Understanding Ileus Risk Factors After Radical Gastrectomy for Gastric Cancer

Introduction Gastric cancer is a common malignant tumor of the digestive tract, which usually requires comprehensive surgery-based treatment.1 Radical gastrectomy is usually extensive and traumatic, which hinders the recovery of gastrointestinal function.2 Postoperative ileus is a common gastrointestinal dysfunction after abdominal surgery, characterized by weakened or absent bowel sounds, abdominal distension, constipation, and poor oral tolerance. Although most cases of postoperative ileus can be relieved within 3 days, some patients experience persistent or recurrent postoperative ileus.3 As a common complication after radical gastrectomy for gastric cancer, postoperative ileus is affected by various factors such as water and electrolyte imbalance, surgical trauma, inflammatory response, excessive sympathetic nerve activity, and drug effects. Its mechanism is complex and not yet fully understood.4,5 Postoperative ileus can lead to prolonged hospital stay, increased medical costs, and even increase the risk of other complications. By analyzing the related factors of postoperative ileus after radical gastrectomy for gastric cancer and establishing a model to predict the probability of postoperative ileus, early intervention and optimal preventive measures can be implemented, thereby benefiting more patients by improving outcomes and reducing medical costs. However, there is currently a lack of simple and precise tools for individualized prediction of the risk of postoperative intestinal obstruction following radical gastrectomy. In this context, the present study aims to analyze the relevant risk factors for intestinal obstruction after radical gastrectomy for gastric cancer and to develop and validate an individualized nomogram model to quantify the probability of postoperative intestinal obstruction in patients. Materials and Methods General Information This study followed the Declaration of Helsinki and obtained approval from the ethics committee. Patients who underwent radical gastrectomy for gastric cancer in our hospital from January 2022 to April 2025 were included as the study subjects. Inclusion criteria: ① adult patients with gastric cancer, pathologically confirmed as gastric cancer, and meeting the criteria;6 ② no neoadjuvant therapy before surgery; ③ no recent history of glucocorticoids or immunosuppressants. Exclusion criteria: ① incomplete or unanalyzable clinical, laboratory, or surgical data; ② death within 30 days after radical gastrectomy for gastric cancer; ③ severe hepatic or renal insufficiency or heart failure; ④ other malignant tumors; ⑤Distant metastasis or peritoneal dissemination was confirmed intraoperatively or by postoperative pathology. The flowchart of case inclusion is shown in Figure 1. A total of 424 patients with gastric cancer were finally included, and they were divided into a modeling group of 297 cases and a validation group of 127 cases according to a ratio of approximately 7:3. The modeling group was further divided into an ileus group of 54 cases and a non-ileus group of 243 cases according to the occurrence of postoperative ileus. Figure 1 Flowchart of case inclusion. Methods Collection and Definition of Clinical Data Clinical data of gastric cancer patients were collected, including age (<60 years or ≥60 years), gender, body mass index (BMI) (weight/height2), smoking (continuous or cumulative smoking for 6 months or more is defined as a history of smoking), alcohol consumption (at least once a month, including social occasions, or drinking for more than half a year is defined as a history of drinking), diabetes mellitus (1. Having symptoms of diabetes with random venous plasma glucose concentration ≥11.1 mmol/L; 2. Venous plasma glucose concentration ≥11.1 mmol/L 2 hours after oral administration of 75 g glucose in an oral glucose tolerance test; 3. Fasting venous plasma glucose concentration ≥7.0 mmol/L), hypertension (without the use of antihypertensive drugs, blood pressure measured 3 times on different days with systolic blood pressure ≥140 mmHg and diastolic blood pressure ≥90 mmHg), tumor size (<5 cm or ≥5 cm), tumor location (gastric antrum or gastric body), previous abdominal surgery, surgical method (laparoscopic or open), TNM stage (III or IIIIV), differentiation degree (moderate/high differentiation or low differentiation), operation time (<400 min or ≥400 min), intraoperative blood loss (<500 mL or ≥500 mL), IL-2, IL-4, IL-6, TNF-α, IL-10, CRP, WBC. Among them, IL-2, IL-4, IL-6, TNF-α, and IL-10 were detected using an Aixkang AE120 fully automatic enzyme immunoassay analyzer, CRP was detected by immunoturbidimetry, and WBC was detected by a Sysmex 800 blood analyzer. The cutoff values for age, tumor size, intraoperative blood loss, and operative time were set at the median values of each respective variable. Evaluation of Postoperative Ileus The definition of postoperative ileus referred to the criteria proposed in recent systematic reviews and global surveys,7 specifically including the diagnosis of postoperative ileus if the patient met two or more of the following five criteria on or after the 4th postoperative day: ① nausea or vomiting within the first 12 hours; ② no passage of gas or stool within the first 24 hours; ③ inability to tolerate oral diet within the first 24 hours; ④ abdominal distension; ⑤ radiological confirmation. The diagnosis of postoperative ileus was made independently by two experienced surgeons. Statistical Methods Measurement data were expressed as ( ), all of which conformed to a normal distribution, and were analyzed using the t-test (two-tailed); count data were expressed as [n (%)], and were analyzed using the Pearsonχ2 test; LASSO regression analysis and multivariate logistic regression analysis were used to screen the influencing factors of postoperative ileus after radical gastrectomy for gastric cancer; a nomogram model was constructed to predict postoperative ileus after radical gastrectomy for gastric cancer, and calibration curves were used to evaluate the model’s calibration, ROC curves were used to evaluate the model’s discrimination, and clinical decision curve analysis was used to analyze the model’s clinical applicability. Nomograms, LASSO regression analysis feature variable selection plots, calibration curves, and decision curves were drawn using R software (R 4.3.3), ROC curves were drawn using SPSS software (version 25.0), and P<0.05 indicated a statistically significant difference. Results Comparison of Clinical Data Between the Modeling and Validation Groups There were no statistically significant differences in age, gender, BMI, smoking, alcohol consumption, diabetes mellitus, hypertension, tumor size, tumor location, previous abdominal surgery, surgical approach, TNM stage, differentiation degree, operation time, intraoperative blood loss, IL-2, IL-4, IL-6, TNF-α, IL-10, CRP, and WBC between the modeling and validation groups (P > 0.05). See Table 1. Univariate Analysis of Postoperative Ileus After Radical Gastrectomy for Gastric Cancer in the Modeling Group There were no statistically significant differences in gender, BMI, smoking, alcohol consumption, diabetes mellitus, hypertension, tumor location, TNM stage, differentiation degree, intraoperative blood loss, IL-2, and IL-4 between the ileus group and the non-ileus group (P > 0.05). The proportions of patients aged ≥60 years, with tumor size ≥5 cm, with previous abdominal surgery, undergoing open surgery, with operation time ≥400 min, and the levels of IL-6, TNF-α, IL-10, CRP, and WBC were significantly higher in the ileus group than in the non-ileus group (P < 0.05). See Table 2. Variable Screening for Postoperative Ileus After Radical Gastrectomy for Gastric Cancer Age, tumor size, previous abdominal surgery, surgical approach, operation time, IL-6, TNF-α, IL-10, CRP, and WBC from the univariate analysis in 2.2 were included in the LASSO regression analysis for variable screening. The relationship between binomial deviance and Log(λ) is plotted in Figure 2. When the λ value was 0.0142, only 5 variables (which may have the greatest impact on the occurrence of postoperative ileus) were retained in the model. Multivariate Logistic Regression Analysis of Postoperative Ileus After Radical Gastrectomy for Gastric Cancer The characteristic variables screened by LASSO regression analysis were used as independent variables, and the occurrence of postoperative ileus was used as the dependent variable. The assignment of variables is shown in Table 3. The results of multivariate logistic regression analysis showed that age (OR=4.999), previous abdominal surgery (OR=3.836), operation time (OR=3.541), IL-6 (OR=1.339), and TNF-α (OR=8.254) were independent risk factors for postoperative ileus after radical gastrectomy for gastric cancer (P < 0.05). See Table 4. Construction of a Nomogram Model for Predicting Postoperative Ileus After Radical Gastrectomy for Gastric Cancer The results of multivariate logistic regression analysis were used to generate a nomogram to predict the occurrence of postoperative ileus after radical gastrectomy for gastric cancer. See Figure 3. The nomogram scores 5 independent risk factors: age, previous abdominal surgery, operation time, IL-6, and TNF-α, with each factor assigned a score ranging from 0 to 100. Calibration Curve and ROC Curve Analysis of the Nomogram in the Modeling and Validation Groups Calibration curve analysis in the modeling group showed that the bias-corrected curve was close to the ideal curve, and the Hosmer-Lemeshow test χ2=7.785, P=0.236, indicating good calibration of the nomogram model. ROC curve analysis showed that the AUC of the nomogram model was 0.940 (95% CI: 0.8980.981), indicating good discrimination of the nomogram model. Calibration curve analysis in the validation group showed that the bias-corrected curve was close to the ideal curve, and the Hosmer-Lemeshow test χ2=6.145, P=0.372, indicating good calibration of the nomogram model. ROC curve analysis showed that the AUC of the nomogram model was 0.904 (95% CI: 0.8550.954), indicating good discrimination of the nomogram model. See Figure 4. Decision Curve Analysis of the Nomogram The results of decision curve analysis showed that the nomogram had high net benefit within the threshold probability range of 0.020.86 and 0.020.80 in the modeling and validation groups, respectively, confirming good clinical applicability of the nomogram in predicting postoperative ileus after radical gastrectomy for gastric cancer. See Figure 5. Discussion Postoperative ileus is a common complication after radical gastrectomy for gastric cancer. Yu et al8 reported its incidence to be as high as 22.54%, while Pan et al9 showed an incidence of 10.9% after gastrectomy for gastric cancer, and Fan et al10 found an incidence of 38.0% after colorectal cancer surgery. In the present study, the incidence of postoperative ileus in the modeling group was 18.18% (54/297), which falls between the incidence rates reported in the above studies. This indicates that there is some heterogeneity in the incidence of postoperative ileus across different studies, which may be related to the surgeon’s technique, surgical conditions, and the patient’s own condition. Current research has limitations, and there is still a lack of predictive models for postoperative ileus in patients undergoing radical surgery. Therefore, the purpose of this study was to identify independent risk factors for postoperative ileus and establish a nomogram prediction model. Studies by Sun et al11 and Xiu et al12 have shown that older age is associated with a higher risk of postoperative ileus in patients undergoing radical cystectomy or colorectal cancer surgery. The above studies mainly focused on tumors at other sites, while our study focused on gastric cancer and found that age ≥60 years was also a risk factor for postoperative ileus after gastrectomy for gastric cancer, which is consistent with the results of Yu et al.8 The analysis suggests that older patients may have a history of various previous surgeries or medication use, which may damage the gastrointestinal neuromuscular system. In addition, as basal metabolism slows down with age, general anesthesia drugs may remain in the body for a longer time, thereby inhibiting the recovery of gastrointestinal function and increasing the risk of ileus.13 The results of this study also showed that previous abdominal surgery was an independent influencing factor for postoperative ileus, which is basically consistent with the findings of Pan et al.9 During abdominal surgery, the intestines are generally exposed to the external environment and are susceptible to mechanical stimulation and injury. Postoperatively, adhesions may occur in the abdominal cavity, and the inflammatory response in the surgical area can cause fibrin exudation, leading to adhesions between adjacent intestinal segments and the abdominal wall, thereby causing ileus.14,15 Some studies have examined the relationship between operation time and postoperative ileus, confirming that longer operation time is a risk factor for early small bowel obstruction after right colectomy.16 Our results are consistent with this, and an operation time ≥400 min was associated with a 3.541 times higher risk of postoperative ileus compared to patients with an operation time <400 min (OR=3.541). The possible reason is that as the operation time prolongs, the anesthesia time will also be prolonged, which may increase the risk of infection or elevate the level of inflammation. Local inflammation can increase tissue edema and fibrin exudation, leading to adhesive ileus. This study found that inflammation-related factors IL-6 and TNF-α were associated with the occurrence of postoperative ileus, which is similar to the results of Sui et al.17 Their study showed that the inflammatory response is an important stage in the progression of postoperative ileus, during which various inflammatory factors are secreted in large quantities, directly or indirectly leading to gastrointestinal motility disorders. Significant increases in cytokines such as IL-6 and TNF-α are considered favorable evidence for the development of postoperative ileus.18 Nomogram models have been widely used in risk assessment and prognostic studies of gastric cancer patients. Compared with traditional regression models, nomograms can provide convenient and accurate risk assessments for different patients by creating user-friendly charts.19,20 There are numerous predictive models for postoperative intestinal obstruction after colorectal surgery and cystectomy, but nomogram-based predictive models for intestinal obstruction following radical gastrectomy for gastric cancer remain to be further developed and validated. In this study, a risk nomogram prediction model was constructed using clinical data including age, previous abdominal surgery, operation time, and inflammatory markers IL-6 and TNF-α as variables. The prediction AUCs were 0.940 and 0.904, which are higher than the predictive AUCs of postoperative intestinal obstruction models in previous studies on other tumors.12,18 Medical staff can use the nomogram model to calculate the risk of postoperative ileus after radical gastrectomy for gastric cancer, identify high-risk patients early, and implement key monitoring. For high-risk patients, fluid management can be optimized, the use of opioid drugs can be reduced, and early ambulation can be encouraged. Furthermore, in this study, the measured values of the model calibration curve were basically consistent with the predicted values, suggesting that the nomogram model constructed in this study has high discrimination and calibration, and good predictive performance. In addition, the decision curve analysis showed that the nomogram model had high net benefit values, indicating good clinical applicability. However, this study still has some limitations. First, although we have tried to maximize the sample size, errors due to selection bias may still occur due to the inclusion and exclusion criteria. Second, this study is a single-center data study, and perioperative management of patients may differ from other institutions. Third, although this study has been validated with data outside the modeling group, it is still data from our center and external validation has not been completed. Fourth, this study included a limited number of inflammatory markers. In future research, more inflammatory markers will be incorporated for comparative analysis to further refine the predictive model. Conclusions In summary, age, previous abdominal surgery, operation time, IL-6, and TNF-α are independent risk factors for postoperative ileus after radical gastrectomy for gastric cancer, and the nomogram model constructed with these factors has important predictive value for postoperative ileus. The nomogram model constructed in this study provides surgeons with a simple method for calculating the risk of ileus, which may be beneficial for them to counsel and treat patients with potential risks.