Review Qing Ji1,2, Yun-quan Luo3, Wen-hai Wang4, Xuan Liu2, Qi Li2, Shi-bing Su1 ABSTRACT Keywords: Citation: Received accepted Correspondence:

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1 Journal homepage: Available also online at Copyright 2015, Journal of Integrative Medicine Editorial Offi ce. E-edition published by Elsevier (Singapore) Pte Ltd. All rights reserved. Review Qing Ji 1,2, Yun-quan Luo 3, Wen-hai Wang 4, Xuan Liu 2, Qi Li 2, Shi-bing Su 1 1. Research Center for Traditional Chinese Medicine Complexity System, Shanghai University of Traditional Chinese Medicine, Shanghai , China 2. Department of Medical Oncology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai , China 3. Department of Liver and Gallbladder Surgery, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai , China 4. Department of Medical Oncology, Seventh People s Hospital of Shanghai, Shanghai , 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 profi le of all clinical manifestations in one patient that can be readily identifi ed 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 September; Epub ahead of print. 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 ph enotypes 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]. TC M theory of tumor pathogenesis describes the invasion of pathogenic evils, such as qi stagnation, blood stasis and phlegm stagnation, over time [3]. These are specifically classified as ca ncer 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 ag ainst diseases. Vital qi is the body s defense and repair system, while evil qi incites pathogenic Received March 27, 2015; accepted May 4, Correspondence: Shi-bing Su, PhD, Professor; shibingsu07@163.com. Qi Li, MD, PhD, Professor; Lzwf@hotmail.com Journal of Integrative Medicine Epub ahead of print

2 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 co-exist. 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 T CM 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 presentation of TCM syndromes, objectivity and standardization of TCM syndrome differentiation, biological basis of TCM syndromes, and TCM syndrome differentiation-based TCM treatment of cancer. 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 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 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 spleenstomach, dampness-heat of liver-gallbladder, internal accumulation of 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 spleen-stomach, 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, phlegm-dampness 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 and blood sta- Epub ahead of print Journal of Integrative Medicine

3 General distributions of TCM syndromes in cancers TCM syndromes in cancers Case number Proportion (%) Reference Liver cancer [8] 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 120 [9] Qi deficiency Others Gastric cancer 767 [10] 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 63 [11] Qi deficiency and yang declination Yin deficiency Phlegm-dampness Blood stasis Pancreatic cancer 47 [12] 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 131 [13] Qi deficiency Blood deficiency Yin deficiency Yang deficiency Colorectal cancer 210 [14] Blood deficiency Qi and yin deficiency Phlegm-dampness Others TCM: traditional Chinese medicine. Journal of Integrative Medicine Epub ahead of print

4 sis 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 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]. 3.1 TCM syndrome differentiation in cancer 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 Clinical TCM syndrome measurement and information collection The four main diagnostic methods in TCM are inspection, auscultation and olfaction, inquiry, and palpation. These are 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 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 Epub ahead of print Journal of Integrative Medicine

5 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 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] 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 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 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 phlegm-stasis-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] Journal of Integrative Medicine Epub ahead of print

6 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 (rs ), 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 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 anal ysis 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 G enes 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 pathway, LKYDS was mainly associated with 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 yin-yang 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, were pound in dampheat syndrome the lowest levels of CCL5 and CCL4 expression. 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 Epub ahead of print Journal of Integrative Medicine

7 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. 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 qi nourishing 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 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 (Rensheng), 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]. 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 Journal of Integrative Medicine Epub ahead of print

8 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 d isease 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. This study was supported by Key Program of National Science Foundation of China (No ), 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 F oundation of China (No , , , and ). The authors declare that they have no competing interests. 1 Su SB, Lu A, Li S, Jia W. Evidence-based ZHENG: a traditional Chinese medicine syndrome. Evid Based Complement Alternat Med. 2012; 2012: Chen Z, Wang P. Clinical distribution and molecular basis of traditional Chinese medicine ZHENG in cancer. Evid Based Complement Alternat Med. 2012; 2012: Ling CQ. 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