combined TCMs and modern medicines. Association rules are presented in the implicative expression of A => B. Support (A -> B) = P (A U B). Support equals the probability of coadministration of drugs A and B. It is used to assess the frequency and importance of association rules. Confidence (A -> B) = P (). Confidence equals the probability of administration of drug B after drug A is used. It is capable of assessing the intensity and reliability of association rules [40].

In terms of features of combination with other TCMs, CKI is most often administrated in conjunction with TCMs with the pharmacological mechanisms of qi-reinforcing, heat-clearing and detoxifying, blood circulation-promoting and stasis-removing, spleen-invigorating and stomach-harmonizing, and qi-regulating. The common combinations include the following: (1) on the basis of combination of CKI and qi-reinforcing, using one of the following: heat-clearing and detoxifying, blood circulation-promoting and stasis-removing, blood-stanching, bowel-relaxing, qi-regulating, spleen-invigorating and stomach-harmonizing, and blood-regulating; (2) on the basis of combination of CKI and heat-clearing and detoxifying, using one of the following: blood circulation-promoting and stasis-removing, blood-stanching, bowel-relaxing, qi-regulating, spleen-invigorating and stomach-harmonizing, blood-regulating, swelling-reducing and mass-resolving, for yin-tonifying, for reviving yang to save from collapse, qi-reinforcing and blood-nourishing; (3) on the basis of combination of CKI and blood circulation-promoting and stasis-removing, using blood-stanching and qi-regulating; (4) on the basis of combination of CKI and qi-regulating, using bowel-relaxing used. In TCM theory, a number of pathogenic factors cause the malfunction of large intestine and stagnant movement of qi, blood, and body fluid, leading to certain pathological changes such as stagnation of qi and blood, phlegm stasis, damp turbidity, and heat-toxicity. Stagnated in large intestine, these pathological products interact with each other and eventually form tangible lumps as time goes by. The above combinations of TCMs when treating CC have effects of reinforcing healthy qi, clearing heat and detoxication, reinforcing qi and invigorating spleen, eliminating dampness and regulating the stomach, regulating qi and relieving pain, smoothing qi, and removing stasis. They are in line with Guideline for Diagnosis and Treatment of Tumor in TCM published by China Association of Chinese Medicine [5].

In terms of features of combination with modern medicines, CKI is most often administrated in conjunction with antibiotics, antineoplastic chemotherapeutic drugs, immunomodulator, 5-HT receptor antagonist drugs, and corticosteroids. The common combinations include the following: (1) on the basis of combination of CKI and antineoplastic chemotherapeutic drugs, using one of the following drugs: immunomodulator, 5-HT receptor antagonist drugs, antibiotics, antifolate, nutritious drugs, corticosteroids, hepatic protector, proton pump inhibitor, dopamine receptor antagonist; (2) on the basis of combination of CKI and immunomodulator, using one of the following drugs: 5-HT receptor antagonist drugs, antibiotics, nutritious drugs, hepatic protector, proton pump inhibitor; (3) on the basis of combination of CKI and antibiotics, using nutritious drugs; (4) on the basis of combination of CKI and corticosteroids, using antifolate, dopamine receptor antagonist, and antineoplastic drugs; (5) CKI being administrated in conjunction with antibiotics, antineoplastic chemotherapeutic drugs, immunomodulator, 5-HT receptor antagonist drugs, and corticosteroids. According to guidelines [41–43], major therapeutic strategy to treat CC includes chemotherapy before operation and administration of antibiotics, immunomodulator, and corticosteroids after operation. Antineoplastic chemotherapeutic drugs, antibiotics, and immunomodulator are strongly recommended with a view to raising total survival rate, preventing postoperative infection, prolonging survival period for recurrent patients, and improving life quality. The above combinations have effects of inhibiting the proliferation of CC cells, preventing infection, alleviating the side effect of radiotherapy and chemotherapy, and mitigating local compression and edema. They are confronted with clinical guidelines for diagnosis and treatment of CC [42, 44, 45].

In merged analysis, the common combinations include the following: (1) on the basis of combination of CKI and heat-clearing and detoxifying, antineoplastic chemotherapeutic drugs and immunomodulator are used at the same time; (2) on the basis of combination of CKI and qi-reinforcing, antineoplastic chemotherapeutic drugs are used; (3) on the basis of combination of CKI and antibiotics, antineoplastic chemotherapeutic drugs, and immunomodulator are used at the same time; (4) on the basis of combination of CKI and antineoplastic chemotherapeutic drugs, 5-HT receptor antagonist drugs, and corticosteroids are used, respectively; (5) on the basis of combination of CKI and 5-HT receptor antagonist drugs, corticosteroids are used; (6) on the basis of combination of CKI and immunomodulator, either antineoplastic chemotherapeutic drugs, 5-HT receptor antagonist drugs, or corticosteroids is added. The combination of TCM and chemotherapeutics has been proved to have the effect of relieving symptoms, raising life quality, strengthening immune functions, and alleviating the side effect of chemotherapy when treating CC [18, 46, 47].

Strengths of our present study should be noted. (1) The data source of this study is of high quality. The large-scale integrated data warehouse records EMR of over three million cases from HIS of 39 Class A tertiary hospitals nationwide in China. It covers demographic data, diagnosis information of TCM and modern medicine, medication orders, common clinical test results, and treatment outcomes [33, 34]. (2) Standardization of database structure, standardization of different categories of variables, and strict logic checking were performed before analysis to ensure quality control. (3) The advantages of ARA include good adaptability for analysis of multidimensional and nonlinear medication and disease related variables [48].

Disadvantages of this study should also be addressed. (1) HIS EMR is derived from real-world records in the process of clinical treatment and is not originally designed for research purposes. (2) Selection bias may exist because data were derived from participants in 22 hospitals in China, and therefore the cases are likely not representative of patients in other medical centers nationwide. (3) Apriori algorithm generates a large quantity of candidate sets in the ARA procedure by repeatedly scanning all the records in database. Hence, such large amount of calculation by apriori algorithm may consume too many resources when it comes to the analysis of large-scale database.

5. Conclusion

CKI has been used extensively integrated with both modern medicines and TCMs when treating CC in China. The pharmacological mechanisms of TCMs that most frequently combined with CKI include heat-clearing and detoxifying, qi-reinforcing, blood circulation-promoting and stasis-removing, blood-stanching, and qi-regulating. For modern medicines, antibiotics, antineoplastic chemotherapeutic drugs, immunomodulator, 5-HT receptor antagonist drugs, and corticosteroids are most often combined with CKI. The associations of medication combinations of CKI in treating CC in real world manifest certain laws for both TCMs and modern medicines. Further explorations are needed to verify and expand the conclusions.

Abbreviations

HIS: | Hospital information system
RWS: | Real-world study
EMR: | Electrical medical record
CKI: | Compound Kushen Injection
TCM: | Traditional Chinese medicine
ARA: | Association rule analysis.

Data Availability

The data that support the findings of this study are available from Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of Prof. Yanming Xie from Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences.

Ethical Approval

This study has been approved by Ethical Review Board of Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences (No. 2011-11).

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

Yin Zhang and Yanming Xie conceived of the study and participated in its design and coordination. Yanming Xie and Yan Zhuang designed the schema of the HIS database and performed data acquisition at each medical center. Huisheng Yang and Yin Zhang performed data cleansing and standardization. Cen Chen performed the data analysis. Huisheng Yang, Jisheng Ni, Yue Liu, Rui Song, and Yin Zhang wrote the manuscript with contributions from all other authors. All authors approved the final manuscript.

Acknowledgments

This study was generously supported by the National Science and Technology Major Project of China (no. 2015ZX09501004-001-002 and no. 2015ZX09501004-001-009), Special Research Project of TCMs by State Administration of Traditional Chinese Medicine (no. 201507003-8), and Independent Project of China Academy of Traditional Chinese Medical Sciences (no. PY1303 and no. Z0472). The authors thank Mr. Ajian Zhou from World Federation of Chinese Medicine Societies for his critical review of this manuscript.

References

Y. Ma, Q. W. Zhang, Z. M. Wang et al., “Advance in study on compound Kushen injection,” Chinese Journal of Experimental Formulas of Chinese Medicine, vol. 18, no. 23, pp. 342–345, 2012 (Chinese).

Z. Zhao, H. Liao, and Y. Ju, “Effect of compound Kushen injection on T-cell subgroups and natural killer cells in patients with locally advanced non-small-cell lung cancer treated with concomitant radiochemotherapy,” Journal of Traditional Chinese Medicine, vol. 36, no. 1, pp. 14–18, 2016.

C. M. Li, Z. J. Zhang, and Y. Shi, “The injection on clinical application of compound Sophora,” Journal of Diseases Monitor & Control, vol. 4, no. 6, pp. 330–332, 2010 (Chinese).

Ministry of Human Resources and Social Security of the People’s Republic of China, “Drug directory for national medical insurance, employment injury insurance, and maternity insurance 2009 version,” China Journal of Pharmaceutical Economics, vol. 12, no. 4, pp. 35–96, 2009 (Chinese).

China Association of Chinese Medicine, Guideline for Diagnosis and Treatment of Tumor in TCM , China Press of Traditional Chinese Medicine, 2008 (Chinese).

H. S. Lin, Clinical Practice Guidelines of Chinese Medicine in Oncology , People’s Medical Publishing House, 2014 (Chinese).

J. Chen, Q. Mei, Y.-C. Xu, J. Du, Y. Wei, and Z.-M. Xu, “Effects of Matrine injection on T-lymphocyte subsets of patients with malignant tumor after gamma knife radiosurgery,” Journal of Chinese Integrative Medicine, vol. 4, no. 1, pp. 78-79, 2006 (Chinese).

P. J. Chang, “The assessment of clinical effect of compound Kunshen Injection to treat colon carcinoma pain,” Guide of China Medicine, vol. 14, no. 15, pp. 205-206, 2016 (Chinese).

L. Gan, S. Chen, J. Zhong et al., “ZIC1 Is downregulated through promoter hypermethylation, and functions as a tumor suppressor gene in colorectal cancer,” PLoS ONE, vol. 6, no. 2, Article ID e16916, 2011.

K. Zhou, H. Ji, T. Mao, and Z. Bai, “Effects of matrine on the proliferation and apoptosis of human medulloblastoma cell line D341,” International Journal of Clinical and Experimental Medicine, vol. 7, no. 4, pp. 911–918, 2014.

Y. X. Han, “Matrine induces apoptosis in human acute myeloid leukemia cells via the mitochondrial pathway and Akt inactivation,” Plos One, vol. 7, no. 10, Article ID e46853, 2012.

X. Ou, Y. Chen, X. Cheng, X. Zhang, and Q. He, “Potentiation of resveratrol-induced apoptosis by matrine in human hepatoma HepG2 cells,” Oncology Reports, vol. 32, no. 6, pp. 2803–2809, 2014.

J. Wu, X. Xue, B. Zhang et al., “The protective effects of paeonol against epirubicin-induced hepatotoxicity in 4T1-tumor bearing mice via inhibition of the PI3K/Akt/NF-kB pathway,” Chemico-Biological Interactions, vol. 244, pp. 1–8, 2016.

H. L. Zhao, G. L. Huang, and Z. S. Huang, “Matrine in inhibiting cell proliferation and its effects on expressions of vascular endothelial growth factor and matrix metalloproteinase 9 in human liver cancer HepG2 cell lines,” Journal of Youjiang Medical University for Nationalities, vol. 38, no. 8, pp. 1–5, 2016 (Chinese).

B. G. Zhou, Y. J. Shen, T. Yang et al., “Effects of matrine on induced human breast cancer cell apoptosis and drug resistance and expression of acidase protein kinase B, Fas and cysteinyl aspartate-specific protease-3,” Chinese Journal of Experimental Surgery, vol. 29, no. 9, pp. 1856-1857, 2012 (Chinese).

Z. Wang, J. Zhang, Y. Wang et al., “Matrine, a novel autophagy inhibitor, blocks trafficking and the proteolytic activation of lysosomal proteases,” Carcinogenesis, vol. 34, no. 1, pp. 128–138, 2013.

H. Zhou, M. Xu, Y. Gao et al., “Matrine induces caspase-independent program cell death in hepatocellular carcinoma through bid-mediated nuclear translocation of apoptosis inducing factor,” Molecular Cancer, vol. 13, no. 1, article 59, 2014.

W. B. Liu, J. X. Ma, and N. Yao, “Meta-analysis of recent curative effect and safety of compound Kushen injection combined with chemotherapy to treat terminal colonic cancer,” Zhejiang Journal of Integrated Traditional Chinese and Modern medicine, vol. 26, no. 8, pp. 759–763, 2016 (Chinese).

J. L. Ma, L. Ai, T. Wu et al., “Systematic analysis of compound Matrine injection combined with chemotherapy in treating advanced colorectal cancer,” Journal of Guangzhou University of Traditional Chinese Medicine, vol. 33, no. 3, pp. 425–431, 2016 (Chinese).

X. Y. Zhou, M. Z. Fan, L. Lai et al., “Systematic review of compound Kushen injection combined with chemotherapy in treating colorectal cancer,” Chinese Journal of Traditional Medical Science and Technology, vol. 23, no. 5, pp. 620–625, 2016 (Chinese).

T. Kang, M. Liu, and D. Wei, “Observation of curative effect of compound Kushen injection combined with chemotherapy in treating colorectal cancer,” People’s Military Surgeon, vol. 58, no. 11, pp. 1336-1337, 2015 (Chinese).

Q. Yin, S. X. Liu, and J. B. Luo, “Inhibitory effect of compound Matrine injection combined with chemotherapy on human colon cancer,” Chinese Journal of Evaluation and Analysis of Drug-Use in Hospitals, vol. 11, no. 1, pp. 50-51, 2011 (Chinese).

L. Zhou, S. P. Han, C. Yang et al., “Apoptosis of human colon cell line SW480 induced by Radix Sophorae Elavescentis compounds preparation contained serum in vitro,” Chinese Journal of Surgery of Integrated Traditional and Modern medicine, vol. 12, no. 1, pp. 54–56, 2006 (Chinese).

M. Li, X. P. Qian, and B. R. Liu, “The research on composite radix sophora flavescentis injection combined with oxaliplatin inhibiting angiogenesis,” China Oncology, vol. 18, no. 3, pp. 167–171, 2008 (Chinese).

F. Hu, F. Wei, Y. Wang, B. Wu, Y. Fang, and B. Xiong, “EGCG synergizes the therapeutic effect of cisplatin and oxaliplatin through autophagic pathway in human colorectal cancer cells,” Journal of Pharmacological Sciences, vol. 128, no. 1, pp. 27–34, 2015.

R. E. Sherman, S. A. Anderson, G. J. Dal Pan et al., “Real-world evidence - What is it and what can it tell us?” The New England Journal of Medicine, vol. 375, no. 23, pp. 2293–2297, 2016.

X. Sun, J. Tian, L. Tang et al., “Real world evidence: experience and lessons from China,” British Medical Journal, vol. 360, Article ID j5262, 2018.

F. Tian and Y.-M. Xie, “Real-world study: A potential new approach to effectiveness evaluation of traditional Chinese medicine interventions,” Journal of Chinese Integrative Medicine, vol. 8, no. 4, pp. 301–306, 2010 (Chinese).

Z. S. Huang, Y. T. Luo, and J. L. Liu, “Method and practice of real world study,” The Journal of Evidence-Based Medicine, vol. 14, no. 6, pp. 364–368, 2014 (Chinese).

L. P. Garrison Jr., P. J. Neumann, P. Erickson, D. Marshall, and C. D. Mullins, “Using real-world data for coverage and payment decisions: the ISPOR Real-World Data Task Force report,” Value in Health, vol. 10, no. 5, pp. 326–335, 2007.

C. Y. Ko, B. L. Hall, A. J. Hart, M. E. Cohen, and D. B. Hoyt, “The American College of Surgeons National Surgical Quality Improvement Program: achieving better and safer surgery,” Joint Commission Journal on Quality and Patient Safety, vol. 41, no. 5, pp. 199–204, 2015.

Y. Zhuang, B. T. Xie, S. X. Wen, and Y. M. Xie, “Designs and thoughts of real world integrated data warehouse from HIS on re-evaluation of post-marketing traditional Chinese medicine,” China Journal of Chinese Materia Medica, vol. 36, no. 20, pp. 2880–2882, 2011 (Chinese).

W. Yang, Y. M. Xie, and Y. Zhuang, “Explore method about post-marketing safety re-evaluation of Chinese patent medicines based on HIS database in real world,” China Journal of Chinese Materia Medica, vol. 36, no. 20, pp. 2779–2782, 2011 (Chinese).

Y. Zhang, Y. M. Xie, C. Chen, P. P. Jia, and Y. Zhaung, “Association rules based analysis of Fufang Kushen injection in combination with modern medications for malignant tumor: a real-world study based on hospital information system,” Central South Pharmacy, vol. 14, no. 12, pp. 1281–1286, 2016 (Chinese).

World Health Organization, The International Statistical Classification of Diseases and Related Health Problems 10th Revision , People’s Medical Publishing House, 2008 (Chinese).

Chinese Pharmacopoeia Commission, Pharmacopoeia of the People's Republic of China 2010 Version , China Medical Science Press, 2010 (Chinese).

J. J. Linmans, M. G. Spigt, L. Deneer et al., “Effect of lifestyle intervention for people with diabetes or prediabetes in real-world primary care: propensity score analysis,” BMC Family Practice, vol. 12, article 95, 2011.

H. M. Najadat, M. Al-maolegi, and B. Arkok, “An improved Apriori algorithm for association rules,” International Research Journal of Computer Science and Application, vol. 1, no. 1, pp. 1–8, 2013.

S. Mahmood, M. Shahbaz, and A. Guergachi, “Negative and positive association rules mining from text using frequent and infrequent itemsets,” The Scientific World Journal, vol. 2014, Article ID 973750, 11 pages, 2014.

G. Cui, L. Li, K. Wang, G. Gou, and H. Zou, “Research and improvement on Apriori algorithm of association rule mining,” Journal of Computer Applications, vol. 30, no. 11, pp. 2952–2955, 2010 (Chinese).

J. D. Xin, “Clinical guideline for colonic cancer,” Chinese Journal of Gastrointestinal Surgery, vol. 8, no. 3, pp. 269–272, 2005 (Chinese).

T. Watanabe, M. Itabashi, Y. Shimada et al., “Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines,” nternational Journal of Clinical Oncology, vol. 20, no. 2, pp. 207–239, 2015.

J. R. T. Monson, M. R. Weiser, W. D. Buie, G. J. Chang, and J. F. Rafferty, “Practice parameters for the management of rectal cancer (revised),” Diseases of the Colon & Rectum, vol. 56, no. 5, pp. 535–550, 2013.

National Comprehensive Cancer Network, “NCCN Guidelines for Colon and Rectal Cancer. Version 2012,” http://www.nccn.org.

J. Q. Cai, S. J. Cai, and X. Y. Qin, “Guideline for diagnosis and comprehensive treatment of colorectal cancer liver metastases,” Chinese Journal of Practical Surgery, vol. 36, no. 8, pp. 858–869, 2016 (Chinese).

X. G. Fang and K. S. Zhang, “Analysis on the clinic effects of compound Sophora Flavescens injection plus,” Chemotherapy on Terminal Colorectal Cancer, vol. 2, no. 4, pp. 293–295, 2012 (Chinese).

L. W. Chen, Y. H. Wang, and Y. J. Jia, “Clinical progress of Traditional Chinese Medicine combined with chemotherapy treating colorectal cancer,” Journal of Liaoning University of Traditional Chinese Medicine, vol. 4, no. 14, pp. 254–256, 2012 (Chinese).

F. Séverac, E. A. Sauleau, N. Meyer, H. Lefèvre, G. Nisand, and N. Jay, “Non-redundant association rules between diseases and medications: An automated method for knowledge base construction,” BMC Medical Informatics and Decision Making, vol. 15, article 29, 2015.