To assess whether preoperative markers could predict the stage of patients with gastric cancer. We analyzed retrospectively the preoperative indicators between stage IV and non-stage IV gastric cancer at the Gastrointestinal Surgery of Nanjing Drum Tower Hospital. A total of 500 patients with gastric cancer were screened. Of all the variables, alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 125, carbohydrate antigen (CA) 199, carbohydrate antigen (CA) 724, carbohydrate antigen (CA) 242, thrombin time (TT), prothrombin time (PT), activated partial thromboplastin time (APTT), blood platelet count (PLT), white blood cell (WBC) count, C-reactive protein (CRP), neutrophil count (NC), lymphocyte count (LC), neutrophil-lymphocyte ratio (NLR), hemoglobin (HB), aspartate aminotransferase (AST), and ascites were found to have statistical differences between the two groups. Then, Stepwise Discriminant Analysis was conducted to establish a prediction model including 7 indexes (CA724, CA242, TT, PLT, CRP, AST, and ascites). According to the model, 90.6% of original grouped cases were correctly classified and 90.6% of cross-validated grouped cases were correctly classified. We built a discriminant including CA724, CA242, TT, PLT, CRP, AST, and ascites for predicting patients with gastric cancer to be either stage IV or non-stage IV. According to this discriminant, 90.6% of patients could be correctly predicted.
Gastric cancer is the second leading cause of cancer deaths worldwide despite a dramatic decline in its incidence over the past century [
Stage IV gastric cancer affects other systems and leads to a change of many indexes such as coagulation, inflammation, and nutrition. These serum biomarkers have the potential to act as supplementary tools for predicting the preoperative stage of gastric cancer. In this study, we analyzed retrospectively the preoperative indicators between stage IV and non-stage IV gastric cancer to investigate whether these indicators could predict the stage preoperatively.
The patients who had an accurate stage for gastric cancer at the Department of General Surgery, the Affiliated Hospital of Nanjing University Medical School, between January 2014 and December 2016 were analyzed retrospectively. Inclusion criteria are as follows: (1) patients with complete medical records, (2) patients without operation or chemoradiotherapy previously, and (3) non-stage IV patients with pathological diagnosis and stage IV patients with pathological or imaging diagnosis. Reasons for exclusion include accompanying other tumors, thrombosis and hemorrhagic disease, viscera function disorder, diabetes mellitus, and acute inflammation. Patients with bone marrow involvement are also excluded. The patients were divided into stage IV and non-stage IV groups. The diagnosis of gastric cancer with stage IV is as follows: (1) patients with metastases of other organs such as the liver, lung, and pancreas; (2) patients with peritoneal spread; and (3) patients with metastases of distant lymph nodes such as the supraclavicular lymph nodes. This study was approved by the IRB of Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School. All methods were performed in accordance with the relevant guidelines and regulations. The written informed consents for participation in the study were obtained from all participants.
The parameters included in the analysis were categorized into clinical, imaging, and pathological data. The clinical indices included age, gender, tumor markers, coagulation function, inflammatory indices, nutritional status, and liver function. The imaging data was on whether the patient had ascites. The pathological data was mainly the TNM stage of gastric cancer. The pathological diagnosis was confirmed by at least two pathologists, and imaging diagnosis was also confirmed by at least two image doctors.
Tumor markers used in this analysis included alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 125, carbohydrate antigen (CA) 199, carbohydrate antigen (CA) 724, and carbohydrate antigen (CA) 242. These tumor markers were tested in the Nuclear Medicine Department through the tumor detection kit made by the Shanghai Biotechnology Co. Ltd. Coagulation function included activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), and blood platelet count (PLT). Inflammatory indices included white blood cell (WBC) count, neutrophil count (NC), lymphocyte count (LC), neutrophil-lymphocyte ratio (NLR), and C-reactive protein (CRP). Nutritional indices included hemoglobin (HB) and albumin (ALB). Liver enzyme parameters included alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), and direct bilirubin (DBIL). TNM staging was performed according to the American Joint Committee on Cancer Staging Manual (7th edition).
A large number of variables (22 variables) were investigated in this study. For comparisons, the chi-squared test and two-tailed Student
500 patients were screened (354 men and 146 women, ages ranging from 21 to 92 years, with mean age 61.9 years). 470 patients were subjected to surgery. They were proved to be 128 cases of stage I, 101 cases of stage II, 172 cases of stage III, and 69 cases of stage IV gastric cancer. The remaining 30 cases were all diagnosed as stage IV by imaging examinations. The patients were divided into non-stage IV and stage IV groups. Stage I, stage II, and stage III were classified as the non-stage IV group. So there were 401 cases in the non-stage IV group and 99 cases in the stage IV group. Table
Comparison of the clinical indexes between stage IV and non-stage IV groups.
Indexes | Stage IV group | Non-stage IV group | |
---|---|---|---|
Gender | 0.085 | ||
Male | 63 | 291 | |
Female | 36 | 110 | |
Age (yr) | 61.29 ± 12.92 | 62.01 ± 11.24 | 0.802 |
AFP (ng/mL) | 8.06 ± 29.37 | 3.5 ± 6.95 | 0.006 |
CEA (ng/mL) | 130.50 ± 784.63 | 6.66 ± 36.10 | 0.002 |
CA125 (U/mL) | 42.45 ± 55.44 | 10.36 ± 8.33 | ≤0.001 |
CA199 (U/mL) | 522.09 ± 2187.79 | 43.35 ± 190.26 | ≤0.001 |
CA724 (U/mL) | 372.37 ± 3129.16 | 7.21 ± 42.39 | 0.022 |
CA242 (U/mL) | 473.32 ± 1925 | 31.30 ± 208.94 | ≤0.001 |
TT (s) | 17.83 ± 1.57 | 18.38 ± 1.45 | 0.001 |
PT (s) | 12.23 ± 0.88 | 11.91 ± 1.21 | 0.015 |
APTT (s) | 29.77 ± 4.20 | 28.37 ± 4.00 | 0.002 |
PLT ( |
233.19 ± 99.08 | 208.22 ± 69.68 | 0.004 |
WBC ( |
6.02 ± 1.83 | 5.5 ± 1.52 | 0.005 |
CRP (mg/L) | 12.41 ± 18.75 | 4.38 ± 4.78 | ≤0.001 |
NC ( |
3.9 ± 1.58 | 3.24 ± 1.15 | ≤0.001 |
LC ( |
1.49 ± 0.56 | 1.73 ± 0.62 | 0.001 |
NLR | 3.10 ± 1.99 | 2.07 ± 1.05 | ≤0.001 |
HB (g/L) | 113.45 ± 25.53 | 124.48 ± 25.53 | ≤0.001 |
ALB (g/L) | 36.80 ± 4.05 | 39.18 ± 15.33 | 0.129 |
ALT (U/L) | 21.30 ± 28.90 | 18.19 ± 10.31 | 0.08 |
AST (U/L) | 24.89 ± 27.71 | 19.28 ± 6.98 | ≤0.001 |
TB ( |
10.63 ± 4.94 | 11.27 ± 5.45 | 0.289 |
DB ( |
3.67 ± 1.97 | 3.55 ± 1.86 | 0.586 |
Ascites | ≤0.001 | ||
Yes | 47 | 0 | |
No | 52 | 401 |
22 variables were analyzed in sequence, and the results are summarized in Table
According to the screened 18 variables which were statistically significant, a prediction model of stage was conducted by a Stepwise Discriminant Analysis (
The most significant variables discriminating between the groups by Stepwise Discriminant Analysis.
Indexes | df1 | df2 | Sig. | ||
---|---|---|---|---|---|
CA724 (U/mL) | 0.525 | 105.874 | 4 | 469 | ≤0.001 |
CA242 (U/mL) | 0.551 | 192.145 | 2 | 471 | ≤0.001 |
TT (s) | 0.511 | 74.545 | 6 | 467 | ≤0.001 |
PLT ( |
0.506 | 64.897 | 7 | 466 | ≤0.001 |
CRP (mg/L) | 0.537 | 134.919 | 3 | 470 | ≤0.001 |
AST (U/L) | 0.519 | 86.86 | 5 | 468 | ≤0.001 |
Ascites | 0.587 | 331.467 | 1 | 472 | ≤0.001 |
The classification function coefficients.
Stage | ||
---|---|---|
Non-stage IV group | Stage IV group | |
Ascites | 15.468 | 25.678 |
CA724 (U/mL) | -0.001 | −0.001 |
CA242 (U/mL) | 0.001 | 0.002 |
TT (s) | 9.366 | 9.091 |
PLT ( |
0.044 | 0.048 |
CRP (mg/L) | 0.282 | 0.33 |
AST (U/L) | −0.035 | 0.002 |
Constant | −97.274 | −108.563 |
The prediction of the accuracy of the prediction model was performed by cross validation (Table
The result of cross validation by using 7 variables.
Category | Groups prediction | Total | |||
---|---|---|---|---|---|
Stage IV | Non-stage IV | ||||
Original | Counting | Stage IV | 53 | 46 | 99 |
Non-stage IV | 1 | 400 | 401 | ||
% | Stage IV | 53.5 | 46.5 | 100 | |
Non-stage IV | 0.2 | 99.8 | 100 | ||
Cross validation | Counting | Stage IV | 53 | 46 | 99 |
Non-stage IV | 1 | 400 | 401 | ||
% | Stage IV | 53.5 | 46.5 | 100 | |
Non-stage IV | 0.2 | 99.8 | 100 |
Cross validation is done only for those cases in the analysis. In cross validation, each case is classified by the functions derived from all cases other than that case. 90.6% of the original grouped cases were correctly classified. 90.6% of the cross-validated grouped cases were correctly classified.
For patients with gastric cancer, preoperative tumor staging is useful to select the appropriate therapeutic strategy. Surgery is the main treatment measure for non-stage IV patients, while comprehensive therapy is proper for stage IV patients. So it is necessary to diagnose a patient as either stage IV or non-stage IV preoperatively. At present, the preoperative stage mainly relies on imaging examinations. However, imaging examinations easily lead to misdiagnosis or missed diagnosis when the metastatic lesion is too small or too hidden. Therefore, another method is needed to make up for the deficiency of imaging.
In the present study, we screened 7 indexes (CA724, CA242, TT, PLT, CRP, AST, and ascites) and got a discriminant for predicting stage. According to the cross validation, 90.6% of original grouped cases were correctly classified and 90.6% of cross-validated grouped cases were correctly classified. Specifically, 99.8% of the non-stage IV patients and 53.5% of the stage IV patients could be diagnosed by this discriminant. This discriminant combining with imaging could improve the accuracy of the preoperative stage of gastric cancer.
Tumor markers are often measured for early detection and preoperative staging of gastric cancer. The commonly used markers are AFP, CEA, CA125, CA199, CA724, and CA242. Some studies have suggested their relevance to predict the preoperative stage. Cidon and Bustamante showed that the preoperative serum level of CA724 has the best predictive value in indicating advanced disease in patients diagnosed with gastric cancer [
Studies showed that the host inflammatory response to cancer cells is associated with tumor progression [
AST is a critical enzyme during the biological process. AST may increase in different hepatic injures, such as hepatitis and cirrhosis induced by alcohol, drugs, viruses, and being under oxidative stress [
Systemic hemostasis and thrombosis activation has been implicated in tumor progression and metastasis. The famous HYPERCAN study showed that hypercoagulation screening was an innovative tool for risk assessment, early diagnosis, and prognosis in cancer [
For patients with advanced gastric cancer, preoperative examinations often revealed abnormal ascites, which could indicate the possibility of peritoneal metastasis. A Japanese research indicated that the presence of ascites was significantly correlated with peritoneal metastasis (
It is important to determine the stage preoperatively in order to choose the appropriate management of gastric cancer. The preoperative stage mainly relies on imaging examinations. Imaging examinations could not make a definite diagnosis when the metastatic lesion is too small or too hidden. So we need to explore new methods to make up for the inadequacy of imaging. However, there were few reports on this topic. Ohi et al. identified that a combination of specific factors is an alternative method to preoperatively discriminate patients with gastric cancer with peritoneal metastasis from those without [
We built a discriminant including CA724, CA242, TT, PLT, CRP, AST, and ascites for predicting patients with gastric cancer to be either stage IV or non-stage IV. According to this discriminant, 90.6% of patients could be correctly predicted. We will also carry out a prospective study to verify whether this discriminant could be used clinically.
This study was approved by the IRB of Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School. The written informed consents for participation in the study were obtained from all participants.
The authors declare that they have no conflicts of interest.
Wei Ge participated in the study design, clinical data collection, and data analysis and wrote the paper. Li-ming Zheng participated in the clinical data collection and data analysis. Gang Chen conceived of the study, participated in its design, and gave final approval of the version to be published. All authors have read and approved the final paper.
The authors thank the patients for giving them written consent for publishing their details.