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Prognostic value of carbohydrate antigen125 and carcino embryonic antigen expression in patients with colorectal carcinoma and its guiding significance for chemotherapy

Abstract The aim of this study is to evaluate the predictive value of carbohydrate antigen125 (CA125) and carcino embryonic antigen (CEA) expression and its guiding role of choosing chemotherapy regimen in post-operation patients with colorectal carcinoma. The clinical data of all patients, including laboratory data and pathological data, were collected from the electronic medical records. Kaplan-Meier Log rank test, COX regression model and subgroup analyses were employed to assess the correlation between the expression of CA125 and CEA in patients with colorectal carcinoma and the survival, and the effect on chemotherapy efficacy. Kaplan-Meier showed that CA125 expression is negatively related to the progression-free survival (PFS) of the post-operative patients, Median PFS was 1140 days in the patients with high expression, and Median PFS was 1387 days in the patients with low expression (χ2 = 4.715, P = .030); CEA expression is also negatively associated with the PFS of the post-operative patients, Median PFS was 1197 days in the patients with high expression, and Median PFS was 1424 days in the patients with low expression (χ2 = 4.992, P = .025). Subgroup analysis also showed that the patients with normal CA125 and CEA had better prognosis, median PFS was 1505 days, and the patients with CA125 and (or) CEA high expression had poor prognosis and median PFS was 1162 days (χ2 = 13.346, P = .001), and found that there was no statistical difference in patients with oxaliplatin plus capecitabine (XELOX) and oxaliplatin, 5-fluorouracil and Calcium folinate (FOLFOX) chemotherapy in patients with CA125 and CEA low expression. However, in these patients with CA125 or (and) CEA high expression, the median PFS of patients treated with XELOX was 1082 days, and the median PFS of patients treated with FOLFOX chemotherapy was 1335 (χ2 = 4.547, P = .033). Expression of CA125 and CEA associated with the survival of patients, and have some guiding significance for chemotherapy in patients with colorectal cancer after operation; Compared with XELOX, FOLFOX chemotherapy is more effective for CA125 or (and) CEA high expression patients with colorectal carcinoma.


Introduction
Tumor markers refer to a class of substances produced by tumor cells and tissues in the process of tumorigenesis and progression or produced by normal tissue after stimulation of tumor. It plays an important role in tumor early diagnosis, tumor progression and monitoring therapeutic effect. [1] Carbohydrate antigen125 (CA125) and carcino embryonic antigen (CEA) are common clinical monitoring indexes about tumor, especially gastrointestinal tumors. [2][3][4] However, there is still a lack of more precise markers that can provide guidance for clinical chemotherapy.
Colorectal carcinoma is a health problem worldwide, and the morality and mortality are increased gradually in recent years, [5][6][7][8] which was also becoming the leading cause of death in the population. [9] For decades, translational medicine plays an important role in the treatment of malignant tumor and clinical research. [10] Therefore, some tumor related substances as biomarkers are used to diagnose early stage of cancers, assess tumor progression and efficacy of anti-carcinoma therapies. [9] Some drugs specifically targeting tumor markers have been used to treat the patients with colon carcinoma. [7,11,12] Some serum biomarkers, such as carbohydrate antigen 199 (CA199), CA125, and CEA, are associated with the prognosis of patients with carcinoma, and it is easy to detect in the clinical work. CA199 is a kind of tumor marker of digestive system cancer. The increase of CA199 is mainly seen in pancreatic cancer. Second, in cholangiocarcinoma and colorectal cancer, the level of CA199 will also increase. [13][14][15] CEA is mainly produced by gastrointestinal tumors. Its chemical component is glycoprotein. As an adhesion molecule, CEA promotes the aggregation and invasion of tumor cell. Elevated CEA levels often indicate tumor progression and recurrence. At present, it is mainly used as a marker of gastrointestinal tumors. [15] CA125 interacts with some receptors to inhibit the apoptosis of cancer cells and promote the implantation and metastasis of tumor cells. [16] Research on biomarkers of tumors has a great progress in the last 2 decades. The value of potential diagnostic and therapeutic of biomarkers is also becoming more and more evident. In this study, the clinical data of 206 patients, including laboratory data and pathological data, were collected from the electronic medical records of the Second Hospital of Lanzhou University, and investigated the correlation between the survival and clinicopathological parameters in patients with colorectal carcinoma, and to explore serum tumor markers that can be used to guide clinical treatment.  Table 1 The correlation between clinical data and PFS of patients with colorectal carcinoma were analyzed by Log-rank test. Whether it is high or not that is based on the normal reference value range of the clinical test result report. A higher than normal reference value is specified as a high expression, and a lower than reference value is specified as a low expression, such as CA125, CA199, CEA and so on.

Patients
We enrolled 206 patients with colorectal carcinoma who underwent tumor resection at Lanzhou University Second Hospital (Gansu Province, China) between 2010 and 2015.
The study was approved by the Ethics Committee of at the Lanzhou University Second Hospital, and the data were anonymously obtained and analyzed. Informed consents from participants were also waived due to the complete anonymity of the patients. The data of all patients, including laboratory data and pathological data, were collected from the electronic medical records of the Lanzhou University Second Hospital. This study was performed in accordance with the relevant guidelines and regulations, and conformed to the Declaration of Helsinki. [17] The inclusion criteria of patients included complete pathological and follow-up data, without long distance metastasis, no other chronic diseases, and without any treatments before the surgery. The exclusion criteria: patients who suffered from other tumor or other chronic diseases, or died from accidental death or other diseases, lack of pathological and follow-up data, long distance metastasis before the surgery. Ultimately, a total of 206 cases were eventually enrolled in this study, including 104 males and 102 females, aged 23 to 90 years, median age of 59 years.

Clinical data and follow-up
Clinical data were totally collected from 206 patients with colorectal carcinoma. The clinical data, including gender, age, results of electronic colonoscopy, pathological results, preoperative serum CA125, CEA, CA19-9, hemoglobin (HGB), lymphocyte and post-operative chemotherapy were collected from the electronic medical records of the Second Hospital of Lanzhou University. The follow-up period was from the operative date to the death date, the follow-up period was 5-years post-surgery, and no patients died during follow-up.

Statistical analysis
SPSS 22.0 statistical software was used to analyze all data. Kaplan-Meier survival estimates model were used to assess the correlation of the progression survival (PFS) and overall survival (OS) with gender, age, CEA, CA125, CA199, HGB, white blood cell, lymphatic metastasis, tumor node metastasis stage (TNM stage) and chemotherapy regimen. Finally, Subgroup analysis was used to assess the correlation between the expression of CEA and CA125 and chemotherapy. P < .05 was considered statistically significant.

Figures of electronic colonoscopy and pathology from typical cases and Statistical results
Most of patients come to the hospital for bloody stool. For instance, a patient was detected by colonoscopy for hematochezia, and the result showed that ascending colon tumor, local necrosis, hemorrhage, ulceration (Fig. 1A). The result of pathological biopsy: Moderately differentiated adenocarcinoma ( Fig. 1 B); Another case who suffered from hematochezia was detected by colonoscopy, the result showed that rectal malignant tumor (about 5 cm from anal verge), it is circumferential hyperplasia with ulceration and local hemorrhage (Fig. 1 C). The result of pathological biopsy: Poorly differentiated adenocarcinoma ( Fig. 1 D) Fig. 5). Whether it is high or not that is based on the normal reference value range of the clinical test result report. A higher than normal reference value is specified as a high expression, and a lower than reference value is specified as a low expression, such as CA125, CA199, CEA and so on.   Table 3 The correlation between the PFS and the expression of CA125 and CEA in the patients with different chemotherapy regimen.

The results of Cox regression
Cox regression is used to analyze the factors that affect the risk of tumor progression and evaluate whether they are independent prognostic factors. Univariate analysis revealed that comparing with the patients with CA125 low, patients with CA125 high had higher tumor progression risk (HR = 1.708, 95% CI: 1.047-2.784, P = .32) and comparing with the patients with CEA low, patients with CEA high had higher tumor progression risk (HR = 1.631, 95% CI: 1.057-2.516, P = .27). The result also showed that comparing with the patients with CA125 and CEA low, patients with CA125 and or CEA high had higher tumor progression risk (HR = 2.356, 95% CI: 1.492-3.722, P = .001); patients with negative lymphatic metastasis vs patients with and positive lymphatic metastasis, the latter is at higher risk of tumor progression (HR = 1.750, 95% CI: 1.127-2.716, P = .013), patients with pathology grade I-II colorectal carcinoma vs patients with pathology grade III-IV colorectal carcinoma, the latter is at higher risk of tumor progression (HR = 1.671, 95% CI: Table 4 The correlation between the OS and the expression of CA125 and CEA in the patients with different chemotherapy regimen.

Discussion
At present, the treatment of colorectal cancer has made some progress. However, the mortality of patients with colorectal carcinoma is still high. Therefore, it is urgent to optimize the current treatment methods to reduce the mortality of patients with colorectal carcinoma. Research on tumor markers is also a means to improve the efficiency of tumor diagnosis and treatment in clinical work. [18] The application of molecular markers means that tumor prognosis assessment is no longer a limit to clinical pathological parameters, research on biomarkers has main 2 parts, including the prognosis of patient with carcinoma and guiding the treatment. The intervention of some tumor related markers could promote anti-tumor effects, this is so-called "targeted therapy" which provides a new method for tumor management. [9] Study showed that CA125 and CEA play an important role in the diagnosis and treatment of colorectal carcinoma. [19] The results of this study also showed that the expression of CA125and CEA had a negative correlation with the OS of patients with colorectal carcinoma.
Recently, CEA and CA125 are widely used in clinical laboratory, but they are mainly used to monitor the recurrence of tumors. There are few reports on the application of CEA and CA125 in clinical chemotherapy. The results of this study showed that the prognosis of patients with colorectal carcinoma was poor, especially these patients with high expression of CEA and CA125 in serum. In patients with normal CA125 and CEA, there was no significant difference in OS, whether it is A or B regimen. However, the median OS was shorter in patients receiving XELOX chemotherapy, and longer in patients receiving FOLFOX chemotherapy than in patients with CA125 or (and) CEA over-expression. The result of this study has some guiding significance for the prognosis evaluation and chemotherapy plan of postoperative patients with colorectal carcinoma. Writingoriginal draft: Peng Du.