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The type of Traditional Chinese Medicine syndrome predicts prognosis and chemotherapeutic outcomes in colorectal cancer
European Journal of Integrative Medicine 33 (2020) 101026
Contents lists available at ScienceDirect
European Journal of Integrative Medicine journal homepage: www.elsevier.com/locate/eujim
Research paper
The type of Traditional Chinese Medicine syndrome predicts prognosis and chemotherapeutic outcomes in colorectal cancer
T
Dan Lia,b,c,1, Weimin Wanga,b,c,1, Liangliang Xianga,c, Tengyang Nia,c, Li Taoa,c, Mengying Lva,c, Jianliang Dengb, Xiancheng Gub, Yanqing Liua,b,c,*, Yan Zhoua,b,c,** a
Institute of Traslational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China Department of Oncology, Yixing Hospital Affiliated to Medical College of Yangzhou University, Yixing, Jiangsu, 214200, PR China c The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou, 225001, PR China b
A R T I C LE I N FO
A B S T R A C T
Keywords: Colorectal cancer Traditional Chinese Medicine syndrome differentiation Pattern identification Prognosis Chemotherapy efficacy Survival time
Introduction: Identifying and targeting patients who can benefit from an intervention by determining the prognostic factors is increasingly important if effective healthcare is to be provided. This study analyzed whether Traditional Chinese Medicine (TCM) syndrome differentiation could be used to determine prognosis and chemotherapeutic efficacy in colorectal cancer (CRC) patients. Methods: A total of 470 patients registered on the CRC database between 2006 and 2010 and with detailed clinical data were categorised according to TCM syndrome differentiation. Patients with CRC were divided into spleen deficiency syndrome, stagnation of cold-heat syndrome, stasis position resistance syndrome, spleenkidney yang deficiency syndrome, liver-kidney yin deficiency syndrome, dual deficiency of qi and blood syndrome. Kaplen-Meier method was used to calculate the cumulative survival curve of TCM syndrome types and the COX regression analysis further analyzed the correlation between TCM syndrome types and prognosis and chemotherapeutic efficacy. Results: The survival rate of patients with deficiency syndrome was higher than that of patients with excess syndrome, and the survival rate of patients with dual deficiency of qi and blood syndrome was higher than other types. The COX regression analysis model, single factor and multi-factor analysis confirmed that TCM syndrome type was an independent factor in predicting the prognosis of patients with CRC; excess syndrome patients can significantly prolong their overall survival through postoperative adjuvant chemotherapy. Conclusions: The prognosis of CRC patients with deficiency syndrome was better than patients with excess syndrome. Patients with excess syndrome could benefit from postoperative adjuvant chemotherapy. Moreover, patients with deficiency syndrome have the best prognosis among the six TCM syndrome types.
1. Introduction Colorectal cancer (CRC) is one of the most common malignant tumors [1]. In the world, it occupies the third place in male cancer mortality and the fourth place in female cancer mortality [2]. There are 30%–40% higher in men than in women [3]. In 2012 the annual incidence of CRC is estimated as 159100 males and 142200 females in China [3,4]. Although surgery is still the main treatment for CRC patients, adjuvant radiotherapy, chemotherapy, targeted therapy, gene therapy, traditional Chinese medicine and other treatments are also used but the 5-year overall survival rate of CRC is still about 60 % [5].
Therefore, finding effective markers to predict the prognosis and treatment efficacy of CRC is an important issue. Because of the intersection of deficiency and excess, eventually leading to the occurrence of disease. The type of Traditional Chinese Medicine (TCM) syndrome of colorectal cancer contains four basic pathological factors: dampness, toxin, stasis and deficiency. The colon is part of the large intestine and in TCM and closely related to the spleen and kidney. It belongs to the category of TCM “intestinal massage”, “accumulation”, “dirty poison”, “lock anal hemorrhoids” and so on. This article mainly analyzes the correlation between TCM syndromes in patients with CRC and the prognosis and effect of
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Corresponding author at: Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China. Corresponding author at: Department of Oncology, Yixing Hospital Affiliated to Medical College of Yangzhou University, Yixing, Jiangsu, 214200, PR China. E-mail addresses: [email protected] (Y. Liu), [email protected] (Y. Zhou). 1 These authors contributed equally to this work. ⁎⁎
https://doi.org/10.1016/j.eujim.2019.101026 Received 12 March 2019; Received in revised form 1 December 2019; Accepted 1 December 2019 1876-3820/ © 2019 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
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database has detailed clinicopathologic data and survival time which was calculated from the date of surgery to the date of death or to the last follow-up. The clinical and pathological information of 470 cases of CRC patients including age at diagnosis, gender, differentiation stage, depth of invasion, lymph node metastasis, TNM stage and tumor diameter were collected. The median age of these CRC patients at tumor resection was 63 years. There were 281 males (59.8 %) and 189 females (40.2 %) cases, with a male to female ratio of 6: 4.
chemotherapy. It discusses whether TCM syndromes can predict the prognosis and chemotherapy effect of CRC patients as independent factors. 2. Data and methods 2.1. Diagnostic criteria for Western Medicine According to the diagnostic criteria of “New compiled Standards for the Diagnosis and Treatment of Common Malignant Tumors” by the China Ministry of Health [6], CRC was diagnosed and confirmed by endoscopy or surgical pathology. For clinical staging, the American Cancer Commission (AJCC) (2002 Edition) was used for tumor-nodemetastasis (TNM) staging [7].
2.4. Observation indicators A total of 470 cases of CRC patients database, the preoperative patients were classified according to TCM syndrome differentiation. The correlation with clinicopathological data, prognosis and chemotherapy efficacy was analyzed.
2.2. TCM syndrome differentiation standards According to the “guidelines for diagnosis and treatment of Oncology Chinese Medicine” on the classification standards for CRC issued by the Chinese Academy of Chinese Medicine in 2008 [8], the syndrome types of CRC are divided into six syndromes: internal obstruction of stagnated posion syndrome, stagnation of cold-heat syndrome, dual deficiency of qi and blood syndrome, liver- kidney yin deficiency syndrome, spleen-kidney yang deficiency syndrome, spleen deficiency syndrome. The main points of syndrome differentiation are:
2.5. Statistical methods Using SPSS16. 0 statistical software for analysis, P < 0.05 was considered statistically significant. Fisher’s test was used to analyze the relationship between TCM syndromes and clinicopathological data. Kaplen-Meier survival curve was used to draw the correlation between TCM syndrome types and prognosis. The COX proportional hazard model was established to further evaluate the relationship between TCM syndromes and survival of CRC.
1) internal obstruction caused by stagnated : abdominal distention and pain discomfort, palpation and pressure pain positive, abdominal mass, thick stool with pus and blood, lingual purple, pale and spotted, tongue coating thin yellow, pulse string or astringent. 2) stagnation of cold-heat: abdominal distention and pain, burning anus, diarrhea and sticky with blood, dry mouth, poor appetite, red tongue, yellow and greasy tongue coating, pulse number. 3) dual deficiency of qi and blood: easy fatigue, poor spirit, pale face, dizziness, dizziness, rotation of visual objects, dull fingernails and lip (not shining), blood in stools, shapeless stools and anus, tongue quality, thin tongue coating, weak pulse. 4) liver- kidney yin deficiency: the middle of hand, foot and chest feel irritable and muggy, dizziness, vision rotation, mild fever, night sweating, mouth bitter hair dry, lower limbs weak and soft, defecation difficult, tongue quality red, tongue coating none or sparce, fine number of veins. 5) spleen-kidney yang deficiency: abdominal pain is continuous, eating warm food relieves, palpation tenderness negative, weight loss, fatigue, facial discoloration, fear the cold, limbs not warm, poor appetite, stool shapeless, stool frequency increased, pale tongue, tongue coating thin white, thin pulse. 6) spleen deficiency: abdominal distention and pain, diarrhea, mental atrophy, fatigue, stools shapeless, pale yellow, glossy tongue, thin and greasy tongue, vein and moist.
3. Results 3.1. Correlation between TCM syndromes and clinicopathological data of CRC patients According to the above syndrome basis analysis, 470 cases of CRC patients were classified into two groups: 260 cases with the excess syndrome and 210 cases with the deficiency syndrome. Fisher’s test showed that there were significant differences between excess syndrome and deficiency syndrome and gender, lymph node metastasis, TNM stage and the lesion site of the disease (P < 0.05), whereas other data had no significant difference (P > 0.05), as shown in Table 1. According to the specific TCM syndrome differentiation of CRC, it can be divided into 161 cases of internal obstruction of stagnated posion syndrome, 99 cases of stagnation of cold-heat syndrome, 100 cases of dual deficiency of qi and blood syndrome, 17 cases of liver- kidney yin deficiency syndrome, 52 cases of spleen-kidney yang deficiency syndrome and 41 cases of spleen deficiency syndrome. Fisher’s test showed that there were significant differences in depth of invasion, lymph node metastasis and TNM stage (P < 0.05), and no significant differences in other data (P > 0.05), as shown in Table 2.
3.2. K-M survival curves of TCM syndromes and prognosis and chemotherapy efficacy of CRC patients
The syndrome caused by internal obstruction caused by stagnation of cold-heat belong to the category of excess syndrome, while the syndrome of spleen deficiency, spleen-kidney yang deficiency, liverkidney yin deficiency and dual deficiency of qi and blood belong to the category of deficiency syndrome.
The overall survival (OS) rate of the deficiency syndrome was higher than that of the excess syndrome. The difference was significant, as shown in Fig. 1. Six TCM syndrome differentiation analysis found that the total survival rate of patients with dual deficiency of qi and blood syndrome was higher than that of patients with other syndromes, the difference was statistically significant, as shown in Fig. 2. The OS rate of patients with chemotherapy was higher than that of patients without chemotherapy, and the difference was statistically significant, as shown in Fig. 3A. The OS rate of patients with deficiency syndrome treated with chemotherapy was higher than that of patients without chemotherapy, but there was no significant difference between the two groups, as shown in Fig. 3B.
2.3. Clinical data A total of 470 cases of CRC patients underwent radical resection during January 2006 and December 2010 in Yixing People’s Hospital of teaching hospital of Yangzhou University. The pathological diagnosis of each patient was confirmed. The Ethics Committee of Yixing People’s Hospital approved all subjects of the study, which was carried out in accordance with the principles of the Declaration of Helsinki. The 2
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showed that chemotherapy and non-chemotherapy in patients with survival were not statistically significant, as shown in Tables 6 and 8. It can be concluded that TCM syndromes can predict the efficacy of chemotherapy and adjuvant chemotherapy can significantly prolong the survival of CRC patients with excess syndrome. However, adjuvant chemotherapy can not obviously prolong the survival of CRC patients with deficiency syndrome.
Table 1 Relationship between TCM syndrome type and clinicopathological features in CRC patients. Variables
All patients Age (years) ≤65 ＞65 Gender Males Females Pathological classificationb Ⅰ/Ⅱ Ⅲ Depth of invasionb T1/T2 T3/T4 Lymph node metastasisb N0 N1/N2/N3 TNM stageb Ⅰ/Ⅱ Ⅲ/Ⅳ Tumor diameterb ≤5 cm ＞5 cm Distant metastasis M0 M1 Lesion site Ascending colon Transverse colon Descending colon Sigmoid colon Rectum Cecum、appendix a b
n = 470 cases excess syndrome (%)
deficiency syndrome (%)
Pa
260(55.3) 145(54.3) 115(56.7) 144(51.2) 116(61.4)
210(44.7)
0.34 0.019 0.179 0.221 0.021 0.013 0.478 0.078 0.002
233(54.4) 23(63.9) 53(51.5) 204(56.4) 141(51.1) 116(61.1) 135(50.6) 121(61.4) 208(55.0) 51(56.0) 246(54.5) 14(73.7)
122(45.7) 88(43.3) 137(48.8) 73(38.6) 195(45.6) 13(36.1) 50(48.5) 158(43.6) 135(48.9) 74(38.9) 132(49.4) 76(38.6) 170(45.0) 40(44.0) 205(45.5) 5(26.3)
62 7 14 28 139 7
30 10 12 47 107 2
4. Discussion In recent years, there are many references about prognostic factors of CRC [9–11]. With the gradual understanding of biological characteristics of CRC and the development of basic and clinical research, many factors that affect the prognosis of CRC have been found. In addition, it is rare to introduce the TCM syndromes into the model and study its impact on the prognosis of CRC. In this study, COX risk ratio model was introduced to predict the prognostic factors of CRC, such as gender, age, lesion site, TNM stage, pathological classification. The correlation between chemotherapy and TCM syndromes were investigated. Based on the data of 470 cases of CRC patients, we discussed the factors influencing the prognosis of CRC and their possible causes. Kaplen-Meier method was used to calculate the cumulative survival rate of the patients with excess syndrome and deficiency syndrome. The results showed that the survival rate of the patients with deficiency syndrome was higher than that of the patients with excess syndrome. CRC patients with deficiency syndrome have a long course of disease. Although they are deficient in vital qi, the pathogenic qi in the body gradually turns to deficiency. So their survival time is long, which is consistent with the theory of TCM. Comparing the general data of the two groups, it can be seen that there are significant differences in gender, lymph node metastasis, TNM stage and lesion site of the disease. Among them, the proportion of the patients with excess syndrome is more. From the lesion site of the disease, CRC frequently occurs in the rectum, which is consistent with the most common lesion site in Chinese CRC patients [12]. This process also reflects the law of the growth and decline of the evil in patients. The vital qi of the patients with excess syndrome changes from strong to weak, the evil qi changes from weak to strong, and lymph node metastasis is more likely to occur. Therefore, attention should be paid to the observation of lymph node in the treatment. Early detection, early diagnosis and early treatment are in line with the idea of “treatment before disease” in TCM [13]. In the treatment of the patients with deficiency syndrome, attention should be paid because of both vital qi and pathogenic qi are changed from strong to weak. Excess syndrome and deficiency syndrome were introduced into COX regression model as one of the prognostic factors. Univariate analysis showed that there was significant difference between excess syndrome and deficiency syndrome. Age at diagnosis, differentiation stage, depth of invasion, lymph node metastasis, TNM stage and distant metastasis could be used as reference factors. Multivariate COX analysis revealed that TNM stage and differentiation stage were independent prognostic factors. It has been studied in some references that TNM stage is one of the main factors affecting the prognosis of CRC. The symptoms of distant metastasis have been found in patients with stage III/IV CRC. Ascites, anemia, hypoproteinemia and organ damage caused by metastasis have been found in most of the patients due to consumption and infiltration of the tumor. The poor physical condition limits the development of treatment, and the sensitivity to various treatments is also low. Therefore, the prognosis is very bad [14]. In the ancient book “Huangdi Neijing”, metastasis is called inheritance. The core pathogenesis of metastasis of CRC is invasion of vital qi deficiency, and blood stasis and toxin inheritance [15]. The differentiation stage of CRC is different, and the biological behavior is also different. It has a certain relationship with TCM syndrome types of CRC, and can be used as a prognostic indicator.
Two-sided Fisher’s exact tests. Some patients missing these clinical pathological parameters.
3.3. Single factor and multi factor analysis of TCM syndromes and prognosis of CRC patients In the COX regression model, the single factor analysis showed that there were significant differences between the excess and deficiency syndrome in prognosis of CRC patients (P < 0.05). Moreover, there were significant differences in age at diagnosis, differentiation stage, depth of invasion, lymph node metastasis, TNM stage, distant metastasis (P < 0.05), as shown in Table 3. We further analyzed the TCM syndromes, differentiation stage, TNM staging, sex and tumor diameter and the results showed that there were significant differences between the two syndromes (P < 0.05), as shown in Table 4.
3.4. Single factor and multi factor analysis of TCM syndromes and postoperative adjuvant chemotherapy in CRC patients In the COX regression model, single factor analysis showed that the survival time of CRC patients of the excess syndrome was significantly prolonged by adjuvant chemotherapy after operation, which was statistically significant compared with those without chemotherapy (P < 0.05). However, the survival time of patients with deficiency syndrome was not significantly prolonged by adjuvant chemotherapy after operation, as shown in Table 5. Then we analyzed the differentiation stage, TNM staging, age at diagnosis, tumor diameter and found that postoperative adjuvant chemotherapy could benefit the survival of CRC patients as shown in Table 7. For CRC patients with deficiency syndrome, COX regression model of single factor and multi-factor were used to analyze. The results 3
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Table 2 Relationship between TCM syndrome type and clinicopathological features in CRC patients. Variables
All patients Age (years) ≤65 ＞65 Gender Males Females Pathological classificationb Ⅰ/Ⅱ Ⅲ Depth of invasionb T1/T2 T3/T4 Lymph node metastasisb N0 N1/N2/N3 TNM stageb Ⅰ/Ⅱ Ⅲ/Ⅳ Tumor diameterb ≤5 cm ＞5 cm Distant metastasis M0 M1 a b
n = 470 cases A (%)
B (%)
C (%)
D(%)
E (%)
F (%)
161(34.2)
99(21.1)
100(21.3)
17(3.6)
52(11.1)
41(8.7)
91(34.0) 70(34.5)
54(20.2) 45(22.2)
60(22.5) 40(19.7)
9(3.4) 8(3.9)
29(10.9) 23(11.3)
24(9.0) 17(8.4)
87(30.9) 74(39.2)
57(20.3) 42(22.2)
64(22.8) 36(19.0)
10(3.6) 7(3.7)
32(11.4) 20(10.6)
31(11.0) 10(5.3)
143(33.3) 15(41.7)
90(21.0) 8(22.2)
97(22.7) 2(5.6)
14(3.3) 3(8.3)
47(11.0) 5(13.9)
37(8.7) 3(8.3)
24(23.3) 134(37.0)
29(28.2) 70(19.3)
31(30.0) 69(19.1)
0(0) 17(4.7)
12(11.7) 39(10.8)
7(6.8) 33(9.1)
75(27.2) 83(43.7)
66(23.9) 33(17.4)
72(26.1) 28(14.7)
12(4.3) 5(2.6)
26(9.4) 25(13.2)
25(9.1) 16(8.4)
70(26.2) 87(44.2)
65(24.3) 34(17.3)
72(27.0) 28(14.2)
12(4.5) 5(2.5)
24(9.0) 27(13.7)
24(9.0) 16(8.1)
122(32.3) 38(41.7)
86(22.8) 13(14.3)
87(23.0) 13(14.3)
14(3.7) 3(3.3)
39(10.3) 13(14.3)
30(7.9) 11(12.1)
150(33.2) 11(57.9)
96(21.3) 3(15.8)
99(22.0) 1(5.3)
17(3.8) 0(0)
50(11.1) 2(10.5)
39(8.6) 2(10.5)
Pa
0.976
0.180
0.087
0.003
0.001
< 0.001
0.077
0.260
Two-sided Fisher’s exact tests. Some patients missing these clinical pathological parameters.
proportion. Most of the patients with this syndrome have exuberant pathogenic qi, which indicates that the disease is in an early stage. Therefore, we should pay attention to specific treatment according to the depth of invasion and differentiation stage to prevent and treat lymph node metastasis. Taking chemotherapy into account, Kaplen-Meier method was used to calculate the cumulative survival rate of chemotherapy in the CRC patients with excess syndrome and deficiency syndrome. The overall survival (OS) rate of patients with chemotherapy was higher than that of no chemotherapy, and the difference was statistically significant. In patients with deficiency syndrome, the overall survival (OS) rate of patients with chemotherapy was higher than that of patients with no chemotherapy, but the difference was not significant. TCM believes that chemotherapy drugs have the effect of eliminating pathogens, and the method of attacking pathogens can obviously prolong the survival time of patients. The patients with deficiency syndrome have deficiency of vital qi and pathogenic qi, so the method of eliminating pathogenic factors will inevitably damage the normal physiological function and make the vital qi more deficient, so the survival time of the patients with deficiency syndrome can not be prolonged. Therefore, attention should be paid to the vital qi in the treatment process. In the patients with excess syndrome, chemotherapy + not as one of the prognostic factors was introduced into the COX regression model. Univariate analysis found that chemotherapy and no chemotherapy patients had significant differences. Univariate and multivariate analysis showed that there was no significant difference between chemotherapy and no chemotherapy, but the age, differentiation stage, TNM stage could be used as a reference factor. The research tells us that different TCM syndromes have different prognosis. It may guide doctors to choose better treatment methods in the clinic. However, the sample is a single population database, which needs to be verified by multi sample database. Moreover, more investigations should be done to support our research.
Fig. 1. Correlation between TCM syndromes and the overall survival of CRC patients. The overall survival (OS) rate of the deficiency syndrome was higher than that of the excess syndrome (P < 0.05).
Kaplen-Meier method was used to calculate the cumulative survival rate of the six TCM syndrome types. The results showed that the survival rate of the patients with dual deficiency of qi and blood was the highest, followed by liver-kidney yin deficiency, spleen-kidney yang deficiency. The survival rate of other syndrome types was lower than those of the three syndrome types, which accorded with the theory of TCM. Dual deficiency of qi and blood syndrome belongs to deficiency syndrome. With the progress of the course of disease, pathogenic qi decreases, and the positive qi deficiency is becoming more and more serious. The patients’ survival time can be relatively prolonged. Six groups of general data were compared, from P < 0.05 we can see that TCM syndromes in the depth of invasion, lymph node metastasis, TNM stage in these three areas there are significant differences. Among them, patients with stagnation of cold-heat syndrome account for a large
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Fig. 2. K-M survival curves of TCM syndromes and of CRC patients. The total survival rate of patients with dual deficiency of qi and blood syndrome was higher than that of patients with other syndromes (P < 0.05).
Fig. 3. K-M survival curves of TCM syndromes and chemotherapy efficacy of CRC patients. The OS rate of patients with/without chemotherapy was higher than that of patients without chemotherapy.
Table 3 Univariate Cox regression analysis of TCM syndrome type and clinicopathological variables predicting survival in patients with CRC patients. Variables
Age (≤65 vs. > 65) Gender (male vs. female) Pathological classification (I/II vs. III) Depth of invasion (T1/T2 vs. T3/T4) Lymph node metastasis (N0 vs. N1/N2) TNM stage (I/II vs. III/IV) Distant metastasis(M0 vs. M1) Tumor diameter (≤5 cm vs. > 5 cm) TCM syndrome type (excess syndrome vs. deficiency syndrome)
Table 4 Multivariate Cox regression analysis of TCM syndrome type and clinicopathological variables predicting survival in patients with CRC.
n = 470 cases HR (95 % CI)
P
1.607(1.215–2.126) 1.013(0.762–1.347) 2.475(1.587–3.860) 3.687(2.270–5.990) 2.807(2.112–3.731) 3.214(2.407–4.291) 8.150(4.849–13.699) 1.196(0.848–1.688) 0.677(0.507-0.904)
0.001 0.927 ＜0.001 ＜0.001 ＜0.001 ＜0.001 ＜0.001 0.307 0.008
Variables
HR (95 % CI)
Pa
Gender (male vs. female) Pathological classification (I/II vs. III) TNM stage (I/II vs. III/IV) Tumor diameter (≤5 cm vs. > 5 cm) TCM syndrome type (excess syndrome vs. deficiency syndrome)
0.875(0.655–1.170) 1.792(1.125–2.855) 3.052(2.273–4.079) 1.116(0.781–1.597) 0.719(0.536-0.963)
0.368 0.014 ＜0.001 0.545 0.027
a Multivariate Cox regression analysis including gender, pathological classification, TNM stage, tumor diameter, TCM syndrome type.
Declaration of Competing Interest The authors declared that they have no conflicts of interest. Ethics approval and consent to participate.
Authors’ contributions Dan Li and Weimin Wang conceived and devised the research, and wrote the manuscript; Weimin Wang, Li Tao and Mengying Lv analyzed the data; Liangliang Xiang and Tengyang Ni done the experiments; Jianliang Deng and Xiancheng Gu supplied technical support; Yan Zhou and Yanqing Liu provided all of the reagent and chemical. All the authors edited and commented on the manuscript. All authors have read and agreed the final manuscript.
Acknowledgements The work was financially supported by the National Natural Science Foundation of China (NO. 81773944, to YQL); Young Medicine Focus Talent Foundation of Jiangsu Province (No. QNRC2016206); Postgraduate Research by Practice Innovation Program of Jiangsu Province (KYCX18_2382); the Natural Science Foundation of Jiangsu 5
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Province for Youths (No. BK20170516, to LT), and the Natural Science Foundation of Jiangsu Province (No. BK20180927 to LMY).
Table 5 Univariate Cox regression analysis of excess syndrome and clinicopathological variables predicting survival in patients with CRC. Variables
Age (≤65 vs. > 65) Gender (male vs. female) Pathological classification (I/II vs. III) TNM stage (I/II vs. III/IV) Tumor diameter (≤5 cm vs. > 5 cm) TCM syndrome type (chemotherapy vs. no chemotherapy)
References
n = 260 cases HR (95 % CI)
P
1.314(0.922–1.872) 1.135(0.796–1.618) 1.788(1.005–3.181) 3.238(2.231–4.700) 1.342(0.876–2.058) 0.591(0.349-0.999)
0.130 0.483 0.048 ＜0.001 0.177 0.050
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Table 6 Univariate Cox regression analysis of deficiency syndrome and clinicopathological variables predicting survival in patients with CRC. Variables
Age (≤65 vs. > 65) Gender (male vs. female) Pathological classification (I/II vs. III) TNM stage (I/II vs. III/IV) Tumor diameter (≤5 cm vs. > 5 cm) TCM syndrome type (chemotherapy vs. no chemotherapy)
n = 210 cases HR (95 % CI)
P
2.109(1.332–3.337) 0.760(0.462–1.252) 4.035(2.001–8.134) 2.956(1.862–4.692) 1.011(0.565–1.808) 0.567(0.291–1.105)
0.001 0.282 ＜0.001 ＜0.001 0.972 0.096
Table 7 Multivariate Cox regression analysis of excess syndrome and icopathological variables predicting survival in patients with CRC.
clin-
Variables
HR (95 % CI)
Pa
TCM syndrome type: excess syndrome Age (≤65 vs. > 65) Gender (male vs. female) Pathological classification (I/II vs. III) TNM stage (I/II vs. III/IV) Tumor diameter (≤5 cm vs. > 5 cm) TCM syndrome type expression (chemotherapy vs. no chemotherapy)
1.388(0.952–2.025) 0.994(0.694–1.424) 1.301(0.713–2.374) 3.652(2.487–5.363) 1.313(0. 834–2.044) 0.510(0.293–0.887)
0.089 0.976 0.391 ＜0.001 0.227 0.017
a Multivariate Cox regression analysis including gender, pathological classification, TNM stage, tumor diameter, TCM syndrome type expression status.
Table 8 Multivariate Cox regression analysis of deficiency syndrome and clinicopathological variables predicting survival in patients with CRC. Variables
HR (95 % CI)
Pa
TCM syndrome type: deficiency syndrome Age (≤65 vs. > 65) Gender (male vs. female) Pathological classification (I/II vs. III) TNM stage (I/II vs. III/IV) Tumor diameter (≤5 cm vs. > 5 cm) TCM syndrome type expression (chemotherapy vs. no chemotherapy)
2.162(1.330–3.514) 0.646(0.385–1.083) 3.224(1.525–6.814) 3.008(1. 866–4.848) 1.008(0. 541–1.878) 0.495(0.241–1.016)
0.002 0.098 0.002 ＜0.001 0.979 0.055
a Multivariate Cox regression analysis including gender, pathological classification, TNM stage, tumor diameter, TCM syndrome type expression status.
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Research paper
The type of Traditional Chinese Medicine syndrome predicts prognosis and chemotherapeutic outcomes in colorectal cancer
T
Dan Lia,b,c,1, Weimin Wanga,b,c,1, Liangliang Xianga,c, Tengyang Nia,c, Li Taoa,c, Mengying Lva,c, Jianliang Dengb, Xiancheng Gub, Yanqing Liua,b,c,*, Yan Zhoua,b,c,** a
Institute of Traslational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China Department of Oncology, Yixing Hospital Affiliated to Medical College of Yangzhou University, Yixing, Jiangsu, 214200, PR China c The Key Laboratory of Syndrome Differentiation and Treatment of Gastric Cancer of the State Administration of Traditional Chinese Medicine, Yangzhou, 225001, PR China b
A R T I C LE I N FO
A B S T R A C T
Keywords: Colorectal cancer Traditional Chinese Medicine syndrome differentiation Pattern identification Prognosis Chemotherapy efficacy Survival time
Introduction: Identifying and targeting patients who can benefit from an intervention by determining the prognostic factors is increasingly important if effective healthcare is to be provided. This study analyzed whether Traditional Chinese Medicine (TCM) syndrome differentiation could be used to determine prognosis and chemotherapeutic efficacy in colorectal cancer (CRC) patients. Methods: A total of 470 patients registered on the CRC database between 2006 and 2010 and with detailed clinical data were categorised according to TCM syndrome differentiation. Patients with CRC were divided into spleen deficiency syndrome, stagnation of cold-heat syndrome, stasis position resistance syndrome, spleenkidney yang deficiency syndrome, liver-kidney yin deficiency syndrome, dual deficiency of qi and blood syndrome. Kaplen-Meier method was used to calculate the cumulative survival curve of TCM syndrome types and the COX regression analysis further analyzed the correlation between TCM syndrome types and prognosis and chemotherapeutic efficacy. Results: The survival rate of patients with deficiency syndrome was higher than that of patients with excess syndrome, and the survival rate of patients with dual deficiency of qi and blood syndrome was higher than other types. The COX regression analysis model, single factor and multi-factor analysis confirmed that TCM syndrome type was an independent factor in predicting the prognosis of patients with CRC; excess syndrome patients can significantly prolong their overall survival through postoperative adjuvant chemotherapy. Conclusions: The prognosis of CRC patients with deficiency syndrome was better than patients with excess syndrome. Patients with excess syndrome could benefit from postoperative adjuvant chemotherapy. Moreover, patients with deficiency syndrome have the best prognosis among the six TCM syndrome types.
1. Introduction Colorectal cancer (CRC) is one of the most common malignant tumors [1]. In the world, it occupies the third place in male cancer mortality and the fourth place in female cancer mortality [2]. There are 30%–40% higher in men than in women [3]. In 2012 the annual incidence of CRC is estimated as 159100 males and 142200 females in China [3,4]. Although surgery is still the main treatment for CRC patients, adjuvant radiotherapy, chemotherapy, targeted therapy, gene therapy, traditional Chinese medicine and other treatments are also used but the 5-year overall survival rate of CRC is still about 60 % [5].
Therefore, finding effective markers to predict the prognosis and treatment efficacy of CRC is an important issue. Because of the intersection of deficiency and excess, eventually leading to the occurrence of disease. The type of Traditional Chinese Medicine (TCM) syndrome of colorectal cancer contains four basic pathological factors: dampness, toxin, stasis and deficiency. The colon is part of the large intestine and in TCM and closely related to the spleen and kidney. It belongs to the category of TCM “intestinal massage”, “accumulation”, “dirty poison”, “lock anal hemorrhoids” and so on. This article mainly analyzes the correlation between TCM syndromes in patients with CRC and the prognosis and effect of
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Corresponding author at: Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, PR China. Corresponding author at: Department of Oncology, Yixing Hospital Affiliated to Medical College of Yangzhou University, Yixing, Jiangsu, 214200, PR China. E-mail addresses: [email protected] (Y. Liu), [email protected] (Y. Zhou). 1 These authors contributed equally to this work. ⁎⁎
https://doi.org/10.1016/j.eujim.2019.101026 Received 12 March 2019; Received in revised form 1 December 2019; Accepted 1 December 2019 1876-3820/ © 2019 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
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database has detailed clinicopathologic data and survival time which was calculated from the date of surgery to the date of death or to the last follow-up. The clinical and pathological information of 470 cases of CRC patients including age at diagnosis, gender, differentiation stage, depth of invasion, lymph node metastasis, TNM stage and tumor diameter were collected. The median age of these CRC patients at tumor resection was 63 years. There were 281 males (59.8 %) and 189 females (40.2 %) cases, with a male to female ratio of 6: 4.
chemotherapy. It discusses whether TCM syndromes can predict the prognosis and chemotherapy effect of CRC patients as independent factors. 2. Data and methods 2.1. Diagnostic criteria for Western Medicine According to the diagnostic criteria of “New compiled Standards for the Diagnosis and Treatment of Common Malignant Tumors” by the China Ministry of Health [6], CRC was diagnosed and confirmed by endoscopy or surgical pathology. For clinical staging, the American Cancer Commission (AJCC) (2002 Edition) was used for tumor-nodemetastasis (TNM) staging [7].
2.4. Observation indicators A total of 470 cases of CRC patients database, the preoperative patients were classified according to TCM syndrome differentiation. The correlation with clinicopathological data, prognosis and chemotherapy efficacy was analyzed.
2.2. TCM syndrome differentiation standards According to the “guidelines for diagnosis and treatment of Oncology Chinese Medicine” on the classification standards for CRC issued by the Chinese Academy of Chinese Medicine in 2008 [8], the syndrome types of CRC are divided into six syndromes: internal obstruction of stagnated posion syndrome, stagnation of cold-heat syndrome, dual deficiency of qi and blood syndrome, liver- kidney yin deficiency syndrome, spleen-kidney yang deficiency syndrome, spleen deficiency syndrome. The main points of syndrome differentiation are:
2.5. Statistical methods Using SPSS16. 0 statistical software for analysis, P < 0.05 was considered statistically significant. Fisher’s test was used to analyze the relationship between TCM syndromes and clinicopathological data. Kaplen-Meier survival curve was used to draw the correlation between TCM syndrome types and prognosis. The COX proportional hazard model was established to further evaluate the relationship between TCM syndromes and survival of CRC.
1) internal obstruction caused by stagnated : abdominal distention and pain discomfort, palpation and pressure pain positive, abdominal mass, thick stool with pus and blood, lingual purple, pale and spotted, tongue coating thin yellow, pulse string or astringent. 2) stagnation of cold-heat: abdominal distention and pain, burning anus, diarrhea and sticky with blood, dry mouth, poor appetite, red tongue, yellow and greasy tongue coating, pulse number. 3) dual deficiency of qi and blood: easy fatigue, poor spirit, pale face, dizziness, dizziness, rotation of visual objects, dull fingernails and lip (not shining), blood in stools, shapeless stools and anus, tongue quality, thin tongue coating, weak pulse. 4) liver- kidney yin deficiency: the middle of hand, foot and chest feel irritable and muggy, dizziness, vision rotation, mild fever, night sweating, mouth bitter hair dry, lower limbs weak and soft, defecation difficult, tongue quality red, tongue coating none or sparce, fine number of veins. 5) spleen-kidney yang deficiency: abdominal pain is continuous, eating warm food relieves, palpation tenderness negative, weight loss, fatigue, facial discoloration, fear the cold, limbs not warm, poor appetite, stool shapeless, stool frequency increased, pale tongue, tongue coating thin white, thin pulse. 6) spleen deficiency: abdominal distention and pain, diarrhea, mental atrophy, fatigue, stools shapeless, pale yellow, glossy tongue, thin and greasy tongue, vein and moist.
3. Results 3.1. Correlation between TCM syndromes and clinicopathological data of CRC patients According to the above syndrome basis analysis, 470 cases of CRC patients were classified into two groups: 260 cases with the excess syndrome and 210 cases with the deficiency syndrome. Fisher’s test showed that there were significant differences between excess syndrome and deficiency syndrome and gender, lymph node metastasis, TNM stage and the lesion site of the disease (P < 0.05), whereas other data had no significant difference (P > 0.05), as shown in Table 1. According to the specific TCM syndrome differentiation of CRC, it can be divided into 161 cases of internal obstruction of stagnated posion syndrome, 99 cases of stagnation of cold-heat syndrome, 100 cases of dual deficiency of qi and blood syndrome, 17 cases of liver- kidney yin deficiency syndrome, 52 cases of spleen-kidney yang deficiency syndrome and 41 cases of spleen deficiency syndrome. Fisher’s test showed that there were significant differences in depth of invasion, lymph node metastasis and TNM stage (P < 0.05), and no significant differences in other data (P > 0.05), as shown in Table 2.
3.2. K-M survival curves of TCM syndromes and prognosis and chemotherapy efficacy of CRC patients
The syndrome caused by internal obstruction caused by stagnation of cold-heat belong to the category of excess syndrome, while the syndrome of spleen deficiency, spleen-kidney yang deficiency, liverkidney yin deficiency and dual deficiency of qi and blood belong to the category of deficiency syndrome.
The overall survival (OS) rate of the deficiency syndrome was higher than that of the excess syndrome. The difference was significant, as shown in Fig. 1. Six TCM syndrome differentiation analysis found that the total survival rate of patients with dual deficiency of qi and blood syndrome was higher than that of patients with other syndromes, the difference was statistically significant, as shown in Fig. 2. The OS rate of patients with chemotherapy was higher than that of patients without chemotherapy, and the difference was statistically significant, as shown in Fig. 3A. The OS rate of patients with deficiency syndrome treated with chemotherapy was higher than that of patients without chemotherapy, but there was no significant difference between the two groups, as shown in Fig. 3B.
2.3. Clinical data A total of 470 cases of CRC patients underwent radical resection during January 2006 and December 2010 in Yixing People’s Hospital of teaching hospital of Yangzhou University. The pathological diagnosis of each patient was confirmed. The Ethics Committee of Yixing People’s Hospital approved all subjects of the study, which was carried out in accordance with the principles of the Declaration of Helsinki. The 2
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showed that chemotherapy and non-chemotherapy in patients with survival were not statistically significant, as shown in Tables 6 and 8. It can be concluded that TCM syndromes can predict the efficacy of chemotherapy and adjuvant chemotherapy can significantly prolong the survival of CRC patients with excess syndrome. However, adjuvant chemotherapy can not obviously prolong the survival of CRC patients with deficiency syndrome.
Table 1 Relationship between TCM syndrome type and clinicopathological features in CRC patients. Variables
All patients Age (years) ≤65 ＞65 Gender Males Females Pathological classificationb Ⅰ/Ⅱ Ⅲ Depth of invasionb T1/T2 T3/T4 Lymph node metastasisb N0 N1/N2/N3 TNM stageb Ⅰ/Ⅱ Ⅲ/Ⅳ Tumor diameterb ≤5 cm ＞5 cm Distant metastasis M0 M1 Lesion site Ascending colon Transverse colon Descending colon Sigmoid colon Rectum Cecum、appendix a b
n = 470 cases excess syndrome (%)
deficiency syndrome (%)
Pa
260(55.3) 145(54.3) 115(56.7) 144(51.2) 116(61.4)
210(44.7)
0.34 0.019 0.179 0.221 0.021 0.013 0.478 0.078 0.002
233(54.4) 23(63.9) 53(51.5) 204(56.4) 141(51.1) 116(61.1) 135(50.6) 121(61.4) 208(55.0) 51(56.0) 246(54.5) 14(73.7)
122(45.7) 88(43.3) 137(48.8) 73(38.6) 195(45.6) 13(36.1) 50(48.5) 158(43.6) 135(48.9) 74(38.9) 132(49.4) 76(38.6) 170(45.0) 40(44.0) 205(45.5) 5(26.3)
62 7 14 28 139 7
30 10 12 47 107 2
4. Discussion In recent years, there are many references about prognostic factors of CRC [9–11]. With the gradual understanding of biological characteristics of CRC and the development of basic and clinical research, many factors that affect the prognosis of CRC have been found. In addition, it is rare to introduce the TCM syndromes into the model and study its impact on the prognosis of CRC. In this study, COX risk ratio model was introduced to predict the prognostic factors of CRC, such as gender, age, lesion site, TNM stage, pathological classification. The correlation between chemotherapy and TCM syndromes were investigated. Based on the data of 470 cases of CRC patients, we discussed the factors influencing the prognosis of CRC and their possible causes. Kaplen-Meier method was used to calculate the cumulative survival rate of the patients with excess syndrome and deficiency syndrome. The results showed that the survival rate of the patients with deficiency syndrome was higher than that of the patients with excess syndrome. CRC patients with deficiency syndrome have a long course of disease. Although they are deficient in vital qi, the pathogenic qi in the body gradually turns to deficiency. So their survival time is long, which is consistent with the theory of TCM. Comparing the general data of the two groups, it can be seen that there are significant differences in gender, lymph node metastasis, TNM stage and lesion site of the disease. Among them, the proportion of the patients with excess syndrome is more. From the lesion site of the disease, CRC frequently occurs in the rectum, which is consistent with the most common lesion site in Chinese CRC patients [12]. This process also reflects the law of the growth and decline of the evil in patients. The vital qi of the patients with excess syndrome changes from strong to weak, the evil qi changes from weak to strong, and lymph node metastasis is more likely to occur. Therefore, attention should be paid to the observation of lymph node in the treatment. Early detection, early diagnosis and early treatment are in line with the idea of “treatment before disease” in TCM [13]. In the treatment of the patients with deficiency syndrome, attention should be paid because of both vital qi and pathogenic qi are changed from strong to weak. Excess syndrome and deficiency syndrome were introduced into COX regression model as one of the prognostic factors. Univariate analysis showed that there was significant difference between excess syndrome and deficiency syndrome. Age at diagnosis, differentiation stage, depth of invasion, lymph node metastasis, TNM stage and distant metastasis could be used as reference factors. Multivariate COX analysis revealed that TNM stage and differentiation stage were independent prognostic factors. It has been studied in some references that TNM stage is one of the main factors affecting the prognosis of CRC. The symptoms of distant metastasis have been found in patients with stage III/IV CRC. Ascites, anemia, hypoproteinemia and organ damage caused by metastasis have been found in most of the patients due to consumption and infiltration of the tumor. The poor physical condition limits the development of treatment, and the sensitivity to various treatments is also low. Therefore, the prognosis is very bad [14]. In the ancient book “Huangdi Neijing”, metastasis is called inheritance. The core pathogenesis of metastasis of CRC is invasion of vital qi deficiency, and blood stasis and toxin inheritance [15]. The differentiation stage of CRC is different, and the biological behavior is also different. It has a certain relationship with TCM syndrome types of CRC, and can be used as a prognostic indicator.
Two-sided Fisher’s exact tests. Some patients missing these clinical pathological parameters.
3.3. Single factor and multi factor analysis of TCM syndromes and prognosis of CRC patients In the COX regression model, the single factor analysis showed that there were significant differences between the excess and deficiency syndrome in prognosis of CRC patients (P < 0.05). Moreover, there were significant differences in age at diagnosis, differentiation stage, depth of invasion, lymph node metastasis, TNM stage, distant metastasis (P < 0.05), as shown in Table 3. We further analyzed the TCM syndromes, differentiation stage, TNM staging, sex and tumor diameter and the results showed that there were significant differences between the two syndromes (P < 0.05), as shown in Table 4.
3.4. Single factor and multi factor analysis of TCM syndromes and postoperative adjuvant chemotherapy in CRC patients In the COX regression model, single factor analysis showed that the survival time of CRC patients of the excess syndrome was significantly prolonged by adjuvant chemotherapy after operation, which was statistically significant compared with those without chemotherapy (P < 0.05). However, the survival time of patients with deficiency syndrome was not significantly prolonged by adjuvant chemotherapy after operation, as shown in Table 5. Then we analyzed the differentiation stage, TNM staging, age at diagnosis, tumor diameter and found that postoperative adjuvant chemotherapy could benefit the survival of CRC patients as shown in Table 7. For CRC patients with deficiency syndrome, COX regression model of single factor and multi-factor were used to analyze. The results 3
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Table 2 Relationship between TCM syndrome type and clinicopathological features in CRC patients. Variables
All patients Age (years) ≤65 ＞65 Gender Males Females Pathological classificationb Ⅰ/Ⅱ Ⅲ Depth of invasionb T1/T2 T3/T4 Lymph node metastasisb N0 N1/N2/N3 TNM stageb Ⅰ/Ⅱ Ⅲ/Ⅳ Tumor diameterb ≤5 cm ＞5 cm Distant metastasis M0 M1 a b
n = 470 cases A (%)
B (%)
C (%)
D(%)
E (%)
F (%)
161(34.2)
99(21.1)
100(21.3)
17(3.6)
52(11.1)
41(8.7)
91(34.0) 70(34.5)
54(20.2) 45(22.2)
60(22.5) 40(19.7)
9(3.4) 8(3.9)
29(10.9) 23(11.3)
24(9.0) 17(8.4)
87(30.9) 74(39.2)
57(20.3) 42(22.2)
64(22.8) 36(19.0)
10(3.6) 7(3.7)
32(11.4) 20(10.6)
31(11.0) 10(5.3)
143(33.3) 15(41.7)
90(21.0) 8(22.2)
97(22.7) 2(5.6)
14(3.3) 3(8.3)
47(11.0) 5(13.9)
37(8.7) 3(8.3)
24(23.3) 134(37.0)
29(28.2) 70(19.3)
31(30.0) 69(19.1)
0(0) 17(4.7)
12(11.7) 39(10.8)
7(6.8) 33(9.1)
75(27.2) 83(43.7)
66(23.9) 33(17.4)
72(26.1) 28(14.7)
12(4.3) 5(2.6)
26(9.4) 25(13.2)
25(9.1) 16(8.4)
70(26.2) 87(44.2)
65(24.3) 34(17.3)
72(27.0) 28(14.2)
12(4.5) 5(2.5)
24(9.0) 27(13.7)
24(9.0) 16(8.1)
122(32.3) 38(41.7)
86(22.8) 13(14.3)
87(23.0) 13(14.3)
14(3.7) 3(3.3)
39(10.3) 13(14.3)
30(7.9) 11(12.1)
150(33.2) 11(57.9)
96(21.3) 3(15.8)
99(22.0) 1(5.3)
17(3.8) 0(0)
50(11.1) 2(10.5)
39(8.6) 2(10.5)
Pa
0.976
0.180
0.087
0.003
0.001
< 0.001
0.077
0.260
Two-sided Fisher’s exact tests. Some patients missing these clinical pathological parameters.
proportion. Most of the patients with this syndrome have exuberant pathogenic qi, which indicates that the disease is in an early stage. Therefore, we should pay attention to specific treatment according to the depth of invasion and differentiation stage to prevent and treat lymph node metastasis. Taking chemotherapy into account, Kaplen-Meier method was used to calculate the cumulative survival rate of chemotherapy in the CRC patients with excess syndrome and deficiency syndrome. The overall survival (OS) rate of patients with chemotherapy was higher than that of no chemotherapy, and the difference was statistically significant. In patients with deficiency syndrome, the overall survival (OS) rate of patients with chemotherapy was higher than that of patients with no chemotherapy, but the difference was not significant. TCM believes that chemotherapy drugs have the effect of eliminating pathogens, and the method of attacking pathogens can obviously prolong the survival time of patients. The patients with deficiency syndrome have deficiency of vital qi and pathogenic qi, so the method of eliminating pathogenic factors will inevitably damage the normal physiological function and make the vital qi more deficient, so the survival time of the patients with deficiency syndrome can not be prolonged. Therefore, attention should be paid to the vital qi in the treatment process. In the patients with excess syndrome, chemotherapy + not as one of the prognostic factors was introduced into the COX regression model. Univariate analysis found that chemotherapy and no chemotherapy patients had significant differences. Univariate and multivariate analysis showed that there was no significant difference between chemotherapy and no chemotherapy, but the age, differentiation stage, TNM stage could be used as a reference factor. The research tells us that different TCM syndromes have different prognosis. It may guide doctors to choose better treatment methods in the clinic. However, the sample is a single population database, which needs to be verified by multi sample database. Moreover, more investigations should be done to support our research.
Fig. 1. Correlation between TCM syndromes and the overall survival of CRC patients. The overall survival (OS) rate of the deficiency syndrome was higher than that of the excess syndrome (P < 0.05).
Kaplen-Meier method was used to calculate the cumulative survival rate of the six TCM syndrome types. The results showed that the survival rate of the patients with dual deficiency of qi and blood was the highest, followed by liver-kidney yin deficiency, spleen-kidney yang deficiency. The survival rate of other syndrome types was lower than those of the three syndrome types, which accorded with the theory of TCM. Dual deficiency of qi and blood syndrome belongs to deficiency syndrome. With the progress of the course of disease, pathogenic qi decreases, and the positive qi deficiency is becoming more and more serious. The patients’ survival time can be relatively prolonged. Six groups of general data were compared, from P < 0.05 we can see that TCM syndromes in the depth of invasion, lymph node metastasis, TNM stage in these three areas there are significant differences. Among them, patients with stagnation of cold-heat syndrome account for a large
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Fig. 2. K-M survival curves of TCM syndromes and of CRC patients. The total survival rate of patients with dual deficiency of qi and blood syndrome was higher than that of patients with other syndromes (P < 0.05).
Fig. 3. K-M survival curves of TCM syndromes and chemotherapy efficacy of CRC patients. The OS rate of patients with/without chemotherapy was higher than that of patients without chemotherapy.
Table 3 Univariate Cox regression analysis of TCM syndrome type and clinicopathological variables predicting survival in patients with CRC patients. Variables
Age (≤65 vs. > 65) Gender (male vs. female) Pathological classification (I/II vs. III) Depth of invasion (T1/T2 vs. T3/T4) Lymph node metastasis (N0 vs. N1/N2) TNM stage (I/II vs. III/IV) Distant metastasis(M0 vs. M1) Tumor diameter (≤5 cm vs. > 5 cm) TCM syndrome type (excess syndrome vs. deficiency syndrome)
Table 4 Multivariate Cox regression analysis of TCM syndrome type and clinicopathological variables predicting survival in patients with CRC.
n = 470 cases HR (95 % CI)
P
1.607(1.215–2.126) 1.013(0.762–1.347) 2.475(1.587–3.860) 3.687(2.270–5.990) 2.807(2.112–3.731) 3.214(2.407–4.291) 8.150(4.849–13.699) 1.196(0.848–1.688) 0.677(0.507-0.904)
0.001 0.927 ＜0.001 ＜0.001 ＜0.001 ＜0.001 ＜0.001 0.307 0.008
Variables
HR (95 % CI)
Pa
Gender (male vs. female) Pathological classification (I/II vs. III) TNM stage (I/II vs. III/IV) Tumor diameter (≤5 cm vs. > 5 cm) TCM syndrome type (excess syndrome vs. deficiency syndrome)
0.875(0.655–1.170) 1.792(1.125–2.855) 3.052(2.273–4.079) 1.116(0.781–1.597) 0.719(0.536-0.963)
0.368 0.014 ＜0.001 0.545 0.027
a Multivariate Cox regression analysis including gender, pathological classification, TNM stage, tumor diameter, TCM syndrome type.
Declaration of Competing Interest The authors declared that they have no conflicts of interest. Ethics approval and consent to participate.
Authors’ contributions Dan Li and Weimin Wang conceived and devised the research, and wrote the manuscript; Weimin Wang, Li Tao and Mengying Lv analyzed the data; Liangliang Xiang and Tengyang Ni done the experiments; Jianliang Deng and Xiancheng Gu supplied technical support; Yan Zhou and Yanqing Liu provided all of the reagent and chemical. All the authors edited and commented on the manuscript. All authors have read and agreed the final manuscript.
Acknowledgements The work was financially supported by the National Natural Science Foundation of China (NO. 81773944, to YQL); Young Medicine Focus Talent Foundation of Jiangsu Province (No. QNRC2016206); Postgraduate Research by Practice Innovation Program of Jiangsu Province (KYCX18_2382); the Natural Science Foundation of Jiangsu 5
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Province for Youths (No. BK20170516, to LT), and the Natural Science Foundation of Jiangsu Province (No. BK20180927 to LMY).
Table 5 Univariate Cox regression analysis of excess syndrome and clinicopathological variables predicting survival in patients with CRC. Variables
Age (≤65 vs. > 65) Gender (male vs. female) Pathological classification (I/II vs. III) TNM stage (I/II vs. III/IV) Tumor diameter (≤5 cm vs. > 5 cm) TCM syndrome type (chemotherapy vs. no chemotherapy)
References
n = 260 cases HR (95 % CI)
P
1.314(0.922–1.872) 1.135(0.796–1.618) 1.788(1.005–3.181) 3.238(2.231–4.700) 1.342(0.876–2.058) 0.591(0.349-0.999)
0.130 0.483 0.048 ＜0.001 0.177 0.050
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Table 6 Univariate Cox regression analysis of deficiency syndrome and clinicopathological variables predicting survival in patients with CRC. Variables
Age (≤65 vs. > 65) Gender (male vs. female) Pathological classification (I/II vs. III) TNM stage (I/II vs. III/IV) Tumor diameter (≤5 cm vs. > 5 cm) TCM syndrome type (chemotherapy vs. no chemotherapy)
n = 210 cases HR (95 % CI)
P
2.109(1.332–3.337) 0.760(0.462–1.252) 4.035(2.001–8.134) 2.956(1.862–4.692) 1.011(0.565–1.808) 0.567(0.291–1.105)
0.001 0.282 ＜0.001 ＜0.001 0.972 0.096
Table 7 Multivariate Cox regression analysis of excess syndrome and icopathological variables predicting survival in patients with CRC.
clin-
Variables
HR (95 % CI)
Pa
TCM syndrome type: excess syndrome Age (≤65 vs. > 65) Gender (male vs. female) Pathological classification (I/II vs. III) TNM stage (I/II vs. III/IV) Tumor diameter (≤5 cm vs. > 5 cm) TCM syndrome type expression (chemotherapy vs. no chemotherapy)
1.388(0.952–2.025) 0.994(0.694–1.424) 1.301(0.713–2.374) 3.652(2.487–5.363) 1.313(0. 834–2.044) 0.510(0.293–0.887)
0.089 0.976 0.391 ＜0.001 0.227 0.017
a Multivariate Cox regression analysis including gender, pathological classification, TNM stage, tumor diameter, TCM syndrome type expression status.
Table 8 Multivariate Cox regression analysis of deficiency syndrome and clinicopathological variables predicting survival in patients with CRC. Variables
HR (95 % CI)
Pa
TCM syndrome type: deficiency syndrome Age (≤65 vs. > 65) Gender (male vs. female) Pathological classification (I/II vs. III) TNM stage (I/II vs. III/IV) Tumor diameter (≤5 cm vs. > 5 cm) TCM syndrome type expression (chemotherapy vs. no chemotherapy)
2.162(1.330–3.514) 0.646(0.385–1.083) 3.224(1.525–6.814) 3.008(1. 866–4.848) 1.008(0. 541–1.878) 0.495(0.241–1.016)
0.002 0.098 0.002 ＜0.001 0.979 0.055
a Multivariate Cox regression analysis including gender, pathological classification, TNM stage, tumor diameter, TCM syndrome type expression status.
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