Abstract
Objective. To explore the role of Chinese prescriptions in non-small cell lung cancer (NSCLC) and provide references for the application of herbs and prescriptions. Methods. Randomized and quasirandomized controlled clinical trials on Chinese herbal medicine in the treatment of NSCLC were collected from seven databases to establish a database of prescriptions on NSCLC. Data-mining analyses were performed by RStudio (v4.0.3) software. Results. A total of 970 prescriptions were obtained from 945 included studies, involving 7 syndromes and 428 herbs. The main patterns of NSCLC included qi deficiency pattern, yin deficiency pattern, blood deficiency pattern, kidney deficiency pattern, heat toxin pattern, phlegm-dampness pattern, and blood stasis pattern. High-frequency herbs on NSCLC were Astragali Radix (Huangqi), Atractylodis Macrocephalae Rhizome (Baizhu), Glycyrrhizae Radix Rhizome (Gancao), Poria (Fuling), Ophiopogonis Radix (Maidong), Hedyotidis Diffusae Herba (Baihuasheshecao), Codonopsis Radix (Dangshen), and Glehniae Radix (Beishashen). The properties of the herbs were mainly cold, warm, and mild. The flavors of the herbs were mainly sweet, bitter, and pungent. The main meridian tropisms were Lung Meridian of Hand-Taiyin, Spleen Meridian of Foot-Taiyin, and Stomach Meridian of Foot-Yangming. Conclusion. Applying clearing and tonifying method by targeting the lung and spleen was the most frequently used therapy in the treatment of NSCLC. This study offered a glimpse of unique views of traditional Chinese medicine on NSCLC and may benefit the treatment of NSCLC.
1. Introduction
Lung cancer is a major cause of deaths worldwide, with approximately 2.2 million new cases and 1.8 million deaths in 2020 [1]. Non-small-cell lung cancer (NSCLC) is the most frequent type of lung cancer, accounting for 80%–85% of total cases [2] and carrying overall 5-year survival rate lower than 15% [3]. Originated from ancient China, traditional Chinese medicine (TCM) is a complementary therapy that has developed rich experience in treating cancers and has been reported to benefit patients with NSCLC [4, 5]. The principle of TCM in practice is syndrome or pattern (zheng) differentiation and treatment. A patient may manifest different patterns in different stages of a disease, while patients with different diseases may share the same pattern. Prescription or formula prescribed by qualified TCM practitioners is the main form of TCM in treating diseases. According to TCM theory, proper combinations of herbs can make the best use of therapeutic effects by mutual reinforcement and mutual assistance, while inappropriate combinations of herbs may reduce efficacy, increase toxicity, or cause side effects by mutual restraint, mutual suppression, and mutual inhibition. Thus, TCM practitioners not only prescribe formulae based on diagnosis and syndrome differentiation, but deliberately modify them according to patient’s specific condition and changing pattern in the development of a disease. However, it is far from simplicity for TCM practitioners to apply and modify formulae flexibly to achieve favorable effects. To explore basic therapeutic principles, identify the main syndromes and common herbs may help to address concerns about the effective application of TCM.
In recent years, accumulative clinical trials on formulae in treating NSCLC have been conducted. Therefore, we collected formulae on NSCLC from randomized and quasirandomized controlled clinical trials to perform a data mining-based analysis, which may provide an available reference for TCM practitioners in the treatment of NSCLC.
2. Materials and Methods
2.1. Literature Research
A comprehensive literature research was conducted in seven databases including China National Knowledge Infrastructure (CNKI), Wanfang Database, Chinese Scientific Journal Database (VIP), Sinomed, PubMed, Embase, and Cochrane Library based on the following research terms: “traditional Chinese medicine,” “Chinese herb,” “Chinese drug,” “Chinese formula,” “Chinese prescription,” “non-small cell lung cancer,” “adenocarcinoma of lung,” and “squamous cell lung carcinoma.”
2.2. Study Selection
Studies that satisfied the following criteria were included. (1) The type of study was limited to randomized or quasirandomized controlled trial. (2) Participants were pathologically diagnosed with NSCLC. (3) Oral Chinese formula or Chinese patent medicine was used alone or in combination with radiotherapy, chemotherapy, targeted therapy, or immunotherapy in trial group. (4) The composition of oral Chinese formula or Chinese patent medicine was recorded specifically. (5) Outcomes were assessed by objective measurements from laboratory tests or imaging techniques, or by measurements from medical staffs, patients, or other informants. (6) Studies provided information that could be used to identify the pattern (zheng).
Studies that met the following criteria were excluded. (1) Studies included participants who were diagnosed with NSCLC and other tumors. (2) Rate of losing follow-up exceeded 20%.
2.3. Data Extraction and Normalization
Two researchers (XJQ and ZHG) independently searched the databases and screened relevant literature. Any disagreement would be discussed or a further decision would be made by QYC. For each article, the title, author, publication date, diagnostic procedure, the composition of prescription, and zheng’s related information were recorded. Duplicate prescriptions were recorded only once. People’s Republic of China Pharmacopoeia (2015 Edition) [6] was referred to standardize names and characteristics of herbs and World Health Organization (WHO) Evidence-Based Complementary and Alternative Medicine International Standard Terminologies on Traditional Medicine in the Western Pacific Region [7] was referred to standardize patterns (zheng).
2.4. Statistical Analysis
All data analyses were performed by RStudio (v4.0.3) software. The frequency, property, flavor, and meridian tropism of herbs were analyzed. Arules and arulesViz packages [8, 9] based on Apriori algorithm were used to analyze the association rules between herbs. The flexclust, dendextend, and magrittr packages [10, 11] were used to construct a hierarchical cluster analysis based on Euclidean metric, and a cluster dendrogram was drew. Both Apriori algorithm and hierarchical cluster have been successfully applied in data-mining analyses on Chinese medicine [12, 13].
3. Results
A total of 17,349 records were obtained, of which 8,414 were duplicate records and 7,990 were excluded according to the eligibility criteria. A total of 945 studies involved 970 Chinese prescriptions were included.
3.1. Overall Characteristics of Herbs in Prescriptions
3.1.1. Frequency of Herbs in Prescriptions
The included 970 Chinese prescriptions involved 428 herbs, and 31 herbs were used more than 100 times as it is shown in Table 1. The most frequently prescribed herbs were Astragali Radix (Huangqi), which appeared 621 times, accounting for 64% of all herbs, followed by Atractylodis Macrocephalae Rhizome (Baizhu) (436 times, 45%), Glycyrrhizae Radix Rhizome (Gancao) (412 times, 42%), Poria (Fuling) (402 times, 42%), Ophiopogonis Radix (Maidong) (374 times, 39%), Hedyotidis Diffusae Herba (Baihuasheshecao) (306 times, 36%), and Codonopsis Radix (Dangshen) (299 times, 31%).
3.1.2. Properties, Flavors, and Meridian Tropisms of Herbs
The most frequently appeared herbal property was cold, followed by warm, mild, and cool (Figure 1(a)). The flavors of herbs (Figure 1(b)) were mainly sweet, bitter, pungent, weak, astringent, sour, and salty. Herbs (Figure 1(c)) were mainly distributed to Lung Meridian of Hand-Taiyin, Spleen Meridian of Foot-Taiyin, Stomach Meridian of Foot-Yangming, Liver Meridian of Foot-Jueyin, Heart Meridian of Hand-Shaoyin, and Kidney Meridian of Foot-Shaoyin.
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3.1.3. Associations between Herbs
In association rule analysis, the minimum support level was set to 15% and the minimum confidence level was set to 60% in order to obtain frequently used herb pairs. A total of 25 rules were obtained, and the detailed information of them was listed in Table 2. Herb pairs with the highest degree of support was {Atractylodis Macrocephalae Rhizome (Baizhu)} => {Astragali Radix (Huangqi)}, followed by {Poria (Fuling)} => {Atractylodis Macrocephalae Rhizome (Baizhu)}, {Poria (Fuling)} => {Astragali Radix (Huangqi)}, {Glycyrrhizae Radix Rhizome (Gancao)} => {Astragali Radix (Huangqi)} and {Ophiopogonis Radix (Maidong)} => {Astragali Radix (Huangqi)}. Herb pairs with the highest confidence and the degree of lift were {Ligustri Lucidi Fructus (Nvzhenzi)} => {Astragali Radix (Huangqi)} and {Adenophorae Radix (Nanshashen)} => {Glehniae Radix (Beishashen)}. Figure 2 visualizes the association rules by a graphics-based visualization technique. The depth of the color and the size of the vertex show the strength of association. Astragali Radix (Huangqi), Atractylodis Macrocephalae Rhizome (Baizhu), Poria (Fuling), and Glycyrrhizae Radix Rhizome (Gancao) were identified as hubs in association rules graph (Figure 2).
The general distribution of association rules is displayed in the grouping matrix diagram (Figure 3) which not only reveals the general rule but also extracts rules that shared commonalities. In the grouping matrix diagram, X-axis and Y-axis represent the right-hand side and left-hand side, respectively. The depth of a circle’s color indicates the degree of lift; the darker the color, the higher the degree of lift. The size of a circle represents the degree of support. As the degree of support becomes higher, the circle becomes larger. Nine core herbs of paired prescriptions were identified: Atractylodis Macrocephalae Rhizome (Baizhu), Poria (Fuling), Citri Reticulatae Pericarpium (Chenpi), Glehniae Radix (Beishashen), Ophiopogonis Radix (Maidong), Codonopsis Radix (Dangshen), Glycyrrhizae Radix Rhizome (Gancao), Hedyotidis Diffusae Herba (Baihuasheshecao), and Astragali Radix (Huangqi).
3.1.4. Cluster Analysis of Herbs
A cluster analysis was performed based on herbs that appeared over 100 times, and 7 clusters were obtained (Figure 4). Cluster 1 included Astragali Radix (Huangqi), Glycyrrhizae Radix Rhizome (Gancao), Codonopsis Radix (Dangshen), Atractylodis Macrocephalae Rhizome (Baizhu), and Poria (Fuling). Cluster 2 contained Ophiopogonis Radix (Maidong), Glehniae Radix (Beishashen) and Adenophorae Radix (Nanshashen). Cluster 3 consisted of Asparagi Radix (Tiandong), Salvia Chinensis (Shijianchuan), Houttuyniae Herba (Yuxingcao), Rehmanniae Radix (Dihuang), Lilii Bulbus (Baihe), Armeniacae Semen Amarum (Kuxinren), Platycodonis Radix (Jiegeng), and Agrimoniae Herba (Xianhecao). Cluster 4 contained Pseudostellariae Radix (Taizishen), Schisandrae Chinensis Fructus, Ligustri Lucidi Fructus (Nvzhenzi), Sinensis Radix (Danggui), Lycii Fructus (Gouqizi), Rehmanniae Radix Preparata (Shudihuang), and Ginseng Radix Et Rhizome (Renshen). Cluster 5 was formed by Curcumae Rhizome (Ezhu), and Salvia Miltiorrhizae Radix Et Rhizome (Danshen). Cluster 6 involved Hedyotidis Diffusae Herba (Baihuasheshecao) and Scutellariae Barbatae Herba (Banzhilian). Cluster 7 included Citri Reticulatae Pericarpium (Chenpi), Pinelliae Rhizome (Banxia), Coicis Semen (Yiyiren), and Fritillariae Thunbergii Bulbus (Zhebeimu).
3.2. Prescription Patterns of Herbs
Seven patterns (zheng) were identified from 970 Chinese prescriptions, including 705 prescriptions related to qi deficiency pattern, 364 prescriptions related to yin deficiency pattern, 355 prescriptions related to heat toxin pattern, 349 prescriptions related to phlegm-dampness pattern, 312 prescriptions related to kidney deficiency pattern, 219 prescriptions related to blood deficiency pattern, and 145 prescriptions related to blood stasis pattern.
The top 10 most frequently used herbs in treating different patterns are presented in Table 3 and their association rule diagrams are shown in Figure 5. Astragali Radix (Huangqi) was the most frequently used herb in treating qi deficiency pattern, yin deficiency pattern, blood deficiency pattern, kidney deficiency pattern, and blood stasis pattern, while Hedyotidis Diffusae Herba (Baihuasheshecao) was the most frequently prescribed herb in treating heat toxin pattern and Coicis Semen (Yiyiren) in treating phlegm-dampness pattern. Most of high-frequency herbs on each pattern were also herbs with effects that are in accordance with the pattern. For example, Astragali Radix (Huangqi), Atractylodis Macrocephalae Rhizome (Baizhu) and Codonopsis Radix (Dangshen) on qi deficiency pattern, Ophiopogonis Radix (Maidong), Tiandong, Glehniae Radix (Beishashen) on yin deficiency pattern, Sinensis Radix (Danggui) and Rehmanniae Radix Preparata (Shudihuang) on blood deficiency pattern, Ligustri Lucidi Fructus (Nvzhenzi) and Lycii Fructus (Gouqizi) on kidney deficiency pattern, Scutellariae Barbatae Herba (Banzhilian) and Hedyotidis Diffusae Herba (Baihuasheshecao) on heat toxin pattern, Fritillariae Thunbergii Bulbus (Zhebeimu) and Poria (Fuling) on phlegm-dampness pattern, Curcumae Rhizome (Ezhu) and Salvia Miltiorrhizae Radix Et Rhizome (Danshen) on blood stasis pattern.
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Paired herbs and herb groups on different patterns were extracted by association rules analysis (Figure 5). Astragali Radix (Huangqi)-Atractylodis Macrocephalae Rhizome (Baizhu) was the most commonly used herb pair on qi deficiency pattern. Ophiopogonis Radix (Maidong), Glehniae Radix (Beishashen), and Adenophorae Radix (Nanshashen) formed a frequently used herb groups on yin deficiency pattern. In the treatment of blood deficiency pattern, Astragali Radix (Huangqi)-Angelicae Sinensis Radix (Danggui) was the most frequently prescribed herb pair. In treating kidney deficiency pattern, Astragali Radix (Huangqi) and Atractylodis Macrocephalae Rhizome (Baizhu) were located centrally in the graph and were prescribed with Ligustri Lucidi Fructus (Nvzhenzi), Lycii Fructus (Gouqizi), and Rehmanniae Radix Preparata (Shudihuang). In treating heat toxin pattern, Hedyotidis Diffusae Herba (Baihuasheshecao) and Scutellariae Barbatae Herba (Banzhilian) combined a pair of herbs. Poria (Fuling), Coicis Semen (Yiyiren), and Fritillariae Thunbergii Bulbus (Zhebeimu) formed an herb group on phlegm-dampness pattern. In treating blood stasis pattern, two herb groups were frequently used: Chuanxiong Rhizoma (Chuangxiong), Persicae Semen (Taoren), and Carthami Flos (Honghua); Curcumae Rhizome (Ezhu) and Sparganii Rhizoma (Sanleng).
4. Discussion
4.1. To Clear and Tonify Lung-Spleen Is the Principal Therapy of TCM on NSCLC
In clinical practice, the properties and actions of herbs are essential bases for practitioners to apply herbal medicines based on therapeutic principles of TCM, theories of yin-yang and zang-fu, and meridian tropisms [14]. In this study, the ten most frequently used herbs and the five most commonly used herb pairs all targeted the spleen and stomach, while the herbs on NSCLC are mainly distributed to lung, spleen, and stomach channels. It indicated that lung and spleen were key viscera in the treatment of NSCLC. The properties of the herbs were mainly sweet and cold, sweet and warm, bitter and cold, and bitter and warm, which were commonly used in clearing method and tonifying method. Thus, the findings suggested that applying clearing and tonifying method by targeting the lung and spleen was the most widely used therapy in the treatment of NSCLC. TCM theories provide explanations for the findings in two aspects. On the one hand, the spleen is considered as the source of the production and transformation of qi and blood. Chinese medicine practitioners attach importance to strengthening and harmonizing the spleen in the treatment of chronic diseases. On the other hand, the spleen is the source of phlegm while the lung is the storage vessel. Therefore, fortifying the spleen to reduce phlegm and alleviate symptoms of the lung has become an important method of treatment in patients with NSCLC.
4.2. Potential Effective Medicinal Compatibility of TCM on NSCLC
The cluster analysis divided the herbs into seven clusters (Figure 4). Herbs in cluster 1 were among the most frequently used herbs and prescribed to fortify the spleen, replenish qi, and drain dampness. Herbs in cluster 2 were prescribed to nourish the yin of the lung and stomach. Herbs in cluster 3 were mainly used to nourish yin, clear heat, diffuse the lung, and resolve phlegm. Herbs in cluster 4 were mainly prescribed to nourish the yin of the kidney and lung and replenish qi. Cluster 5 consisted of herbs for activating blood and resolving stasis, while cluster 6 included heat-clearing and detoxicating herbs. Cluster 7 contained herbs for regulating qi, draining dampness, resolving phlegm, and dissipating binds. These clusters provided an available reference for medicinal compatibility in the treatment of NSCLC.
4.3. Pattern (Zheng) Differentiation and Treatment of TCM on NSCLC
Visualized by modern computer technology, the high-frequency herbs, herb pairs, and herb groups on different patterns offered a glimpse of unique views of TCM on the cause, mechanism, and treatment of NSCLC. (1) The high-frequency herbs on qi deficiency pattern were mainly distributed to the lung and spleen, indicating that dual deficiency of the lung-spleen was common in NSCLC patients with qi deficiency pattern. High-frequency herbs on yin deficiency pattern were mainly distributed to the lung and stomach, suggesting that yin deficiency patterns of NSCLC were mainly manifested in the lung and stomach.(1)High-frequency herbs on blood deficiency pattern generally targeted the spleen and stomach, which reflected that the spleen and stomach were regarded as sources of qi and blood in TCM. As patients with blood deficiency are prone to blood stasis, Astragali Radix (Huangqi) was often prescribed with Sinensis Radix (Danggui) (Figure 5(c)) to fortify the spleen and replenish qi and tonify and activate blood as well.(2)High-frequency herbs on kidney deficiency pattern included more herbs for tonifying the spleen than herbs for tonifying the kidney, and no herb for tonifying the kidney yang was included, indicating that tonifying the spleen and the kidney yin was a major method in treating kidney deficiency pattern of NSCLC. Herb groups on kidney deficiency pattern also supported the findings (Figure 5(d)).(3)In the treatment of heat toxin pattern, two heat-clearing and detoxicating herbs, Hedyotidis Diffusae Herba (Baihuasheshecao) and Scutellariae Barbatae Herba (Banzhilian), formed an herb pair (Figure 5(e)). Hedyotidis Diffusae Herba (Baihuasheshecao) was the only heat-clearing and detoxicating herb that was listed in the ten most frequently prescribed herbs. It was also one of the high-frequency herbs on the common patterns except blood deficiency. It is reported that chemical constituents of Hedyotidis Diffusae Herba (Baihuasheshecao) exhibited cytotoxicity to tumor cell lines [15] and suppressed proliferation of various types of tumor cells often through inducting apoptosis or affecting cell cycle progression [16]. Hedyotidis Diffusae Herba (Baihuasheshecao) is a source of anticancer agents warranting further study.(4)Herbs with corresponding effects were identified as herb groups or herb pairs on phlegm-dampness pattern and blood stasis pattern (Figures 5(f) and 5(g)). In treating these patterns, herbs for tonifying the lung and spleen were prescribed with herbs for reducing phlegm-dampness and blood stasis, suggesting that deficiency in the root caused the accumulation of pathological products and resulted in excess syndromes.(5)Herbs for fortifying the spleen, tonifying the lung, and replenishing qi were identified as high-frequency herbs in seven patterns, which added to the support for the method of clearing and tonifying the lung and spleen in the treatment of NSCLC.
5. Conclusion
Our study found that applying clearing and tonifying method through targeting the lung and spleen was the most widely used therapy in treating NSCLC. The ten most frequently used herbs were identified. The 428 herbs were generally distributed to lung, spleen, stomach, liver, and heart channels. Atractylodis Macrocephalae Rhizome (Baizhu) paired with Astragali Radix (Huangqi), Poria (Fuling) paired with Atractylodis Macrocephalae Rhizome (Baizhu), Poria (Fuling) paired with Astragali Radix (Huangqi), Glycyrrhizae Radix Rhizome (Gancao) paired with Astragali Radix (Huangqi), and Ophiopogonis Radix (Maidong) paired with Astragali Radix (Huangqi) were the five most frequently used herb pairs. Qi deficiency pattern, yin deficiency pattern, blood deficiency pattern, kidney deficiency pattern, heat toxin pattern, phlegm-dampness pattern, and blood stasis pattern were the most common syndromes in NSCLC.
Data Availability
The data used to support the findings of this study are included within the article.
Conflicts of Interest
The authors report no conflicts of interest regarding the publication of this work.
Authors’ Contributions
ZHG and QYC contributed equally to this study. XJQ and LZL conceptualized the study; ZHG and XJQ were responsible for methodology; XJQ provided software; ZZC and WMC validated the study; XJQ was responsible for formal analysis; QYC investigated the study; XJQ and ZHG provided resources; XJQ and WNL were responsible for data curation; XJQ, ZHG, and QYC prepared the original draft; XJQ and QYC reviewed and edited the manuscript; WNL visualized the study; LZL supervised the study; and LZL was responsible for project administration.
Acknowledgments
The authors would like to express their appreciation to China Center for Evidence Based Traditional Chinese Medicine and China Academy of Chinese Medical Sciences for funding. This study was supported by the National Administration of Traditional Chinese Medicine: 2019 Project of Building Evidence-Based Practice Capacity for TCM (2019XZZX-ZL001).