Research advances in traditional Chinese medicine syndromes in cancer patients

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Review

Research advances in traditional Chinese medicine syndromes in cancer patients Qing Ji1,2, Yun-quan Luo3, Wen-hai Wang4, Xuan Liu2, Qi Li2, Shi-bing Su1 1. Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China 2. Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China 3. Department of Liver and Gallbladder Surgery, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China 4. Department of Medical Oncology, Seventh People’s Hospital of Shanghai, Shanghai 310000, China ABSTRACT Traditional Chinese medicine (TCM) syndrome, also known as TCM ZHENG or TCM pattern, is an integral and essential part of TCM theory that helps to guide the design of individualized treatments. A TCM syndrome, in essence, is a characteristic profile of all clinical manifestations in one patient that can be readily identified by a TCM practitioner. In this article, the authors reviewed the presentations of TCM syndromes in seven common malignancies (liver, lung, gastric, breast, colorectal, pancreatic and esophageal cancers), the objectivity and the standardization of TCM syndrome differentiation, the evaluation of TCM syndrome modeling in cancer research, and syndrome differentiation-guided TCM treatment of cancers. A better understanding of TCM syndrome theory, as well as its potential biological basis, may contribute greatly to the clinical TCM diagnosis and the treatment of cancer. Keywords: traditional Chinese medicine; TCM syndrome differentiation; biological basis; TCM treatment; cancer; review Citation: Ji Q, Luo YQ, Wang WH, Liu X, Li Q, Su SB. Research advances in traditional Chinese medicine syndromes in cancer patients. J Integr Med. 2016; 14(1): 12–21.

1 Introduction

stasis and phlegm stagnation, over time [3]. These are specifically classified as cancer toxins[4]. Cancer toxins must exist before the formation of malignant tumors, which grow in the target organs (“the soil”); the stasis, phlegm and other pathological factors are “the fertilizers” that feed the tumors. Therefore, stasis, phlegm and other pathological patterns produce cancer toxins in the target organ, take root, grow and metastasize to other sites. The TCM concept of qi is akin to the human body’s vital energy. It helps to maintain blood circulation, warm the body, and fight against diseases. Vital qi is the body’s defense and repair system, while evil qi incites pathogenic

Traditional Chinese medicine (TCM) has the concept of syndromes, known as ZHENG in Chinese, an integral and essential part of TCM theory[1]. A TCM syndrome is a profile of signs and symptoms that are clinical phenotypes reflecting the essence of pathological changes at certain stages of a disease. TCM syndromes can be useful for identifying patterns in the human body, and helping to guide TCM treatments[2]. TCM theory of tumor pathogenesis describes the invasion of pathogenic evils, such as qi stagnation, blood

http://dx.doi.org/10.1016/S2095-4964(16)60237-6 Received March 27, 2015; accepted May 4, 2015. Correspondence: Shi-bing Su, PhD, Professor; E-mail: [email protected]. Qi Li, MD, PhD, Professor; E-mail: [email protected]

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factors. The interplay between vital qi and evil qi determines how diseases such as cancer develop in the body[5]. An evil qi, i.e., cancer toxin, can accumulate in the body, and if it overcomes the vital qi, cancer can befall. At the early stage of cancer, both the evil qi and the vital qi are strong, so the patient may have an excessive syndrome. Once cancer toxins impair the vital qi, excess and deficiency syndromes may coexist. During the development of cancer, the cancer toxins often deplete the vital qi, accelerating cancer progression and metastasis. Deficiency syndrome in the progression of cancer is an extremely important clinical phenotype and cause of pathology, especially in the advanced stages[6]. Strengthening the vital qi and eliminating the evil qi are general TCM principles in the treatment of disease, including cancer. An effective TCM treatment must begin with a correct syndrome differentiation. One type of cancer may exhibit different TCM syndromes, while different cancers may have an identical syndrome. Therefore, the classical TCM therapeutic principle, “same disease treated by different therapies” or “different diseases treated by same therapy”, is usually adopted in cancer treatments. Patients who have undergone tumor resection, postoperative chemotherapy, radiotherapy or immunotherapy, or have not tolerated the above therapies, can be treated by TCM based on syndrome differentiation[7]. In this study, the authors reviewed the recent advances in research on TCM syndromes in cancer patients, including presentations of TCM syndromes, objectivity and standardization of TCM syndrome differentiation, biological basis of TCM syndromes, and TCM syndrome differentiation-based TCM treatment of cancer.

dampness-heat, as well as deficiency of qi and yin. In non-small-cell lung cancer (NSCLC), according to the reports by Yuan et al[9] in 2011, qi deficiency, blood stasis, yin deficiency, phlegm-dampness dominated in TCM syndromes of the 120 patients with advanced NSCLC. In gastric cancer, a summary of TCM syndromes in 767 patients were ranked as follows: liver-stomach disharmony, exuberance of stomach heat, deficiency-cold of spleenstomach, internal retention of blood and toxin stagnation, stagnation of phlegm-dampness and qi deficiency[10]. In esophageal cancer, the main TCM syndromes were qi deficiency and yang declination, yin deficiency, phlegmdampness and blood stasis[11]. In pancreatic cancer, 47 late-stage patients mainly suffered from 4 syndromes: qi stagnation and blood stasis, spleen deficiency and qi stagnation, deficiency of qi and yin, and qi deficiency and blood stasis[12]. In breast cancer, 95 patients were categorized into qi deficiency (n = 37), blood deficiency (n = 26), yin deficiency (n = 40), and yang deficiency (n = 28); taking all the accompanying syndromes into account, there were a total of 131 TCM syndromes. As a whole, the patients with qi deficiency syndrome had a lower quality of life[13]. In colorectal cancer[14], the most common syndromes arranged in descending order were blood deficiency, qi and yin deficiency, phlegm-dampness, and relative equilibrium of yin-yang (not meeting with the syndrome diagnostic criteria). Within TCM theory, yin and yang are complementary but opposite parts of a dynamic system that interact within a greater whole. Generally speaking, yang embodies characteristics such as moving, ascending, brightness, progressing, hyperactivity, and is often attributable for functional diseases of the body; while yin embodies characteristics such as stillness, descending, darkness, degeneration, hypo-activity, and is more involved in organic diseases. 2.2 Different TCM syndromes, same cancers; same TCM syndromes, different cancers Analysis of Table 1 shows that deficiency syndromes account for 27.89% of liver cancer, 67.54% of lung cancer, 18.64% of gastric cancer, 44.44% of esophageal cancer, 38.31% of pancreatic cancer, 80.15% of breast cancer, and 61.90% of colorectal cancer. This demonstrates that the deficiency syndrome exists in nearly all the cancer patients. Particularly, qi deficiency is the main deficiency syndrome in liver, lung, esophageal, breast and colorectal cancers, and yin deficiency is commonly seen in liver, esophageal, breast and colorectal cancers. However, blood deficiency is only seen in colorectal cancer and breast cancer (Table 1). In addition, blood stasis is another syndrome existing in and different cancers including liver, esophageal, pancreatic and breast cancers, ranking first in liver, esophageal and pancreatic cancers. Otherwise, blood stasis is seldom seen in other cancers. Qi stagnation

2 Presentations and changes of TCM syndromes in cancers First of all, we systematically analyzed the clinical presentations of TCM syndromes in patients of seven types of cancer: liver, lung, gastric, pancreatic, breast, colorectal and esophageal cancers. Results are listed in Table 1. 2.1 General presentations of TCM syndromes in cancers According to TCM theory, liver cancer develops by the following process: depressed emotions, heat toxin, stagnation, improper diet and other internal injuries give rise to the disharmony of liver and spleen, and further aggravate the phlegm and blood stasis, which gradually accumulate and form a blockage in the flank [15]. After analyzing TCM syndrome types of 2 492 patients with primary liver cancer (PLC), Liu et al[8] found that the most common syndrome types were qi stagnation and blood stasis, liver stagnation and spleen deficiency, yin deficiency of liver-kidney, liver stagnation and qi stagnation, qi deficiency of spleen-stomach, dampnessheat of liver-gallbladder, internal accumulation of Journal of Integrative Medicine

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www.jcimjournal.com/jim Table 1 General distributions of TCM syndromes in cancers TCM syndromes in cancers

Case number

Liver cancer Qi stagnation and blood stasis Liver stagnation and spleen deficiency Yin deficiency of liver-kidney Liver stagnation and qi stagnation Qi deficiency of spleen-stomach Dampness-heat of liver-gallbladder Internal accumulation of dampness-heat Deficiency of qi and yin Others Lung cancer Qi deficiency Others Gastric cancer Liver-stomach disharmony Exuberance of stomach heat Deficiency-cold of spleen-stomach Internal retention of blood and toxin stagnation Stagnation of phlegm-dampness Qi deficiency Esophageal cancer Qi deficiency and yang declination Yin deficiency Phlegm-dampness Blood stasis Pancreatic cancer Qi stagnation and blood stasis Spleen deficiency and qi stagnation Deficiency of qi and yin Qi deficiency and blood stasis Internal accumulation of dampness-heat Qi stagnation and damp obstruction Spleen deficiency and damp obstruction Yin deficiency Phlegm obstruction and blood stasis Breast cancer Qi deficiency Blood deficiency Yin deficiency Yang deficiency Colorectal cancer Blood deficiency Qi and yin deficiency Phlegm-dampness Others

2 492 576 419 342 295 285 185 148 68 174 120 89 31 767 252 233 88 74 65 55 63 14 14 12 23 47 23 6 4 4 3 2 2 2 1 131 37 26 40 28 210 70 60 40 40

Proportion (%)

Reference [8]

23.11 16.81 13.72 11.84 11.44 7.43 5.94 2.73 6.98 [9] 74.17 25.83 [10] 32.86 30.38 11.47 9.65 8.47 7.17 [11] 22.22 22.22 19.05 36.51 [12] 48.94 12.77 8.51 8.51 6.38 4.26 4.26 4.26 2.11 [13] 28.24 19.85 30.53 21.37 [14] 33.33 28.57 19.05 19.05

TCM: traditional Chinese medicine.

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and blood stasis were found as accompanying syndromes in liver and pancreatic cancers, and were both the primary syndromes (Table 1). Our analysis of the clinical TCM syndromes in seven cancer types showed that each cancer has different sets of TCM syndromes. For example, in liver cancer[15], qi stagnation and blood stasis, liver stagnation and spleen deficiency, yin deficiency of liver-kidney, liver stagnation and qi stagnation, and qi deficiency of spleen-stomach were identified. Moreover, in PLC patients treated by transcatheter arterial chemoembolization (TACE), eight TCM single syndromes occurred in the 106 patients before the treatment, and those eight syndromes occurred in 456 cases after TACE. The number of qi stagnation syndrome cases decreased, while that of excess-heat syndrome, qi deficiency syndrome, blood deficiency syndrome, and yang deficiency syndrome cases increased after TACE[16]. 2.3 Dynamic changes of TCM syndromes in liver and colorectal cancers In the progression of cancer, TCM syndromes also change from early stage to late stage. TCM syndrome analysis for 2 060 patients with PLC showed that, comparing early to advanced stages, the occurrence rate and severity of the vital qi deficiency increased. This demonstrates that weaker vital qi from deficiency increases the ability of the evil qi pathogenic factors to do harm, which results in heightened seriousness of the illness[17]. Elsewhere, TCM syndrome changes help to explain the progression of colorectal cancer: the early stages show excessive syndromes, including qi stagnation and blood stasis, and damp-heat and toxin accumulation; in the intermediate stage, evil qi becomes stronger and vital qi is deficient, and both excessive and deficiency syndromes such as phlegm-dampness and qi and yin deficiency are present; and the advanced stage presents predominantly deficiency syndromes, including vital qi deficiency, blood deficiency, and qi and yin deficiency[18].

used with a questionnaire for TCM syndrome measurement and information collection. Cheng et al[19] established a questionnaire comprised of three parts: patient’s demographics, patients’ perception of bowel function, and the TCM syndrome patterns, which is diagnosed by a registered Chinese medicine practitioner who collects data with the four classic diagnostic methods, completes the table included in the questionnaire, and makes the patient’s TCM diagnosis. Traditional diagnoses are mainly dependent upon the TCM practitioner’s experience. In recent years, clinicians and researchers have worked on improving the four traditional diagnostic methods. Objective measures seek to quantify what were traditionally qualitative measures. These objective measures include computer-assisted quantitative approach for lip and tongue images; TCM pulse detectors that take place of pulse diagnosis based solely on the clinician’s tactile sense; and digitalization and quantification of techniques of auxiliary diagnosis based on the combination of the four TCM diagnostic methods[20–25]. Specifically, Liu et al[26] established the fuzzy mathematical model for syndrome differentiation of gastric cancer. Li et al[27] set up a quantitative model for evaluating the degree of the TCM basic syndromes often encountered in PLC patients. Hou et al[28] proposed a quantified diagnostic standard for colon cancer of spleen qi deficiency syndrome. 3.1.3 Data analysis and mining for TCM syndrome differentiation TCM syndromes are not merely an assembly of various disease symptoms, but also an organization of interrelated clinical manifestations defined by TCM theory. The symptoms and signs in TCM syndrome measurement can be analyzed by statistical tools for their use in TCM syndrome differentiation. Recent research has presented clinical information dimensionality reduction and data mining for TCM syndrome differentiation. Data mining for TCM syndrome differentiation in cancer has been carried out using logistic regression in gastric cancer[29]. Liu et al[26] developed a method for establishing the fuzzy mathematical model for syndrome differentiation of gastric cancer based on the analysis of 769 cases, and found that the actual coincidence rate in TCM syndromes of disharmony between liver and stomach was 65.00%; in yin deficiency due to gastric heat was 72.22%; in deficiencycold of spleen and stomach was 70.00%; in blood stasistoxin was 57.14%; in phlegm-dampness was 53.33%; and in exhaustion of both qi and blood was 72.22%. The overall coincidence rate was 65.71%, which offers a solution for objective research of TCM syndrome differentiation. This analysis model offers a good solution for objective research of syndrome differentiation in diagnosing cancers. Li et al[27] established a quantitative model for evaluating the degree of the TCM basic syndromes often encountered

3 Objectivity of TCM syndrome differentiation in cancer 3.1 TCM syndrome differentiation in cancer 3.1.1 General understanding of TCM syndrome differentiation Syndrome differentiation is an important tool that TCM practitioners use to accurately understand and treat diseases, including cancer. Different syndromes can exist for one kind of cancer, and all the diagnostic methods of TCM may be used for identifying the syndromes. 3.1.2 Clinical TCM syndrome measurement and information collection The four main diagnostic methods in TCM are inspection, auscultation and olfaction, inquiry, and palpation. These are Journal of Integrative Medicine

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in patients with PLC, and the verification on 459 times/cases of PLC showed that the coincidence rate between the outcomes derived from specialists and those from the additive model was 84.53%, and with those from the additive-multificative model was 62.75%; the difference between the above two showed statistical significance. This principle model is suitable for quantitative evaluation for the degrees of TCM basic syndromes in patients with PLC. Hou et al[28] set up a quantified diagnostic standard for colon cancer of spleen qi deficiency syndrome, including weakness, fatigue, loose stool and poor appetite. The data analyzed by this method were in accordance with clinical characteristics of “colon cancer” and “TCM syndrome”. However, to apply this method to the actual patients, validation in large-sample clinical trials is needed. 3.2 Biological basis of TCM syndrome differentiation in cancer 3.2.1 Physiological and pathological features Many physiological and pathological features are associated with the TCM syndromes in cancers, such as tongue images[30,31], fungal pneumonia[32], glucose metabolic rate[33], trace elements[34,35], and function of autonomic nervous system[36,37]. With regard to tongue images, Su et al [30] revealed a significant statistical difference between different syndrome groups of lung cancer on tongue color, coating color, and thickness of tongue coating. Deng et al[31] found that the proportion of normal tongue manifestation was higher in healthy adults (38.89%) than that in patients with PLC (2.32%), which provided supportive evidence for the use of tongue inspection in syndrome differentiation . For the trace elements, previous research results demonstrated that the levels of serum selenium (Se) reflected the change between the pathogenic factors and body resistance in lung cancer, suggesting that some Chinese medicinal herbs rich in Se should be selected to treat lung cancer so as to improve the therapeutic effect[34]. Other authors found that the Cu/Zn ratio can reflect the change of body resistance and pathogenic factors, suggesting that the ratio of Cu/Zn may be used as the criteria of TCM syndrome differentiation in lung cancer[35]. 3.2.2 Tumor markers in clinical application In Western medicine, many tumor markers are used as indicators for diagnosis and prognosis of cancers. Hence, the correlations between tumor markers and TCM syndromes were investigated. Yan et al[38] showed that the levels of a variety of tumor markers including CA19-9, CEA and CA242 were elevated in all 30 patients with lung cancer. The levels of tumor markers in patients with excessive syndromes, such as qi stagnation and blood stasis, phlegm turbidity and lung obstruction, and excessive heat and toxin, all increased significantly, and were higher than those of deficiency January 2016, Vol.14, No.1

syndromes such as qi and yin deficiency. These results show that CA19-9, CEA and CA242 may be related to the “excessive pathogens” in lung cancer, which supports the basic TCM therapeutic principles of “clear the excessive pathogens” when treating cancer. Yu et al[39] demonstrated higher levels of CEA, CA19-9, CA125, AFP and CA153 in 200 colorectal cancer patients who had different TCM syndromes. CEA levels were the highest in patients with the syndrome of internal accumulation of blood-toxin. The levels of CA19-9, CA125 and CA153 in patients with yin deficiency of liver-kidney syndrome were higher than those in patients with other syndromes. These results implied that, tumor markers can define TCM syndrome differentiation and guide the alternative TCM treatments in colorectal cancer. 3.2.3 Gene expression and gene polymorphism Cancer is known to be influenced by changes to genes that control the body’s phenotypes[40]. Gene polymorphisms and expressions are correlated tightly with tumorigenesis and the progression of cancer. The correlation between TCM syndromes and gene expression and polymorphism has been studied. Wang et al [41] found that heat shock 70 kD protein (HSP70) and P53 positive ratio and HSP70 expression levels in patients with malignant tumor with TCM heat syndrome were higher than those in patients with nonheat syndrome. Chen et al [42] demonstrated that high vascular endothelial growth factor (VEGF) expression levels positively correlated with gastric cancer metastasis with liver-stomach disharmony syndrome and phlegmstasis-poison stagnant syndrome. Luo et al[43] showed that the serum levels of VEGF, endostatin, soluble intercellular adhesive molecule-1 and CD44 can serve as the microcosmic basis for qi-deficiency and blood stasis syndrome differentiation. Pan et al [44] revealed the characteristics of gene expression (33 up-regulated coincident genes and 26 down-regulated coincident genes) in adrenal glands of H22 tumor mice correlated with typical syndromes and the different liver cancer stages. All these results demonstrated that the altered gene expressions significantly affect the patients’ TCM syndromes. Gene polymorphism was shown to be another important factor affecting the TCM syndromes in various cancer patients. Cui et al[45] found that the frequencies of crosscomplementing 1 (ERCC1) C19007T genotype and allele in different TCM syndrome types of colorectal cancer patients had statistical difference. Moreover, statistical difference existed between dampness-heat accumulation syndrome and yang deficiency of spleen-kidney syndrome as well as yin deficiency of liver-kidney syndrome, and between qi stagnation with blood stasis syndrome and yang deficiency of spleen-kidney syndrome as well as yin deficiency of liver-kidney syndrome. Zhang et al[46]

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showed significant difference in E-cadherin (CDH1) gene (rs13689) genotype distributions between several pairs of TCM syndromes of gastric cancer, and the formation of the syndrome was related to EGF, TGFA (rs11466285), and EGFR (rs884225) gene polymorphisms. This tight connection of the gene polymorphism and TCM syndromes will provide benefits for syndrome differentiation and TCM treatment. 3.3 TCM syndrome identification following systemomics approach Systems biology (“-omics”) technologies including genomics, transcriptomics, proteomics and metabonomics are rapidly growing large-scale detection technologies[47]. With features such as non-destructiveness, integrity, multi-target, high-throughput, and digitalization, it may be feasible to use system-omics to investigate TCM syndromes, which will be characterized by multi-factors, multi-phenotypes, and dynamic-status approaches[48]. Gao et al[49] showed in pancreatic cancer that, certain miRNAs miR-17, miR-21 and miR-181b were found to be specifically expressed in TCM dampness-heat syndrome, and miR-196a in spleen deficiency syndrome. These studies indicated that miRNAs may play important roles in different syndromes, and can be potential molecular markers for the diagnosis of TCM syndromes in cancer. Liu et al[50] screened serum tumor biomarkers by surfaceenhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) to establish a subset which could be used for the prediction of qi deficiency syndrome and phlegm and blood stasis syndrome in NSCLC patients. Fifteen serum proteins were selected as significant biomarkers, and the predictive model can be used to discriminate among Chinese medicine diagnostic models of disease. Yang et al[51] studied the different expression levels of serum proteins in patients with PLC, and showed that different peaks of serum proteins occurred in different TCM syndromes of PLC in the perioperative period of interventional treatment. Additionally, compared with the healthy control group, the expression of serum proteins was significantly down-regulated in liver depression syndrome, damp-heat syndrome, and yin deficiency syndrome, while being up-regulated in spleen deficiency syndrome and in blood stasis syndrome. Compared with that in the preintervention patients, the expression of serum proteins was down-regulated in Gan depression syndrome, Pi deficiency syndrome, damp-heat syndrome and blood stasis syndrome, while being up-regulated in yin deficiency syndrome[52]. 3.4 Molecular mechanisms of TCM syndromes in cancer TCM syndrome is a phenotype, underlined by the multi-level, complicated interaction of biological molecules, their functions and/or signal pathways in the live body, suggesting an imbalance in the biological molecular network at the systematic level. The biological molecular “multiple factor interaction-biological network-multiple function” Journal of Integrative Medicine

network warrants a new research direction for TCM syndromes of cancer, TCM syndrome-oriented effects of Chinese herbal medicines or formulas, and ultimately a better understanding of the molecular mechanisms of cancer. In an miRNA array analysis by Chen et al[53], hepatocellular carcinoma (HCC) had gene ontology terms that were more stringently associated with liver-kidney yin deficiency syndrome (LKYDS) and deregulated the core cellular functions. Compared with Kyoto Encyclopedia of Genes and Genomes pathway, liver-gallbladder dampness heat syndrome was only related to small-cell lung cancer, liver depression and spleen deficiency syndrome (LDSDS) mainly associated with cell cycle, focal adhesion, endocytosis and cancer pathways, and LKYDS associated with apoptosis, chronic/acute myeloid leukemia and many cancer related pathways. Compared with BIOCARTA p a t h w a y, L K Y D S w a s m a i n l y a s s o c i a t e d w i t h transcriptional regulation and map kinase pathways, while LDSDS more likely related to cell cycle, cyclins, and cell cycle regulation. By analysis of gene-chip, Pan et al [54,55] found that compared to normal mice, in H22 tumor mice, ERK signal pathway was activated most in yang deficiency syndrome, p38 and ERK5 signal pathway was activated most in toxin syndrome, and JNK signal pathway was inhibited most in yang deficiency syndrome. In addition, gene products of Smad signal pathway in adrenal gland were activated most in mice bearing H22 liver cancer with different TCM syndromes. For example, TGF-Br1, Bmp3 and Smad8 decreased in evil-toxin exuberance syndrome, but increased in yang qi deficiency syndrome; TGF-Br2 and Bmp5 increased in evil-toxin exuberance syndrome and qi deficiency syndrome, but decreased in qi and yinyang deficiency syndrome. 3.5 Animal models of TCM syndromes in cancer Appropriate animal models can help in our understanding of the onset and development of TCM syndromes and the TCM syndrome-based treatment in the progression of cancer. Dai et al[56] established subcutaneous tumor models of pancreatic cancer syndromes of damp-heat and spleen deficiency, and found that the tumor growth of dampheat syndrome was slower than that of the control nonsyndrome group. They found that the levels of CCR5 protein increased in damp-heat syndrome and spleen deficiency syndrome. Additionally, the lowest levels of CCL5 and CCL4 expression were found in damp-heat syndrome. All the results suggested that different TCM syndromes may influence the tumor growth in pancreatic cancer via regulating the expression of CCR5/CCL5/CCL4. Chen et al[57] established a xenograft tumor mouse model with blood stasis syndrome, and found that mice with the blood stasis syndrome developed less metastasis than their counterparts without blood stasis. Yin et al[58] established

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a pancreatic cancer xenograft mouse model with dampheat syndrome, and found that damp-heat syndrome mice exhibited altered cancer-associated myofibroblast proliferative activities and tumor-associated macrophage infiltration. In our previous study[59], we established 4T1 mouse breast cancer with “liver fire invading stomach” syndrome model (4T1 LFISS mice), and there were the features of LFISS including irritability, loss of appetite, yellow urine, and hot tails and/or claws in the 4T1 LFISS mice. In summary, good animal models will provide effective tools for understanding the TCM syndromes in cancers and guide the syndrome differentiation-based TCM treatment.

was treated with Erchen decoction for awaking spleen and removing dampness; blood stasis syndrome was treated with Xuefu Zhuyu decoction for removing stasis; intestinal damp-heat syndrome was treated with Siteng decoction for clearing intestine and removing dampness[65]. 4.2 Different cancers with the same treatment If presenting the same TCM syndromes, different cancers can be treated with the same medicine. One example is Aidi injection, which is used to treat several types of cancer with qi deficiency, such as small-cell lung cancer, colorectal cancer, gastrointestinal cancer and liver cancer. Aidi injection is generally combined with chemotherapy[66]. More than 140 clinical studies between the years of 2001 and 2009 tested the Aidi recipe, which consists of the four herbs Radix Astragali (Huangqi), Radix Ginseng (Renshen), Acanthopanacis Senticosi (Ciwujia), and Mylabris (Banmao). Among them, Ginseng mainly strengthens vital qi, while Astragali and Mylabris have anti-cancer and detoxification effects. Shenling Baizhu powder, a broadly used anti-cancer TCM medicine in the treatment of various malignant tumors, has spleen-strengthening and qi-nourishing effects. Clinical studies showed that Shenling Baizhu powder improves the deficiency of spleen and stomach qi syndrome of colorectal cancer with liver metastases, lung cancer, ovarian cancer with peritoneal metastases, or breast cancer with lung and bone metastases[67].

4 Syndrome differentiation-based TCM cancer treatment 4.1 The same cancer with different treatments If two people with the same type of cancer present with different TCM syndromes, they should be treated with different therapeutic approaches. For example, liver cancer could manifest as spleen deficiency and qi stagnation, and thus be treated by spleen-strengthening and qi-regulating principles[60], or it can manifest as blood stasis syndrome, in which case the treatment would focus on removing blood stasis[61]. Previous study of treating PLC indicated that the most frequently used herbs were for strengthening the spleen, which helped promote appetite, remove toxic materials, inhibit tumor growth and activate blood circulation[62]. As for lung cancer, Chen et al[63] treated patients of different TCM syndrome types with different oral Chinese herbal medicines. For example, spleen deficiency and phlegm-dampness syndrome was treated with Liujunzi decoction for strengthening the spleen, removing dampness, regulating qi, and removing phlegm; yin deficiency inner heat syndrome was treated with Baihegujin decoction for clearing lung-heat and nourishing lung-yin; qi and yin deficiency syndrome was treated with Shengmai powder and Shashen-Maidong decoction for nourishing qi and yin; yin and yang deficiency syndrome was treated with Shashen-Maidong decoction and Zanyudan for warming yang and nourishing yin; qi stagnation and blood stasis syndrome was treated with Fuyuan Huoxue decoction for regulating qi and removing blood-stasis. In addition, intravenous injection of Kanglaite is frequently used as a basic TCM treatment choice for lung cancer[64]. As for colorectal cancer, the same treatment strategy is also applied. For instance, patients with spleen qi deficiency syndrome were treated with Sijunzi decoction for strengthening spleen and nourishing qi; kidney yang deficiency syndrome was treated with Erxian decoction for invigorating kidney yang; kidney yin deficiency syndrome was treated with Liuwei Dihuang decoction for nourishing kidney yin; dampness stagnation syndrome January 2016, Vol.14, No.1

5 Prospects and challenges In TCM practice, Chinese herbal medicines are prescribed according to a syndrome, and that syndrome guides the treatment. However, some important issues still need to be addressed. First of all, as syndrome differentiation is usually based upon the treating physician’s intuition and personal experience, the results may be different between different physicians or clinics. The differentiation process lacks reproducibility, and no standard diagnostic criteria have been published. It remains one of the main obstacles to the wide application of TCM in the clinical and research settings. Therefore, a large, multi-center, high-throughput data collection and analysis platform of TCM syndromes in clinical cancer research is direly needed. Secondly, in this review, we emphasized the importance of TCM syndromes since they help guide the design of individual patients’ treatment regimen, and the reported studies we referred to may be helpful for the clinical diagnosis and treatment in TCM syndromes of cancer. However, it bears mentioning that so far syndrome differentiation-based TCM treatments have not produced consistent satisfactory therapeutic effects in cancer treatment. Recently, there has been increasing interest in the potential clinical use of the theory “analogous TCM syndrome type existing in

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the same disease”[68], which means that the patients who suffer from the same disease may manifest a common basic syndrome type, in spite of slight differences in other accompanying minor syndromes. Therefore, a strategy combining TCM syndrome differentiation and disease diagnosis is considered as the most promising approach for future cancer treatment. While many studies have attempted to elucidate the molecular basis of the cancer-associated TCM syndromes, the available data are subject to several limitations when guiding the clinical cancer treatment. First, TCM is focused on alleviating a particular disease or a symptom, while the TCM syndrome is based on systemic and holistic concepts. Thus, a systems biology approach may be the optimal way to investigate the clinical use and therapeutic efficacy of TCM syndrome. Second, at present, TCM is practiced with respect to the rules of “treating the same diseases with different methods” and “treating different diseases with the same methods”. The same molecular mechanisms underlying the same TCM syndromes in different cancers have been elucidated by many researchers. So cancer- or diagnosis-specific molecular mechanisms, which may share a TCM syndrome, might prove particularly important in designing effective individualized TCM treatment regimens. Third, a comprehensive profile of TCM syndrome-specific molecules has not been identified, and the correlation between TCM syndromes and biological molecules has to be firmly established. And last, we should acknowledge that TCM syndromes are now considered as multisystem and multiorgan functional impairment as well as a phenotype. With more and more modern technologies being applied in TCM syndrome research, we are getting closer to obtaining a clear understanding of the exact molecular basis and mechanisms of TCM syndromes in cancers.

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6 Acknowledgements This study was supported by Key Program of National Science Foundation of China (No. 81330084), 085 First-Class Discipline Construction Innovation Science and Technology Support Project of Shanghai University of TCM (No. 085ZY1206), E-institutes of Shanghai Municipal Education Commission (No. E03008), and National Natural Science Foundation of China (No. 81303102, 81303103, 81473478, and 81473628).

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7 Competing interests The authors declare that they have no competing interests.

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REFERENCES 1

Su SB, Lu A, Li S, Jia W. Evidence-based ZHENG: a traditional

Journal of Integrative Medicine

18

19

Chinese medicine syndrome. Evid Based Complement Alternat Med. 2012; 2012: 246538. Chen Z, Wang P. Clinical distribution and molecular basis of traditional Chinese medicine ZHENG in cancer. Evid Based Complement Alternat Med. 2012; 2012: 783923. Ling CQ. My view on traditional Chinese medicine etiology and pathogenesis of cancer. Zhong Yi Za Zhi. 2009; 50(10): 952–953. Chinese. Ling CQ. Cancerous toxin is the key pathogenic factor of malignant tumor. J Chin Integr Med. 2008; 6(2): 111–114. Chinese with abstract in English. Yue XQ. Towards better understanding the definition of cancerous toxin. J Chin Integr Med. 2010; 8(9): 829–831. Chinese with abstract in English. Wang XM, Zhang Q. Discussion on occurrence and development of tumor based on ‘cancerous toxin’. Zhonghua Zhong Yi Yao Za Zhi. 2011; 26(7): 1533–1536. Chinese with abstract in English. Ling CQ. Problems in cancer treatment and major research of integrative medicine. J Chin Integr Med. 2003; 1(3): 168–170. Chinese with abstract in English. Liu YJ, Fang ZQ, Di RH, Xu LY. Statistical analysis of clinically reported syndromes differentiation of 2492 PHC cases. Zhongguo Zhong Yi Ji Chu Yi Xue Za Zhi. 2001; 7(6): 69–71. Chinese with abstract in English. Yuan L, Zhang PT, Yang ZY. Study on Qi deficiency syndrome distribution and quality of life in patients with advanced non-small cell lung cancer. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2011; 31(7): 880–883. Chinese with abstract in English. Sun DZ, Liu L, Jiao JP, Wei PK, Jiang LD, Xu L. Syndrome characteristics of traditional Chinese medicine: summary of a clinical survey in 767 patients with gastric cancer. J Chin Integr Med. 2010; 8(4): 332–340. Yang ZJ, Zhang Y, Guo ZQ. Preliminary study on relationship between syndrome differentiation of esophageal cancer and changes of exfoliated cells of tongue coating. Zhongguo Zhong Xi Yi Jie He Za Zhi. 1995; 15(5): 277–280. Chinese with abstract in English. Liang F, Sun J, Li Q, Li CH, Fan ZZ. Analysis of clinical syndromes in 47 patients with pancreatic cancer at late stage. J Tradit Chin Med. 2011; 31(3): 182–184. Chien TJ, Song YL, Lin CP, Hsu CH. The correlation of traditional Chinese medicine deficiency syndromes, cancer related fatigue, and quality of life in breast cancer patients. J Tradit Complement Med. 2012; 2(3): 204–210. Guo Y, Zou Y, Xu YF, Wang H, Li Y, Qian LY, Yang WH. Study on Chinese medicine syndrome of colorectal carcinoma in perioperative period. Chin J Integr Med. 2015; 21(3): 183–187. Cheng RF, Wu ZL. Discussion of the pathogenesis theory of primary liver cancer: deficiency, depression, phlegm, blood stasis, toxin. Shandong Zhong Yi Za Zhi. 2014; 33(10): 804–806. Chinese with abstract in English. Zhang YH, Qin X, Xu J. Analysis of Chinese medical syndrome features of patients with primary liver cancer before and after transcatheter arterial chemoembolization. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2012; 32(9): 1171–1174. Chinese with abstract in English. Fang ZQ, Li YJ, Tang CL, Ma J, Guan DY, Chen DS. Analysis on characteristics of syndromes in 2060 cases of primary hepatic cancer. Zhong Yi Za Zhi. 2004; 45(1): 53–55. Chinese with abstract in English. Zhang YM. Bo Liansong’s experience in treating large January 2016, Vol.14, No.1

www.jcimjournal.com/jim

19

20

21

22 23

24

25

26

27

28

29

30 31

32

33

intestine cancer by supporting healthy qi and eliminating pathogenic facors. Shanghai Zhong Yi Yao Za Zhi. 2005; 39(9): 28. Chinese. Cheng CW, Kwok AO, Bian ZX, Tse DM. The quintessence of traditional Chinese medicine: syndrome and its distribution among advanced cancer patients with constipation. Evid Based Complement Alternat Med. 2012; 2012: 739642. Li F, Zhao C, Xia Z, Wang Y, Zhou X, Li GZ. Computer-assisted lip diagnosis on traditional Chinese medicine using multi-class support vector machines. BMC Complement Altern Med. 2012; 12: 127. Yue XQ, Liu Q. Analysis of studies on pattern recognition of tongue image in traditional Chinese medicine by computer technology. J Chin Integr Med. 2004; 2(5): 326–329. Chinese with abstract in English. Pang B, Zhang D, Li N, Wang K. Computerized tongue diagnosis based on Bayesian networks. IEEE Trans Biomed Eng. 2004; 51(10): 1803–1810. Hu JQ, Zhao T, Xu GC, Wu L, Kou QA, Zhuang H, Li ZH, Su ML, Zhang GF. Assessment on the accuracy of four types of pulse by SM-1A TCM pulse detector. Shi Jie Ke Xue Ji Shi Zhong Yi Yao Xian Dai Hua. 2011; 13(1): 74–77. Chinese with abstract in English. Niu X, Yang XZ, Zhu QW, Li HY, Ma LX, Niu TL, Guo Z, Dong XY. Realization of the digitalization and quantification of key techniques of auxiliary diagnosis based on the four TCM diagnostic methods used in combination. Shi Jie Ke Xue Ji Shi Zhong Yi Yao Xian Dai Hua. 2011; 13(1): 64–69. Chinese with abstract in English. Wang YQ, Yan HX, Guo R, Li FF, Xia CM, Yan JJ, Xu ZX, Liu GP, Xu J. Study on intelligent syndrome differentiation in traditional Chinese medicine based on multiple information fusion methods. Int J Data Min Bioinform. 2011; 5(4): 369–382. Liu L, Xu L, Sun DZ, Wei PK. Establishment of a fuzzy mathematical model for syndrome differentiation of gastric cancer. J Chin Integr Med. 2008; 6(11): 1117–1121. Chinese with abstract in English. Li DT, Ling CQ, Zhu DZ. Study on the quantitative evaluation on the degree of TCM basic syndromes often encountered in patients with primary liver cancer. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2007; 27(7): 602–605. Chinese with abstract in English. Hou FG, Cen Y, Guan J, Zhu LY, Yin XL. Quantified diagnostic standard for large intestinal cancer of spleen qi deficiency syndrome. J Chin Integr Med. 2009; 7(9): 814–818. Chinese with abstract in English. Luo HG, Han Z, Li JX, Ma R, Yuan Q, Song XJ, Huang XM. Study on syndrome law of gastric precancerous lesion in traditional Chinese medicine. Zhonghua Zhong Yi Yao Za Zhi. 2007; 22(6): 399–401. Chinese. Su W, Xu ZY, Wang ZQ, Xu JT. Objectified study on tongue images of patients with lung cancer of different syndromes. Chin J Integr Med. 2011; 17(4): 272–276. Deng WZ, Yue XQ, Liu Q, Gao JD, Ren RZ, Ling CQ. Comparative study on normal tongue manifestation in patients with primary liver cancer and healthy adults. J Chin Integr Med. 2006; 4(1): 13–16. Chinese with abstract in English. Hu KW, Wang F, Cao Y, He XL, Zuo MH, Chen WQ. Risk factors of traditional Chinese medical syndromes in moderate and advanced lung cancer patients with concurrent fungal pneumonia. J Chin Integr Med. 2004; 2(5): 337–339. Chinese with abstract in English. He SL, Dong JC, Guan YH. Study on glucose metabolic

January 2016, Vol.14, No.1

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35

36

37

38 39 40 41

42

43

44

45

46

47

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rate in non-small cell lung cancer patients with blood stasis syndrome and non-blood stasis syndrome. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2004; 24(1): 44–46. Chinese with abstract in English. Mi YY, Hu YJ, Zhou MZ. Study of relationship between level of serum selenium and syndrome differentiation and typing of traditional Chinese medicine in lung cancer. Zhongguo Zhong Xi Yi Jie He Za Zhi. 1995; 15(11): 658– 660. Chinese with abstract in English. Mi YY, Zhou MZ. Probe into internal relation between classification of the differentiation-syndrome in traditional Chinese medicine and serum copper and zinc in lung cancer. Zhongguo Zhong Xi Yi Jie He Za Zhi. 1992; 12(3): 154–156. Chinese with abstract in English. Lin SC, Huang ML, Liu SJ, Huang YF, Chiang SC, Chen MF. Severity of Yin deficiency syndrome and autonomic nervous system function in cancer patients. J Altern Complement Med. 2009; 15(1): 87–91. Lin SC, Chen MF. Increased yin-deficient symptoms and aggravated autonomic nervous system function in patients with metastatic cancer. J Altern Complement Med. 2010; 16(10): 1059–1063. Yan XS, Li HM, Peng YQ. The relevant research on neoplastic marker of lung cancer and TCM differentiation of syndromes. Hubei Zhong Yi Za Zhi. 2007; 29(9): 11–12. Chinese. Yu LJ, Chen Q, Mo CW, Wang J. Study on the correlation between TCM syndrome differentiation and tumor markers in colorectal cancer. Yi Xue Qian Yan. 2013; (18): 79–80. Chinese. Lech A, Daneva T, Pashova S, Gagov H, Crayton R, Kukwa W, Czarnecka AM, Szczylik C. Ovarian cancer as a genetic disease. Front Biosci (Landmark Ed). 2013; 18: 543–563. Wang HQ, Zhang Z, Zhao YP, Li J, Chen K. Expression of HSP70 and P53 in malignant tumor tissues and its relationship to heat syndrome of TCM. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2004; 24(10): 897–900. Chinese with abstract in English. Chen W, Ouyang XN, Lin QC. Study on the relationship between vascular endothelial growth factor and syndrome type of traditional Chinese medicine in patients with gastric carcinoma. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2007; 27(2): 127–130. Chinese with abstract in English. Luo XQ, Xu YM, Tang Y. Pathological basis of qi-deficiency and blood stasis syndrome in patients with non-small cell lung cancer viewing from tumor metastasis related factors. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2009; 29(10): 886– 888. Chinese with abstract in English. Pan ZQ, Fang ZQ, Lu WL, Liang C, Wu ZH, Liu XM, Hou L, Zhang H, Zhuo SY, Liao MJ, Gao BF. Differentially expressed genes in adrenal gland of H22 liver cancer mice with different syndromes and in different stages. J Chin Integr Med. 2008; 6(8): 843–851. Chinese with abstract in English. Cui TJ, Chen YQ, Dai YM. Study of the correlation between the colorectal cancer Chinese medicine syndrome types and (excision repair cross-complementing 1, ERCC1) gene polymorphisms. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2012; 32(5): 628–632. Chinese with abstract in English. Zhang J, Zhan Z, Wu J, Zhang C, Yang Y, Tong S, Wang R, Yang X, Dong W. Association among lifestyle, clinical examination, polymorphisms in CDH1 gene and traditional Chinese medicine syndrome differentiation of gastric cancer. J Tradit Chin Med. 2013; 33(5): 572–579. Hood L, Heath JR, Phelps ME, Lin B. System biology and new technologies enable predictive and preventative medicine. Science. 2004; 306(5696): 640–643. Journal of Integrative Medicine

www.jcimjournal.com/jim 48 Dai J, Sun S, Cao H, Zheng N, Wang W, Gou X, Su S, Zhang Y. Applications of new technologies and new methods in ZHENG differentiation. Evid Based Complement Alternat Med. 2012; 2012: 298014. 49 Gao S, Chen LY, Wang P, Liu LM, Chen Z. MicroRNA expression in salivary supernatant of patients with pancreatic cancer and its relationship with ZHENG. Biomed Res Int. 2014; 2014: 756347. 50 Liu Z, Yu Z, Ouyang X, Du J, Lan X, Zhao M. Applied research on serum protein fingerprints for prediction of Qi deficiency syndrome and phlegm and blood stasis in patients with nonsmall cell lung cancer. J Tradit Chin Med. 2012; 32(3): 350–354. 51 Yang SF, Qiu SP, Liu QH. Observation of serum protein fingerprinting in primary liver cancer patients of different Chinese medical syndromes before and after interventional treatment. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2013; 33(10): 1352–1355. Chinese with abstract in English. 52 Yang SF. Differentially expressed proteins in serum among different Chinese medical syndrome types of primary liver cancer in the perioperative period of interventional treatment. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2013; 33(3): 314–317. Chinese with abstract in English. 53 Chen QL, Lu YY, Zhang GB, Song YN, Zhou QM, Zhang H, Zhang W, Tang XS, Su SB. Characteristic analysis from excessive to deficient syndromes in hepatocarcinoma underlying miRNA array data. Evid Based Complement Alternat Med. 2013; 2013: 324636. 54 Pan ZQ, Fang ZQ, Lu WL, Liang C, Wu ZH, Liu XM, Gao BF. Differentially expressed genes of MAPK signal pathway in different symptoms and signs about H22 tumour mice on base of adrenal gland gene-chip. Zhongguo Zhong Xi Yi Jie He Gan Bing Za Zhi. 2009; 19(1): 27–31. Chinese with abstract in English. 55 Pan ZQ, Fang ZQ, Lu WL, Liang C, Wu ZH, Liu XM, Gao BF. Gene expression of Smad signal pathway in adrenal gland in H22 tumor-bearing mice with different syndromes. Beijing Zhong Yi Yao Da Xue Xue Bao. 2009; 32(5): 336– 340. Chinese with abstract in English. 56 Dai HY, Wang P, Feng LY, Liu LM, Meng ZQ, Zhu XY, Wang K, Hua YQ, Mao YX, Chen LY, Chen Z. The molecular mechanisms of traditional Chinese medicine ZHENG syndromes on pancreatic tumor growth. Integr Cancer Ther. 2010; 9(3): 291–297. 57 Chen Z, Liu LM, He YB. Characteristics of W256 tumor growth and liver metastasis in rats with blood stasis syndrome. Zhong Yi Yao Xue Kan. 2003; 21(6): 866–872. Chinese.

58 Yin JH, Shi WD, Zhu XY, Chen Z, Liu LM. Qingyihuaji formula inhibits progress of liver metastases from advanced pancreatic cancer xenograft by targeting to decrease expression of Cyr61 and VEGF. Integr Cancer Ther. 2012; 11(1): 37–47. 59 Du J, Sun Y, Wang XF, Lu YY, Zhou QM, Su SB. Establishment of an experimental breast cancer ZHENG model and curative effect evaluation of Zuo-Jin Wan. Evid Based Complement Alternat Med. 2013; 2013: 324732. 60 Yang XB, Long SQ, Wu WY, Deng H, Pan ZQ, He WF, Zhou YS, Liao GY. Treating primary liver cancer patients by Pi-strengthening and Qi-regulating method: univariate and multivariate analyses of their prognoses. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2014; 34(2): 162–166. Chinese with abstract in English. 61 Chen XZ, Tian HQ, Huang XQ, Liang GW, Huang ZQ. Effect of Ganji formula on blood stasis in patients with advanced liver cancer. Shaanxi Zhong Yi. 2005; 26(9): 891–893. Chinese. 62 Wang P, Huang WX, Liu LM. Overview of clinical and experimental study on Spleen-nourishing and Qi-regulating therapy for liver cancer. Shanghai Zhong Yi Yao Za Zhi. 2005; 39(5): 60–62. Chinese with abstract in English. 63 Chen XP, Zhang YP, Zhu XR. Clinical study on effects of Tiepi fengdou granule/capsule combined with chemotherapy and/or radiotherapy in treating lung cancer with Qi-yin asthenia syndrome. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2006; 26(5): 394–397. Chinese with abstract in English. 64 Qin ZF, Wei PK, Li J. Effect of kanglaite injection combined with Chinese drug therapy according to syndrome differentiation on quality of life and immune function in patients with advanced lung cancer. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2002; 22(8): 618–619. Chinese with abstract in English. 65 Tao L, Zhu YJ, Lu XM, Gu Y, Zhao AG, Zheng J, Fu CG, Yang JK. Clinical study on survival benefit for elderly patients with resected stage II or III colorectal cancer based on traditional Chinese medicine syndrome differentiation and treatment. J Chin Integr Med. 2010; 8(12): 1159–1164. Chinese with abstract in English. 66 Lang WJ. Analysis of the clinical application of Aidi injection in treating cancer. Zhongguo Shi Yong Yi Yao. 2011; 6(32): 173–174. Chinese. 67 Xue Q, Zhao JF. The clinical application of Shenling Baizhu decoction in the treatment of malignant tumor. Neimenggu Zhong Yi Yao. 2014; 33(1): 54–55. Chinese. 68 Wang P, Chen Z. Traditional Chinese medicine ZHENG and Omics convergence: a systems approach to post-genomics medicine in a global world. OMICS. 2013; 17(9): 451–459.

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