1. Introduction
Colon cancer is a common gastrointestinal malignancy, and its incidence continues to increase with changes in lifestyle and diet structure.[1] The etiology of colon cancer is not yet well defined, but its associated risk factors have been gradually clarified with the development of research, such as high-fat and low-fiber diet, lack of physical activity, and genetic factors.[2] More than half of colon cancers develop from adenomas and are characterized by a progressive accumulation of genetic and epigenetic disorders, with molecular events accompanied by histological disturbances.[3] It develops from normal colonic epithelium to small adenomas, and then from mild crypt structural abnormalities of small adenomas to the final invasive cancer.[4] With the economic development of China, the improvement of people living standard and the change of diet structure, the incidence and mortality rate of colon cancer in China are increasing year by year, and this situation needs urgent attention to strengthen the research on the prevention and treatment of colon cancer and improve the prognosis.[5]
Currently, the principle of colon cancer treatment is a comprehensive treatment plan based on surgery, supplemented by radiotherapy, biologic and targeted therapy.[6] Individual-related factors, tumor pathological factors and treatment-related factors are the 3 categories of factors that affect patient prognosis.[7] Previous reports on factors influencing survival after radical colon cancer surgery have provided a large amount of information on biological markers and pathological factors, with mixed conclusions.[8] Disease-free survival, with tumor recurrence or death due to disease progression as the temporal endpoint, is more sensitive than overall survival in determining the efficacy of surgery.[9] Therefore, identifying which indicators are associated with the prognosis of colon cancer patients so that the most appropriate treatment can be selected based on such indicators has become an important issue for surgeons. In other words, the establishment of a comprehensive prognostic assessment system for colon cancer is a guide for clinical decision making. In our study, 116 colon cancer patients were enrolled to investigate the factors influencing the 5-year survival rate.
2. Materials and Methods
2.1. Patient characteristics
The clinical data of 116 colon cancer patients who underwent treatment in our hospital from January 2017 to December 2017 were retrospectively selected. The pathological diagnosis of colon cancer was referred to the pathological histological or cytological diagnostic criteria of the WHO Pathology and Genetics of Gastrointestinal Tumors (4th edition, 2010) published by the International Agency for Research on Cancer, and the tumor TM staging criteria were referred to the American Joint Committee on Cancer (7th edition, 2010) staging system.[10] The stage II high-risk diagnosis was based on the criteria in the National Comprehensive Cancer Network (NCCN) “NCCN Guidelines for the Treatment of Colorectal Cancer” (1st edition, 2012).[11] This study has been approved by the Ethics Board of Guangzhou University of Chinese Medicine.
2.2. Inclusion and exclusion criteria
Inclusion criteria: patients with colon cancer who underwent radical surgery for the primary tumor of colon cancer for the first time and were pathologically diagnosed as stage II high-risk and stage III colon cancer after surgery; those who completed 3 to 6 months of postoperative adjuvant chemotherapy with FOLFOX or XELOX regimen, combined or not combined with traditional Chinese medicine; those who had complete medical records; those who had not received radiotherapy and other anti-tumor treatments (including other traditional Chinese medicine treatment); those without serious impairment of heart and lung function and other organ functions; those who had left a reliable contact phone number or correspondence address; those who agreed to publish the data of treatment as scientific research.
Exclusion criteria: patients with missing medical record data or missing contents of the return visit; patients who had not completed 3 to 6 months of adjuvant chemotherapy after surgery; patients with incomplete case data; patients without reliable contact telephone numbers or mailing addresses; patients who had received other chemotherapy regimens or Chinese herbal medicine before surgery; patients with severe impairment of heart, lung and other organ functions; patients with mental or intellectual impairment due to those whose return visit results were affected by related diseases.
2.3. Methods
Information was collected from all patients who met the requirements according to the inclusion criteria. The medical history information of all patients who met the criteria was summarized using excel sheet records, including age, gender, whether preoperative obstruction or blood in stool, history of previous underlying disease, HB, ALB, and TNM stage of the tumor. The follow-up was to find out the postoperative survival of the patients by outpatient review or telephone, with the date of performing surgical treatment as the starting point of follow-up and the end point at 5 years after surgery or patient death. The final patient survival was treated as an outcome event, and patients who survived after 5 years of follow-up were treated as truncated data. The basic information of patients’ age, gender, whether they had obstruction and blood in stool manifestation before surgery, whether they had weight loss, combined underlying diseases, history of alcohol consumption and smoking were collected. The levels of platelet count (PLT), white blood cell count (WBC), ALB and HB at the first serological examination after admission. The location of tumor, showing the maximum diameter of tumor, the degree of tumor differentiation, the depth of muscle infiltration (T stage), lymph node metastasis (N stage), and distant metastasis.
2.4. Statistical analysis
All statistical data in this study were entered into excel software by the first author and the corresponding author respectively, and the statistical processing software was SPSS 25.0 for calculation. Repeated measures analysis of variance between groups was used to measure the measurement expressed as mean ± standard deviation. The Kaplan–Meier method was used for the analysis of overall survival and the prognostic impact of single factors, and the indicators associated with 5-year survival were screened and included in a logistic risk regression model for multifactor analysis. Count data expressed as a percentage (%) were tested by χ2. The statistical significance was P < .05.
3. Results
3.1. Overall survival rate
Among the 116 colon cancer patients, 14 patients were lost to follow-up after hospital discharge, 33 patients were died, and the remaining 69 patients were alive at the end of the follow-up period. The shortest survival time was 1 month and the 5-year overall survival rate was 67.6%, as shown in Figure 1.
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Figure 1.: Overall survival rate of colon cancer patients.
3.2. Univariate analysis of prognosis
Univariate analysis was applied to analyze potential factors that may be associated with the prognosis in patients after radical colon cancer surgery. As shown in Table 1, univariate analysis revealed that there were significant differences in distant metastasis (χ2 = 10.493, P = .001), lymph node metastasis (χ2 = 25.145, P < .001), depth of muscle infiltration (χ2 = 14.929, P < .001), alcohol consumption (χ2 = 15.263, P < .001), and obstruction (χ2 = 9.555, P = .002). However, we did not find significant differences in age, height, body mass index, ALB, smoking status, and HB.
Table 1 -
Baseline clinical characteristics of the study participants.
| Influencing factors |
Death group (58) |
Survival group (58) |
χ
2
|
P
|
| Age (>60 yr) |
17 |
27 |
3.662 |
.056 |
| Height (>150 cm) |
36 |
38 |
0.149 |
.699 |
| Body mass index (>25.0 kg/m2) |
10 |
19 |
3.724 |
.054 |
| ALB < 30 g/L |
11 |
17 |
1.695 |
.193 |
| Smoking history (10 cigarettes/d) |
12 |
16 |
0.753 |
.385 |
| HB < 90 g/L |
13 |
18 |
1.101 |
.294 |
| Distant metastasis |
14 |
31 |
10.493 |
.001 |
| Lymph node metastasis (>N2) |
15 |
42 |
25.145 |
<.001 |
| Depth of myometrial invasion (>T2) |
11 |
31 |
14.929 |
<.001 |
| Drinking (500 mL/d) |
10 |
30 |
15.263 |
<.001 |
| Obstruction |
13 |
29 |
9.555 |
.002 |
ALB = albumin, HB = hemoglobin.
3.3. Multivariate logistic regression analysis
The risk factors in univariate analysis were further applied multivariate logistic regression analysis. In the multivariate logistic regression analysis, the results showed that distant metastasis (odds ratio [OR]: 1.932, 95% confidence intervals [CI]: 1.272–2.934, P = .002), lymph node metastasis (OR: 1.219, 95% CI: 1.091–1.362, P < .001), and obstruction (OR: 1.970, 95% CI: 1.300–2.990, P < .001) were significant independent risk factors affecting the prognosis in patients after radical colon cancer surgery, as shown in Table 2.
Table 2 -
Analysis of factors affecting the prognosis of radical colon cancer surgery.
| Index |
β
|
S.E. |
Wald/χ
2
|
P
|
OR |
95% CI |
| Distant metastasis |
0.658 |
0.213 |
9.535 |
.002 |
1.932 |
1.272–2.934 |
| Lymph node metastasis |
0.198 |
0.057 |
12.298 |
<.001 |
1.219 |
1.091–1.362 |
| Depth of muscle invasion |
0.101 |
0.175 |
0.336 |
.562 |
1.107 |
0.786–1.599 |
| Drinking |
0.267 |
0.165 |
2.606 |
.106 |
1.305 |
0.945–1.643 |
| Obstruction |
0.6116 |
0.119 |
19.45 |
<.001 |
1.97 |
1.300–2.990 |
CI = confidence intervals, OR = odds ratio.
3.4. Survival analysis
According to the survival curve, the 5-year survival rate of patients with no history of drinking was higher than that of patients with drinking history (hazard ratios [HR]: 1.581, 95% CI: 1.165–2.493, P = .025), the 5-year survival rate of patients without distant metastasis was higher than that of patients with distant metastasis (HR: 1.249, 95% CI: 1.118–1.728, P = .029), the patients with lymph node metastasis (>N2 stage) was lower than that of patients without lymph node metastasis (<N2 stage) (HR: 1.295, 95% CI: 1.163–1.584, P = .009), the patients with muscle invasion (>T2 stage) was lower than that of patients without muscle invasion (<T2 stage) (HR: 1.362, 95% CI: 1.049–1.819, P = .014), and the patients with obstruction was lower than that of patients without obstruction (HR: 1.693, 95% CI: 1.377–2.186, P = .003) (Fig. 2).
Figure 2.: Survival analysis of various clinical characteristics.
4. Discussion
Colorectal cancer has become a major cause of cancer morbidity and mortality worldwide, with approximately 600,000 cases dying from colorectal cancer worldwide each year.[12] The incidence of colorectal cancer in China is increasing year by year and has been on the trend of surpassing that of Europe and the United States, but the long-term survival is much less than that of Europe and the United States.[13] Although with the advancement of surgical techniques and chemotherapy regimens, some patients still develop metastasis and recurrence after surgery, which causes early postoperative death.[14] Therefore, risk factors affecting prognosis need to be identified and targeted in order to improve the prognosis of progressive colorectal cancer.[15] Our study focused on preoperative indicators, so some of them were collected with more complete and accurate information, in order to investigate whether, for full-stage colorectal cancer, there are other indicators that can have the same impact at the same time, in addition to those that can affect prognosis that are more certain in existing studies.[16] Also, existing studies have demonstrated that both open surgery and lumpectomy can achieve radical tumor resection for colon cancer, so this factor was not included in the study.[17] In addition, during the telephone follow-up, some patients reported symptoms suspected to be complications such as postoperative obstruction, but the patients did not visit the clinic and their self-reports were vague and could not be specifically identified, so postoperative complications were not included in the analysis of our case study to avoid increasing statistical errors.[18]
There are inconsistent conclusions about the influence of age on the prognosis of colon cancer, and we grouped patients to study whether this factor is associated with prognosis because of the different physical conditions of patients in different age groups.[19] Some studies have concluded that age is not an influential factor in 5-year survival after radical colon surgery, and the effect of age as a factor on the prognosis of colon cancer was performed in patients with colon cancer, and the study confirmed that age is not an influential factor in 5-year survival for patients who underwent surgical treatment, but can significantly affect the prognosis for patients who were treated non-surgically.[20] Also a univariate analysis on the effect of age on 5-year survival in colon cancer yielded negative results.[21] This is in agreement with the conclusion reached in our study that the survival of postoperative patients aged < 60 years is slightly higher than that of those aged ≥ 60 years, but such differences lack statistical significance. Although it has also been confirmed that a greater proportion of colon cancer patients younger than 50 years of age have high-grade tumors, reflecting that age seems to have some association with the benign and malignant phenotype of the tumor and thus may have some impact on prognosis, there is a lack of studies to prove this.[22]
Colon cancer can be associated with obstruction in advanced stages, and it is more common in patients with right hemicolon cancer surgery. Obstruction is a reflection of the depth of muscle infiltration, that is, T-stage, in the clinical presentation.[23] Therefore, the degree of obstruction or the presence or absence of symptoms correlates with the degree of local tumor infiltration, and the more severe the degree of obstruction, the more severe the degree of local tumor infiltration and metastasis, and the worse the prognosis.[24] The survival curve also shows that the prognosis differs significantly with different manifestations of obstruction, which is consistent with the results of existing studies, and therefore patients without obstructive manifestations but with poor individual test indicators should be taken seriously.[25] Colon cancer is a malignant neoplastic disease, especially in advanced stages, when patients develop cachexia, which is characterized by progressive weight loss, fat loss, and muscle wasting.[26] Therefore, rapid weight loss is suggestive of the malignant phenotype and rapid progression of colon cancer, and this study counted weight change in combination with postoperative survival time for analysis to determine whether weight change has an impact on prognosis.[27] Studies have shown that weight loss in colon cancer patients is not only a symptom but also a prognostic factor for poor prognosis including overall survival and tumor recurrence, as there is a significant correlation between this factor of weight loss and with tumor location, size and depth.[28] In our study, we do not exclude that some patients with mild weight loss and early tumor stage have a better prognosis. Because patients are often not regularly and accurately monitored for weight change prior to consultation, our grouping of patients for weight change can only be based on the presence or absence of weight loss, and cannot be more accurately classified according to the degree of reduction, thus concluding that other studies that more accurately count weight change differ.[29] There are also studies showing no correlation between weight loss and prognosis of colon cancer, and most of these studies were also analyzed based on the presence or absence of weight loss, without statistical information such as the specific degree of reduction included in the analysis, which is consistent with the conclusion we reached in this study, so it is considered that the degree of weight loss is more significant in patients with advanced cancer, and early stage patients can also show weight loss as a manifestation, but to a lesser extent.[30] The presence or absence of weight loss is not a prognostic influence, while severe weight loss has a correlation with prognosis.
B-galactosidase (B-GAL) is a lysosomal exo-glycosidase that participates in the catabolism of glycoconjugates by sequentially releasing B-linked galactosyl residues.[31] Higher B-GAL activity reflects the ability of cancer to accelerate growth, invasion, metastasis and maturation.[32] Serum B-GAL activity is higher in colon cancer patients with a history of alcohol and nicotine dependence compared to colon cancer patients without a history of alcohol or tobacco use, and thus the prognosis may be poorer for patients with a previous history of tobacco and alcohol use, especially in those who have not quit smoking and alcohol during is disease course and postoperatively.[33] In addition, smoking may have an effect on serum levels of carcinoembryonic antigen, which may have an impact on prognosis, and it has also been shown that smoking suppresses the immune system and affects the functioning of immune cells, thus causing immune escape of tumor cells.[34] Because the oncological markers tested in our patients at the time of consultation were different, and because some patients did not undergo postoperative review with us, relevant tumor marker data were not available, so they were not included in the analysis of prognosis in our experiment, which only investigated whether smoking history had an effect on prognosis.[35] In our study, smoking had no effect on the prognosis of colon cancer. Alcohol consumption is one of the risk factors for the development of colon cancer has been revealed by studies.[36] In addition, in vivo and in vitro studies have shown that ethanol significantly promotes mast cell-mediated tumor migration and facilitates tumor dissemination, but the exact mechanism still needs further study. Therefore, when considered together, alcohol consumption has a negative impact on prognosis.[37] In our study, alcohol consumption was associated with 5-year survival of patients after radical colon resection and had a worse prognosis in patients with due promptness. Usually, patients with right hemicolectomy are dominated by systemic manifestations, including anemia and cachexia, while those with left hemicolectomy are dominated by intestinal symptoms such as obstruction and blood in the stool, and those with low HB levels and preoperative blood loss are mostly present, so they are mostly seen in patients with right hemicolectomy, and the prognosis of right hemicolectomy is worse than that of left hemicolectomy.[38] In addition, it has also been shown that patients who present with anemic manifestations have a higher likelihood of tumor vascular invasion. Different HB levels in this group of patients had no effect on the prognosis of colon cancer patients. ALB is one of the good indicators of the nutritional status of the body and liver function, and 20% of colon cancer patients have a poor nutritional status and this malnutrition is associated with a poor prognosis of colon cancer. Some studies have proven that there is a link between liver function and colon cancer, and ALB is a good predictor of liver function.[39] Also, clinical studies have confirmed that preoperative ALB levels in colon cancer patients are positively correlated with prognosis.
The degree of tumor infiltration to the intestinal wall varies with T-stage. The more advanced the stage, the more serious the tumor invasion to the intestinal wall vessels and lymphatic vessels, etc, which predicts a worse prognosis. The conclusion that T-stage can affect prognosis has been clearly established and was demonstrated in this study. It has been conclusively demonstrated that the survival and prognosis of colon cancer patients are closely related to lymph node metastasis, and the degree of lymph node metastasis represents, in a sense, the degree of tumor spread; therefore, the proportion of metastatic lymph nodes and the number of metastatic lymph nodes are negatively correlated with prognosis.[40] This conclusion can also be drawn in our study, where the prognosis of patients was extremely poor and all patients died before 5 years of follow-up. Distant metastasis refers to the transfer of tumor cells to sites far from the tumor through blood and lymphatic routes. Patients with distant metastasis are clinically classified as colon cancer, with poor prognosis and high recurrence rate. Previous studies have also demonstrated that distant metastasis is a close indicator of poor prognosis. In our study, the difference in 5-year survival rate between the distant metastasis group and the non-distant metastasis group in colon cancer was significant and consistent with previous studies.
In conclusion, preoperative obstruction, lymph node metastasis, and distant metastasis (M stage) are independent influencing factors of 5-year survival rate after radical surgery for colon cancer, and patients with risk factors should be followed up more closely and reasonable postoperative adjuvant chemotherapy regimens should be used to improve long-term survival.
Author contributions
Conceptualization: Jin-Jun Ye.
Data curation: Ruo-Yu Wei, Jin-Jun Ye.
Formal analysis: Wen-Yi Zhong, Jin-Jun Ye.
Funding acquisition: Wen-Yi Zhong, Jin-Jun Ye.
Investigation: Wen-Yi Zhong, Jin-Jun Ye.
Methodology: Chun-Hong Li, Jin-Jun Ye.
Project administration: Ruo-Yu Wei, Wen-Yi Zhong, Chun-Hong Li.
Resources: Ruo-Yu Wei, Wen-Yi Zhong, Chun-Hong Li.
Software: Ruo-Yu Wei, Wen-Yi Zhong, Chun-Hong Li.
Supervision: Ruo-Yu Wei, Wen-Yi Zhong, Chun-Hong Li.
Validation: Ruo-Yu Wei, Wen-Yi Zhong, Chun-Hong Li, Jin-Jun Ye.
Visualization: Ruo-Yu Wei, Chun-Hong Li, Jin-Jun Ye.
Writing – original draft: Ruo-Yu Wei, Jin-Jun Ye.
Writing – review & editing: Ruo-Yu Wei, Jin-Jun Ye.
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