Introduction
Lung cancer accounts for 20% of cancer-related deaths worldwide. Among all malignancies, this tumor, with the highest incidence and fatality rates, is also one of the most common and deadly cancers in older people.1 While the incidence and mortality of lung cancer are continually rising in our country and other emerging nations, in many developed countries the mortality and morbidity of lung cancer are progressively stabilizing and exhibiting a decreasing tendency.2 In emerging nations, lung cancer incidence is rising annually as a result of the current air pollution, radiation, chemical pollution, and other environmental factors in addition to smoking, diet, psychological stress, and other variables. Furthermore, early lung cancer identification is often difficult in clinical practice, and the overall 5-year survival rate is still about 15%.3 Most people with lung cancer experience a subtle onset making it hard to detect in the early stages; thus, by the time they are diagnosed, the window of opportunity for surgery to be most helpful has passed.4 Although surgery has been supplanted by radiation and chemotherapy as the main modalities of treatment, patients still find it difficult to accept these treatments due to their high costs, serious side effects, and toxicities.5,6 Clinical research has demonstrated that by reducing the harmful effects of molecularly targeted therapies such as radiation and chemotherapy through boosting their efficacy and controlling their overall function, traditional Chinese medicine (TCM) syndrome differentiation can alleviate symptoms, improve quality of life, and lengthen patient survival times. These days, an increasing number of clinical research investigations have verified that TCM offers some benefits when treating lung cancer. The fundamental idea of TCM treatment is syndrome differentiation and treatment. According to TCM, sputum fever is the medium term for lung cancer, and fluid consumption is the key factor in the late stage, which is caused by the cancer poisoning of the lungs and results in stagnant blood clots, pulmonary arthritis, and other symptoms. In the clinical staging of lung cancer, tumor-node-metastasis (TNM) can be used to make clear judgments based on the primary focus of the cancer, its size and scope, and whether there are distant lymph nodes and other organ metastases. It can be divided into Qi Yin deficiency syndrome, Qi stagnation and blood stasis syndrome, Yin deficiency internal heat syndrome, phlegm dampness syndrome, and other syndrome types.7
Numerous clinical investigations have examined the relationship between TCM syndrome types and TNM staging in lung cancer,8 Nevertheless, the sample size is small, and no comprehensive summary studies have been conducted. Thus, to provide a reference for the differentiation of TCM syndrome types for enhanced treatment of lung cancer patients, this study applied a meta-analysis to further clarify the correlation between TCM syndrome types of lung cancer and TNM staging, assisting in the diagnosis, treatment, and syndrome differentiation process.
Methods
Literature sources and search strategies
This meta-analysis was conducted in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. The literature was searched electronically, including the CNKI, PubMed, VIP, and Wanfang databases. The search deadline was May 2023. The Chinese search keywords were: lung cancer, lung malignancy, differential diagnosis, syndrome type, and TNM stage. First, search for subject words and unrestricted words using various database search retrieval techniques. To weed out the studies that satisfied the inclusion requirements, an advanced search was carried out in accordance with the features of various databases.
Data selection
According to the design, we imported the literature search results into Endnote to ensure that no duplicate literature appeared and that each study was performed independently by two reviewers. Any differences were resolved by discussing and backtracking the original research based on the following inclusion and exclusion criteria.
Inclusion criteria
Study design: This study was a controlled trial, and the design was based on published literature;
Subjects: According to the TNM staging system recommended by the Union for International Cancer Control, the American Joint Committee on Cancer, and the National Comprehensive Cancer Network guidelines, patients who have been diagnosed with lung cancer based on pathology or cytology are divided into four stages (I, II, III, and IV).9 Stages I and II are categorized in this study as early to mid-stage lung cancer, and Stages III and IV are categorized as advanced-stage lung cancer. Patients of all ages, geographical areas, and genders were included in the study;
Treatment method: No relevant requirement;
Results evaluation: The four syndrome kinds that were examined the most frequently in the literature were primarily TCM syndrome types, namely Qi Yin deficiency syndrome, Qi stagnation and blood stasis syndrome, Yin deficiency internal heat syndrome, and phlegm dampness syndrome. The correlation between the four syndromes was compared.
Exclusion criteria
Repeated publication or repeated detection of literature;
Too few included cases (less than 10);
Full text unavailable;
Complicated with other serious diseases, such as heart failure, kidney failure, etc;
Those not meeting diagnostic criteria; conclusions with incomplete data or data errors.
Research quality assessment
The ROBINS-I in the Cochrane Risk of Bias tool was used to assess the quality of the included literature. Studies involved: 1 Bias due to confounding; 2 Bias due to selection of participants; 3 Bias in the classification of interventions; 4 Bias due to deviations from intended interventions; 5 Bias due to missing data; 6 Bias in the measurement of outcomes; 7 Bias in selection of the reported result. Two inspectors carried out quality checks independently and a third researcher was asked to participate in consultation and judgment when there was disagreement.
Data analysis
The Meta outcomes were analyzed using RevMan 5.4 software (Nordic Cochrane Centre, Copenhagen, Denmark). The reference data of binary variables had a relative risk (RR) and 95% confidence interval (CI), and an χ2 test showed heterogeneity among different studies. A fixed effect model can be used if p > 0.5, I2 ≤ 50%, indicating good homogeneity. If p ≤ 0.5, I2 > 50%. The representative heterogeneity was large, so the random effects model could be used.
Results
Included in the study screening process
172 references were found in the initial search. After 10 duplicates were eliminated, 149 references were checked for relevance using the titles, abstracts, and keywords. Thirteen complete texts were read following the first round of screening. Finally, 7 references were included in this evaluation after 6 investigations were discarded. The sample sizes involved ranged from 11 to 120 (Fig. 1). This study mainly analyzed the TNM staging and pathological classification of four syndrome types: Qi Yin deficiency syndrome, Qi stagnation and blood stasis syndrome, Yin deficiency internal heat syndrome, and phlegm dampness syndrome.
Include the basic information of the article
The basic information included in the paper is shown in Table 1.10–16
Table 1Basic information about the article
Author and year | Diagnostic criteria | Phlegm dampness syndrome | Yin deficiency internal heat syndrome | Qi Yin deficiency syndrome | Qi stagnation and Blood stasis syndrome |
---|
Yu Weixia, 201712 | Histopathological confirmation | 36 | 12 | 40 | 21 |
Zeng Liang, 200811 | Confirmed by CT, cytology, or pathology | 20 | 14 | 11 | 7 |
Yang Qi, 201713 | The pathological results of lung cancer confirmed the diagnosis | 27 | 51 | 85 | 37 |
He Wenfeng, 201116 | Guidelines for Clinical Research of New Chinese Medicines | 63 | 29 | 8 | 12 |
Dong Jingbo, 201614 | Diagnostic criteria for primary bronchial lung cancer | 16 | 31 | 51 | 22 |
Bao Jianmin, 201815 | Diagnostic criteria for primary bronchial lung cancer in Internal Medicine | 33 | 22 | 21 | 26 |
Huang Donghua, 201310 | Cytological or pathological diagnosis of lung cancer, | 30 | 40 | 38 | 32 |
Results of meta-analysis
Correlation analysis of syndrome types in stages I and II
Seven studies reported a correlation between stages I and II and phlegm dampness syndrome and Yin deficiency internal heat syndrome.10–16 A heterogeneity test of the meta-analysis showed that χ2 = 9.73, p = 0.05, I2 = 59%, and there was no significant difference among all studies, allowing for the use of a fixed effects model. The difference between phlegm dampness syndrome and Yin deficiency internal heat syndrome was statistically significant (n = 264, RR = 3.77; 95%CI: 1.80–7.39, p = 0.0005; Fig. 2). The results show that in early lung cancer, phlegm dampness syndrome is more common than Yin deficiency internal heat syndrome.
Seven studies reported a correlation between stages I and II and phlegm dampness syndrome and deficiency of Qi Yin deficiency syndrome.10–16 A heterogeneity test of the meta-analysis showed that χ2 = 2.07, p = 0.72, I2 = 0%, and there was no significant difference among all studies, allowing for the use of a fixed effects model. The difference between phlegm dampness syndrome and Qi Yin deficiency syndrome was statistically significant (n = 264, RR = 6.67; 95%CI: 3.83–11.6, p < 0.00001; Fig. 3). The results show that in early lung cancer, phlegm dampness syndrome is more common than Qi Yin deficiency syndrome.
Seven studies reported a correlation between stages I and II and phlegm dampness syndrome and Qi stagnation and blood stasis syndrome.10–16 A heterogeneity test of the meta-analysis showed that χ2 = 10.86, p = 0.03, I2 = 63%, and there was no significant difference between the studies; thus, a fixed effects model could be used. The difference between phlegm dampness syndrome and Qi stagnation and blood stasis syndrome was statistically significant (n = 264, RR = 3.81; 95%CI: 2.50–5.79, p < 0.00001; Fig. 4). The results show that in early lung cancer, phlegm dampness syndrome is more common than Qi stagnation and blood stasis syndrome.
Seven studies reported a correlation between stages I and II and Yin deficiency internal heat syndrome and Qi Yin deficiency syndrome.10–16 A heterogeneity test of the meta-analysis showed that χ2 = 6.32, p = 0.18, I2 = 37%, and there was no significant difference among all studies; thus, a fixed effects model could be used. The difference was not statistically significant (n = 264, RR = 1.58; 95%CI: 0.8–3.15, p < 0.18; Fig. 5).
Seven studies reported a correlation between stages I and II and Yin deficiency internal heat syndrome and Qi stagnation and blood stasis syndrome.10–16 A heterogeneity test of the meta-analysis showed that χ2 = 8.49, p = 0.08, I2 = 53%, there was no significant difference among all studies, allowing for the use of a fixed effects model. The difference was not statistically significant (n = 264, RR = 0.90; 95%CI: 0.51–1.61, p = 0.73; Fig. 6).
Seven studies reported a correlation between stages I and II and Qi Yin deficiency syndrome and Qi stagnation and blood stasis syndrome.10–16 A heterogeneity test of the meta-analysis showed that χ2 = 7.16, p = 0.13, I2 = 44%, and there was no significant difference among all studies, allowing for the use of a fixed effects model. The difference between Qi Yin deficiency syndrome and Qi stagnation and blood stasis syndrome was statistically significant (n = 264, RR = 0.57; 95%CI: 0.29–1.12, p = 0.1; Fig. 7).
To sum up, in the middle of stages I and II, phlegm dampness syndrome > Yin deficiency internal heat syndrome (p < 0.5), phlegm dampness syndrome > Qi Yin deficiency syndrome (p < 0.5), and phlegm dampness syndrome > Qi stagnation and blood stasis syndrome (p < 0.5).
Correlation analysis of stage III and IV syndrome types
Seven studies reported correlations between stages III and IV and phlegm dampness syndrome and Yin deficiency internal heat syndrome.10–16 A heterogeneity test of the meta-analysis showed that χ2 = 81.29, p < 0.00001, I2 = 93%, and there was no significant difference among all studies; thus, a fixed effects model could be used. Yin deficiency internal heat syndrome was higher than phlegm dampness syndrome, and the difference was statistically significant (n = 264, RR = 0.61; 95%CI: 0.26–1.42, p = 0.25; Fig. 8).
Seven studies reported a correlation between stages III and IV and phlegm dampness syndrome and Qi Yin deficiency syndrome.10–16 A heterogeneity test of the meta-analysis showed that χ2 = 97.64, p < 0.00001, I2 = 94%, and there was no significant difference among all studies, allowing for the use of a fixed effects model. The difference between phlegm dampness syndrome and Yin deficiency internal heat syndrome was statistically significant (n = 264, RR = 0.53; 95%CI: 0.21–1.35, p = 0.18; Fig. 9). The results show that in advanced lung cancer, phlegm dampness syndrome is more common than Qi Yin deficiency syndrome.
Seven studies reported correlations between stages III and IV and phlegm dampness syndrome and Qi stagnation and blood stasis syndrome.10–16 A heterogeneity test of the meta-analysis showed that χ2 = 65.19, p < 0.0001, I2 = 91%, there was no significant difference between various studies; thus, a fixed effects model could be used. The difference between phlegm dampness syndrome and Qi Yin deficiency syndrome was statistically significant (n = 264, RR = 0.88; 95%CI: 0.38–2.02, p = 0.77; Fig. 10). The results show that in advanced lung cancer, phlegm dampness syndrome is more common than Qi stagnation and blood stasis syndrome.
Seven studies reported a correlation between stages III and IV and Yin deficiency internal heat syndrome and Qi Yin deficiency syndrome.10–16 A heterogeneity test of the meta-analysis showed that χ2 = 42.48, p < 0.00001, I2 = 86%, and there was no significant difference among all studies; thus, a fixed effect model could be used. The difference between Yin deficiency internal heat syndrome and Qi deficiency syndrome was statistically significant (n = 264, RR = 0.86; 95%CI: 0.53–1.38, p = 0.52; Fig. 11). The results show that in advanced lung cancer, Qi Yin deficiency syndrome is more common than Yin deficiency internal heat syndrome.
Seven studies reported a correlation between stages III and IV and Yin deficiency internal heat syndrome and Qi stagnation and blood stasis syndrome.10–16 A heterogeneity test of meta-analysis showed that χ2 = 14.27, p = 0.03, I2 = 58%, and there was no significant difference among all studies, allowing for the use of a fixed effects model. The difference between Yin deficiency heat syndrome and Qi stagnation and blood stasis syndrome was statistically significant (n = 264, RR = 1.35; 95%CI: 0.97–1.87, p = 0.08; Fig. 12). The results show that Yin deficiency internal heat syndrome is more common in advanced lung cancer than Qi stagnation and blood stasis syndrome.
Seven studies reported a correlation between stages III and IV and Qi Yin deficiency syndrome and Qi stagnation and blood stasis syndrome.10–16 A heterogeneity test of meta-analysis showed that χ2 = 16.36, p = 0.01, I2 = 63%, and there was no significant difference among all studies; thus, a fixed effect model could be used. The difference between Qi and Yin deficiency syndrome and Qi stagnation and blood stasis syndrome was statistically significant (n = 264, RR = 1.68; 95%CI: 1.21–2.33, p < 0.00001; Fig. 13). The results show that in advanced lung cancer, Qi Yin deficiency syndrome is more common than Qi stagnation and blood stasis syndrome.
To sum up, in stages III and IV, Qi Yin deficiency syndrome > Qi stagnation and blood stasis syndrome > Yin deficiency internal heat syndrome > phlegm dampness syndrome (p < 0.5).
Bias risk
Figure 14 presents the Cochrane risk assessment of bias for the included articles. The results showed that 2 trials had a moderate risk of bias and 5 trials had a low risk of bias.
Publication bias analysis
Seven pieces of literature that were part of the study were analyzed using the RevMan 5.4 program. The published pieces of literature were distributed in a concentrated manner, according to a funnel plot analysis, and both the symmetrical distribution and the funnel plot’s sides were invalid, indicating a potential publication bias that may be connected to the low caliber of the included research (Fig. 15).
Discussion
Chinese medicine categorizes lung cancer as “lung accumulation” and “cough” based on the clinical signs and symptoms.17 The loss of good Qi in the body, the combination of external pathogenic factors, the stagnation of evil Qi, the stagnation of lung Qi, the obstruction of Qi and blood flow, the obstruction of body fluid transport, the stagnation of water and fluid in the lungs, prolonged phlegm, the stagnation of Qi, the stasis of the veins, and the formation of lung accumulation over time are some of the theories put forth by scholars regarding the etiology and pathogenesis of lung cancer. The phrases “where evil is gathered, its Qi will be empty” and “ where healthy Qi is stored, evil cannot gather” in “Huangdi Neijing” show that the strength of good and evil Qi in the body determines the beginning, course, and prognosis of the disease.18
Early-stage solid lung cancer, characterized by both blood depletion and long-term deficiency, manifests as a body-wide insufficiency with local solid tumor manifestations.19 Common indicators of lung cancer include Qi Yin deficiency syndrome, Qi stagnation and blood stasis syndrome, Yin deficiency internal heat syndrome, and phlegm dampness syndrome. The book “Za Bing Yuan Liu Xi Zhu”, considers that lung cancer occurs when “evil accumulates in the chest and obstructs the airway; Qi cannot pass, becoming phlegm and blood; all the evil is fighting and winning, it is not controlled, and then forms a shape and a block.” Jiaozang’s lung is harmed by the external wind, cold, heat, dampness, dry fire, or internal injuries, as well as by food and exhaustion, leading to lung “Xuanfa Sujiang” function disorder and tumor formation.
TNM staging and TCM syndrome types have some correlation, which could serve as an additional foundation for differentiating TCM syndrome types and classifying lung cancer.20 When assessing the many forms of syndrome for lung cancer, the TNM staging results might serve as a reference index. The differentiation and categorization of lung cancer are influenced by various aspects, including the tumor’s nature, size, and development, as well as the patient’s experience with it. The diagnosis of lung cancer is aided by the study of TNM staging, which is also crucial for managing treatment, raising the rate of cure, and prolonging survival.21 The study of Bao Jianmin confirmed that the TNM stage of NSCLC patients has a certain relationship with TCM syndrome types.22 Using syndrome differentiation and classification of 113 cases of non-small cell lung cancer, he discovered that spleen-deficiency phlegm dampness syndrome was most common in stage I and II lung cancer; in contrast, Yin deficiency internal heat syndrome and Qi Yin deficiency syndrome dominated stage III lung cancer and stage IV lung cancer, respectively. Additionally, Dong et al.23 discovered a relationship between TNM stages and various indications of intermediate and advanced lung cancer.
This study conducted a meta-analysis of 7 included literature and compared the four syndrome types of Qi Yin deficiency syndrome, Qi stagnation and blood stasis syndrome, Yin deficiency internal heat syndrome, and phlegm dampness syndrome pairwise in TNM stages I, II, III, and IV. It was found that in stages I and II, phlegm dampness syndrome > Yin deficiency internal heat syndrome (p < 0.5), phlegm dampness syndrome > Qi Yin deficiency syndrome (p < 0.5), and phlegm dampness syndrome > Qi stagnation and blood stasis syndrome (p < 0.05), with all having statistical significance; in stages III and IV, Qi Yin deficiency syndrome > Qi stagnation and blood stasis syndrome > Yin deficiency internal heat syndrome > phlegm dampness syndrome (p < 0.05), with all being statistically significant. Phlegm dampness syndrome dominated in TNM stages I and II, and Qi Yin deficiency syndrome dominated in TNM stages III and IV.
Correct syndrome distinction is the key to improving the quality of diagnosis and treatment and syndrome differentiation and treatment is an important modality of TCM diagnosis and treatment. The academic community has consistently focused on the standardization and objectification of TCM syndrome-based diagnosis.24,25 Pathogenic buildup, phlegm dampness, Qi stagnation, blood stasis, stagnation heat, and toxicity are the key causes of cancer in its early stages. The primary causative element is phlegm dampness, which is a combination of positive deficiency and evil accumulation in the intermediate stage. Poison stasis persists during the late stage, but positive decay predominates. This is the most dangerous stage of lung cancer development if there is a coexisting Qi and Yin shortage.26 Adopting appropriate treatment methods based on syndrome differentiation can prolong the survival period of patients with advanced lung cancer.27,28 According to this study, the likelihood of a Qi Yin deficiency type increases the later the TMN stage, and the more likely it is that solid evil will invade the lung in its early stages or combine with a positive deficiency, mainly phlegm dampness syndrome. This observation essentially aligns with traditional Chinese medicine’s understanding of the pathological development process of lung cancer. It is evident that pathogenic variables change from shallow to deep when lung cancer advances, its TMN stage progressively increases, Qi continues to be depleted, Yin is harmed, and Qi Yin deficiency syndrome emerges.
Conclusion
The small sample size of the included literature may lead to a publishing bias. Therefore, clinical experimental investigations should be used to reinforce the regulations and standards for publishing bias. Research procedures for TCM syndrome sorts and Western medicine detection indicators should also be as random as possible. In conclusion, more weight should be given to the phlegm dampness syndrome type in TNM stages I and II and the Qi Yin deficiency syndrome in TNM stages III and IV. Because of this study’s shortcomings, a larger sample size and a traditional scientific research design are still needed.
Abbreviations
- CI:
confidence interval
- CT:
computed tomography
- PRISMA:
preferred reporting items for systematic review and meta-analyses
- RR:
relative risk
- SE:
standard error
- TCM:
traditional Chinese medicine
- TNM:
tumor-node-metastasis
Declarations
Data sharing statements
The data used to support the findings of this study are available from the corresponding author upon request.
Funding
This research was supported by the National Natural Science Foundation of China (Grant no. 81603412); Hebei Provincial Administration of Traditional Chinese Medicine (2019008); Hebei Province “Three Three Three Talent Project” funded project (Grant no. A202002008). General Projects for Improving Scientific Research Capacity of Hebei College of Traditional Chinese Medicine (Grant no. KTY2019009); Key Laboratory of Integrated Traditional Chinese and Western Medicine Hepatonephrosis in Hebei Province (Grant no. A201902); Hebei Graduate Innovation Funding Project (Grant nos. XCXZZSS2023017; XCXZZSS2023027).
Conflict of interest
DHL has been an editorial board member of Future Integrative Medicine since November 2021. The other authors report no conflict of interests in this work.
Authors’ contributions
DHL, HFF, JPZ, and XKL designed this research and were responsible for data preparation, writing, and revision of manuscripts; XHZ, HFF, LJZ, ML, and WLY were responsible for collecting data and translating the manuscript. The final manuscript has been read and approved by all authors.