Timeliness of postoperative serum carcinoembryonic antigen monitoring for predicting recurrence after gastric cancer surgery

Abstract

BACKGROUND

Postoperative recurrence remains a major challenge in gastric cancer management. Monitoring serum biomarkers such as carcinoembryonic antigen (CEA) may enable earlier detection of recurrence and improve patient outcomes.

AIM

To evaluate postoperative serum CEA expression and its efficacy in predicting gastric cancer recurrence.

METHODS

This retrospective study analyzed clinical data from 120 patients with primary gastric cancer treated between January 2022 and January 2023. Patients were categorized into recurrence and non-recurrence groups. Serum levels of CEA, alpha-fetoprotein (AFP), and carbohydrate antigen 19-9 (CA19-9) were measured at one week, three months, and six months postoperatively. Logistic regression identified independent risk factors for recurrence, Pearson correlation assessed the association with recurrence timing, and receiver operating characteristic (ROC) curves evaluated the predictive performance of combined CEA and AFP levels.

RESULTS

During 24 months of follow-up, 39 patients (32.50%) experienced recurrence. No significant baseline differences were observed between groups (P > 0.05). CEA, AFP, and CA19-9 levels at one week were comparable between groups (P > 0.05), whereas levels at three and six months were significantly higher in the recurrence group (P < 0.05). Logistic regression identified postoperative CEA and AFP as independent risk factors for recurrence (P < 0.05). Pearson correlation showed a negative association between CEA and AFP levels and recurrence interval (P < 0.05). ROC curve analysis demonstrated that combined CEA and AFP yielded an area under the curve of 0.826, with specificity of 94.36% and sensitivity of 90.50%, outperforming either marker alone (P < 0.05).

CONCLUSION

Dynamic postoperative monitoring of serum CEA and AFP enables early prediction and detection of gastric cancer recurrence.

Key Words: Gastric cancer; Radical resection; Carcinoembryonic antigen; Dynamic monitoring; Recurrence prediction

Core Tip: Dynamic monitoring of carcinoembryonic antigen (CEA) and alpha-fetoprotein (AFP) levels at three and six months after gastrectomy is crucial for postoperative management of gastric cancer. Elevated levels of these markers serve as independent risk factors for recurrence. Combined assessment of CEA and AFP enhances predictive accuracy, yielding an area under the curve of 0.826, and offers superior sensitivity and specificity compared with either marker alone. This combined approach facilitates earlier detection and timely intervention for recurrent gastric cancer.

INTRODUCTION

Gastric cancer is one of the most common malignant tumors of the digestive system and ranks first among digestive tract malignancies in China, with a high incidence among individuals aged 55-70 years[1]. In recent years, its incidence has shown an upward trend. The disease typically has an insidious onset and lacks specific clinical manifestations in the early stages. By the time it is clinically detected or diagnosed, most patients have already reached an advanced stage, posing a serious threat to their health and survival[2]. Gastric adenocarcinoma is the predominant pathological type, accounting for more than 95% of cases. Although gastric cancer mortality has declined in recent years, the average annual mortality rate remains relatively high[3,4]. Surgical resection remains the primary treatment for gastric cancer. However, clinical studies indicate that recurrence occurs in more than 50% of patients within two years after surgery, and the five-year survival rate remains around 30%[5]. Therefore, early detection of postoperative recurrence and timely intervention are essential for improving survival outcomes. Currently, serum tumor marker testing, such as carcinoembryonic antigen (CEA), is widely used to predict prognosis in patients with malignant tumors and has shown good clinical utility. However, the predictive value of dynamic postoperative monitoring for recurrence remains unclear. Thus, further investigation is needed to determine the role of these biomarkers in predicting recurrence after gastric cancer surgery. With ongoing advances in the combined detection of multiple serum tumor markers and their integration into clinical diagnosis, treatment, and prognostic evaluation, their clinical value continues to grow[6]. This study retrospectively analyzed the clinical data of 120 patients who underwent gastric cancer surgery to evaluate the predictive value of dynamic postoperative monitoring of serum CEA changes for recurrence, aiming to provide evidence to support its clinical application.

MATERIALS AND METHODS

General data

This retrospective study included 120 patients with primary gastric cancer who received treatment at our hospital between January 2022 and January 2023. The study was conducted in accordance with the principles of the Declaration of Helsinki. Patients were eligible for inclusion if they met the following criteria: (1) Their diagnosis was confirmed by imaging and histopathology consistent with gastric adenocarcinoma[7]; (2) They were between 18 and 75 years of age; (3) Their disease was classified as TNM stage I-IIIa; (4) They were suitable candidates for surgical resection with no residual tumor following surgery; (5) They had no history of gastrointestinal surgery; and (6) Their clinical and diagnostic data were complete. Patients were excluded if they had other concurrent organic lesions or malignant tumors, hematologic or immunologic disorders, or distant metastasis of gastric cancer. Those who died during the follow-up period were also excluded from the analysis. The cohort consisted of 68 men and 52 women aged 31-73 years (mean 59.37 ± 4.16 years). Pathological staging included stage I in 34 cases, stage II in 67 cases, and stage IIIa in 19 cases. Regarding differentiation, five tumors were well-differentiated, 46 were moderately differentiated, and 69 were poorly differentiated. The mean body mass index was 20.19 ± 0.62 kg/m² (range 19.36-21.08 kg/m²).

Methods

Treatment: All enrolled patients underwent elective radical gastrectomy after diagnosis. Before surgery, neoadjuvant chemotherapy (NACT) was administered according to individualized clinical assessments and multidisciplinary team decisions. The main NACT regimens included the SOX regimen, consisting of S-1 (40-60 mg orally twice daily for 14 days) combined with oxaliplatin (130 mg/m² administered intravenously on day 1), and the XELOX regimen, consisting of capecitabine (1000 mg/m² orally twice daily for 14 days) combined with oxaliplatin (130 mg/m² administered intravenously on day 1). Both regimens were repeated every three weeks. Patients received two to four cycles of NACT, and treatment response was evaluated by imaging. After completing NACT, all patients underwent minimally invasive radical gastrectomy, either laparoscopic or robotic-assisted.

Postoperative adjuvant chemotherapy was administered according to pathological stage and patient recovery, typically beginning within 4-8 weeks after surgery. The adjuvant regimens corresponded to the preoperative protocols, primarily consisting of SOX or XELOX, and were planned for a total of four to eight cycles.

CEA, alpha-fetoprotein, and carbohydrate antigen 19-9 testing: Peripheral venous blood samples (5 mL) were collected from all patients one week, three months, and six months after surgery. Samples were centrifuged at 4000 rpm for five minutes, and the supernatant was submitted for analysis. When immediate testing was not feasible, samples were stored at -80 °C and analyzed within one week. Levels of CEA, alpha-fetoprotein (AFP), and carbohydrate antigen 19-9 (CA19-9) were measured using chemiluminescence immunoassay on fully automated analyzers, following the protocols of the manufacturers. The normal reference ranges were as follows: CEA ≤ 5 ng/mL, CA19-9 ≤ 37 U/mL, and AFP < 30 ng/mL.

In this study, blood samples were also scheduled for collection at 12 months and 24 months postoperatively. For patients who experienced recurrence before a scheduled sampling time point, no further samples were collected. All laboratory testing was performed independently of clinical decision-making.

Follow-up: All patients were followed for 24 months after surgery, with evaluations conducted every three months. Follow-up was completed in January 2025 and consisted of regular outpatient visits that included abdominal ultrasound and gastroscopy, supplemented by positron emission tomography/computed tomography (PET/CT) scans when clinically indicated. The interval from postoperative discharge to documented recurrence was recorded for each patient.

Criteria for recurrence

Gastric cancer recurrence was determined based on the following criteria: (1) Imaging or PET/CT scans showing new masses within the primary surgical field; (2) Imaging or PET/CT scans revealing space-occupying lesions in other organs after exclusion of primary tumors; (3) Detection of metastatic lesions in the lungs, bones, or other organs without alternative etiology; (4) Confirmation of recurrence by gastroscopy and pathological biopsy; (5) Confirmation of recurrence through reoperation or exploratory surgery; and (6) Presence of uncontrollable hemorrhagic ascites or detection of cancer cells in ascitic fluid cytology[8]. The diagnosis of recurrence was established comprehensively based on clinical, imaging, and pathological findings. The specific diagnostic criteria and the number of patients meeting each criterion in the recurrence group (n = 39) are presented in Table 1. For patients who fulfilled multiple criteria, the most definitive diagnostic method, such as pathological confirmation, was used for classification.

Table 1 Criteria for recurrence and case distribution.

Criterion for recurrence	Number of cases (n)	Percentage (%)
Imaging (CT or PET/CT) revealing new masses within the primary surgical field	15	38.5
Imaging (CT or PET/CT) detecting space-occupying lesions in other organs (distant metastasis), with primary tumors excluded	12	30.8
Confirmation of recurrence via gastroscopy and pathological biopsy (local recurrence)	8	20.5
Confirmation of recurrence through reoperation or exploratory surgery	2	5.1
Presence of uncontrollable hemorrhagic ascites, or detection of cancer cells in ascites cytology (peritoneal carcinomatosis)	2	5.1
Total	39	100

CT: Computed tomography; PET: Positron emission tomography.

Statistical analysis

All statistical analyses were performed using SPSS version 25.0 (IBM Corp., Armonk, NY, United States). The normality of continuous variables was assessed using the Shapiro-Wilk test. Quantitative data following a normal distribution are presented as mean ± SD, with intergroup comparisons conducted using independent-samples t-tests. Non-normally distributed data are presented as median (interquartile range), with intergroup comparisons performed using the Mann-Whitney U test. Categorical variables are expressed as counts and percentages, with intergroup comparisons conducted using the χ² test or Fisher’s exact test, as appropriate. The exact statistical test used for each baseline characteristic is specified in Table 2. For the comparison of serial biomarker measurements, a two-way repeated-measures analysis of variance was used to evaluate the effects of group (recurrence vs non-recurrence), time, and their interaction on biomarker levels. This approach accounted for the family-wise error rate associated with multiple time-point comparisons. When significant interactions were observed, post hoc pairwise analyses were performed with Bonferroni correction. Multivariate logistic regression analysis was conducted to identify independent risk factors for postoperative recurrence in gastric cancer, including variables that were significant in univariate analysis. The correlation between biomarker levels and time to recurrence was analyzed within the recurrence subgroup (n = 39). The normality of both recurrence time and biomarker data within this subgroup was confirmed using the Shapiro-Wilk test (all P > 0.05), allowing the use of Pearson correlation analysis to assess the relationships. Receiver operating characteristic (ROC) curves were generated to assess the predictive performance of serum CEA and AFP levels measured at six months postoperatively, as this time point demonstrated the greatest intergroup differences in preliminary analyses. Comparisons between the areas under the ROC curves (AUCs) were performed using the DeLong test. A two-tailed P value < 0.05 was considered statistically significant.

Table 2 Comparison of baseline clinical characteristics between groups.

Items		Recurrence group (n = 39)	Non-recurrence group (n = 81)	t/χ2	P value
Sex	Male	21 (53.85)	47 (58.02)	0.826	0.106
	Female	18 (46.15)	32 (41.98)
Age (years)		59.48 ± 4.09	59.29 ± 4.11	0.883	0.217
Pathological staging	I	12 (30.77)	22 (27.16)	0.907	0.114
	II	20 (51.28)	47 (58.02)
	IIIa	7 (17.95)	12 (14.81)
Differentiation	Low differentiation	23 (58.97)	46 (56.79)	0.746	0.083
	Medium differentiation	15 (38.46)	31 (38.27)
	High differentiation	1 (2.57)	4 (4.94)
BMI (kg/m2)		20.16 ± 0.68	20.23 ± 0.73	0.842	0.103

Continuous data are presented as mean ± SD and compared by independent t-test. Categorical data are presented as n (%) and compared by χ² test, except where expected cell counts were below 5, in which case Fisher's exact test was used. BMI: Body mass index.

RESULTS

Comparison of recurrence rates and clinical characteristics

At the final follow-up, 39 of the 120 patients (32.50%) experienced recurrence, whereas 81 patients (67.50%) remained recurrence-free. No significant differences were observed in baseline clinical characteristics between the two groups (P > 0.05), as shown in Table 2.

Comparison of preoperative and postoperative CEA, AFP, and CA19-9 levels between groups

Serum CEA, AFP, and CA19-9 levels measured one week after surgery showed did not differ significantly between the recurrence and non-recurrence groups (P > 0.05). However, at three and six months postoperatively, levels of all three markers were significantly higher in the recurrence group compared with the non-recurrence group (P < 0.05), as shown in Table 3.

Table 3 Comparison of preoperative and postoperative serum carcinoembryonic antigen, alpha-fetoprotein, and carbohydrate antigen 19-9 levels between groups.

Group	CEA (ng/mL)			CA19-9 (U/mL)			AFP (μg/L)
	Post-1 week	Post-3 months	Post-6 months	Post-1 week	Post-3 months	Post-6 months	Post-1 week	Post-3 months	Post-6 months
Recurrence group (n = 39)	16.11 ± 3.18	25.23 ± 4.08a	29.12 ± 4.26a,b	26.34 ± 5.17	29.19 ± 5.08a	35.27 ± 4.16a,b	20.13 ± 3.27	24.29 ± 3.18a	27.15 ± 3.41a,b
Non-recurrence group (n = 81)	16.09 ± 3.22	19.12 ± 3.18a	21.11 ± 4.17a,b	26.24 ± 5.17	22.47 ± 5.15a	26.08 ± 3.86a,b	20.09 ± 3.23	22.21 ± 3.32a	24.32 ± 3.41a
t value	0.322	9.317	10.441	0.989	7.297	12.576	0.063	3.416	4.298
P value	0.064	0.000	0.000	0.103	< 0.01	0.000	0.074	0.000	0.001

^aP < 0.05 vs the same group at one week postoperatively.

^bP < 0.05 vs three months postoperatively.

CEA: Carcinoembryonic antigen; AFP: Alpha-fetoprotein; CA19-9: Carbohydrate antigen 19-9.

Multivariate regression analysis of postoperative recurrence

Multivariate logistic regression analysis identified postoperative changes in CEA and AFP levels as independent risk factors for recurrence in patients with gastric cancer (P < 0.05), as shown in Table 4.

Table 4 Logistic regression analysis of postoperative recurrence in gastric cancer.

Independent variable	Coefficient of regression	SE	β	P value	OR (95%CI)
CEA	0.427	0.221	0.315	0.001	1.318 (0.787-4.846)
AFP	0.245	0.143	0.127	0.010	1.327 (1.304-2.132)
CA19-9	0.337	0.371	0.135	0.074	0.414 (0.126-0.627)

CEA: Carcinoembryonic antigen; AFP: Alpha-fetoprotein; CA19-9: Carbohydrate antigen 19-9; OR: Odds ratio; 95%CI: 95% confidence interval.

Correlation between serum CEA, AFP, CA19-9 and time to recurrence

The recurrence interval among patients ranged from five to 16 months, with a mean of 7.18 ± 1.83 months. Pearson correlation analysis demonstrated a significant negative correlation between serum CEA and AFP levels and the time to recurrence (P < 0.05), as shown in Table 5.

Table 5 Correlation between carcinoembryonic antigen, alpha-fetoprotein, and carbohydrate antigen 19-9 and time to recurrence following gastric cancer surgery.

Items		CEA	AFP	CA19-9
Time of postoperative recurrence	r value	-0.634	-0.603	-0.589
	P value	0.001	< 0.001	0.001

CEA: Carcinoembryonic antigen; AFP: Alpha-fetoprotein; CA19-9: Carbohydrate antigen 19-9.

Predictive efficacy of serum CEA and AFP for postoperative recurrence

ROC curve analysis, using the six-month postoperative levels of serum CEA and AFP, showed that their combined measurement predicted recurrence with an AUC of 0.826, specificity of 94.36%, and sensitivity of 90.50%. The combined model demonstrated superior predictive accuracy compared with either marker alone (P < 0.05), as shown in Table 6 and Figure 1.

Figure 1 Receiver operating characteristic curve. CEA: Carcinoembryonic antigen; AFP: Alpha-fetoprotein.

Table 6 Predictive value of serum carcinoembryonic antigen and alpha-fetoprotein for postoperative recurrence of gastric cancer.

Variable	AUC	95%CI	Youden index	P value	Specificity (%)	Sensitivity (%)
CEA	0.702	0.608-0.783	0.55	0.001	68.11	81.09
AFP	0.688	0.514-0.732	0.62	0.001	45.20	80.52
Combination of the two	0.826	0.702-0.878	0.69	0.001	94.36	90.50

CEA: Carcinoembryonic antigen; AFP: Alpha-fetoprotein; 95%CI: 95% confidence interval; AUC: Areas under the receiver operating characteristic curve.

DISCUSSION

Gastric cancer is a malignant tumor arising from the epithelial cells of the gastric mucosa, with major etiologic factors including genetic predisposition, dietary habits, and Helicobacter pylori infection[9,10]. Surgical resection remains the cornerstone of treatment, aiming to improve survival by removing the primary tumor and regional lymph nodes. Clinical studies have shown that radical surgery significantly prolongs survival in patients with gastric cancer. However, a substantial proportion of patients still experience postoperative recurrence, highlighting the need for targeted preventive and therapeutic strategies to further enhance treatment outcomes[11,12]. Integrating pathological characteristics and patterns of disease progression with serologic markers for early detection could markedly improve prognosis[13]. Although several studies have demonstrated the diagnostic value of tumor markers in gastric cancer, their role in monitoring postoperative recurrence remains to be fully validated through evidence-based research. Recurrence after NACT combined with minimally invasive radical surgery involves multiple biological mechanisms and is accompanied by changes in antibodies, cytokines, and other serum markers[14]. These tumor markers may originate either from the host response to malignant stimulation or directly from tumor cells through secretion or shedding of specific substances[15,16]. Dynamic monitoring of marker concentrations provides insight into tumor burden, disease progression, and the risk of metastasis or recurrence, thereby offering valuable guidance for clinical decision-making.

In the clinical diagnosis, treatment, and prognostic evaluation of malignant tumors of the digestive system, the detection of tumor markers such as CEA, AFP, and CA19-9 plays an important role. Among these, CEA is a glycoprotein commonly expressed on the membranes of malignant cells in digestive tract cancers, including gastric and colorectal cancers[17]. Studies have shown that CEA can also be detected during normal embryonic development of the digestive tract, suggesting a possible role in physiological processes[18]. In healthy individuals, serum CEA levels are extremely low but remain measurable using highly sensitive assays. As malignant tumors proliferate, CEA detaches from tumor cell membranes and enters the bloodstream, leading to elevated serum levels. Therefore, CEA serves as a valuable adjunctive marker in the diagnosis of gastrointestinal malignancies[19]. However, CEA lacks organ specificity, as mild elevations can also occur in benign conditions such as inflammatory bowel disease and pancreatitis. Clinical interpretation should therefore be made in conjunction with other diagnostic findings. AFP is a glycoprotein primarily synthesized by the fetal liver, yolk sac, and placenta, and its levels are typically very low in healthy adults. In malignant conditions such as hepatocellular carcinoma, AFP production is reactivated, resulting in significantly elevated serum concentrations. It also serves as a useful biomarker for the diagnosis and recurrence monitoring of gastric cancer[20]. CA19-9, a ganglioside derivative, is a high-molecular-weight carbohydrate antigen associated with adenocarcinoma cells of epithelial origin. Its serum levels are often markedly increased in patients with digestive system malignancies, including pancreatic, gastric, and colorectal cancers[21,22]. Although CA19-9 is commonly used in the assessment of gastric and colorectal cancers, its diagnostic sensitivity remains relatively limited[23]. This study employed dynamic monitoring of these tumor markers to provide early detection and prediction of postoperative recurrence in patients with gastric cancer.

This retrospective study analyzed 120 patients who underwent gastric cancer surgery. Among them, 39 patients experienced recurrence during follow-up, corresponding to a recurrence rate of 32.50%, which aligns with previously reported rates[24]. Comparison of postoperative serum tumor marker levels showed that patients in the recurrence group had significantly higher CEA, AFP, and CA19-9 levels at three and six months after surgery compared with the non-recurrence group, whereas no significant differences were observed one week preoperatively. These findings suggest that serum tumor markers have considerable clinical value in monitoring postoperative recurrence in gastric cancer. In particular, CEA and AFP exhibited more pronounced differences at three and six months, indicating that these two markers possess high sensitivity for the early detection of recurrence. Multivariate logistic regression analysis identified CEA and AFP as independent risk factors for postoperative recurrence. The regression coefficient for CEA was 0.427 (P = 0.014), with an odds ratio (OR) of 1.318, indicating a 31.8% increase in recurrence risk for each unit increase in CEA level. The regression coefficient for AFP was 0.245 (P = 0.001), with an OR of 1.327, suggesting a 32.7% increase in recurrence risk per unit rise in AFP level. Although CA19-9 showed an association with recurrence in univariate analysis, it did not reach statistical significance in multivariate analysis, possibly reflecting its greater susceptibility to confounding factors or a more complex biological role in gastric cancer recurrence[23]. Pearson correlation analysis demonstrated a negative correlation between CEA and AFP levels and the time to postoperative recurrence, indicating that higher concentrations of these markers were associated with earlier recurrence. Furthermore, ROC curve analysis revealed that the combined detection of CEA and AFP yielded an AUC of 0.826, which was significantly higher than that of either marker alone, indicating that combined testing could more effectively distinguish between patients with and without recurrence. The combined assay achieved specificity and sensitivity of 94.36% and 90.50%, respectively, both superior to those of single-marker analyses. These findings further support the clinical value of serum CEA and AFP as predictive biomarkers for postoperative recurrence in gastric cancer.

Despite the valuable insights gained, this study has several limitations that warrant consideration. First, as a single-center retrospective analysis, it is subject to potential selection bias, which may limit the generalizability of the findings. The sample size, particularly the number of recurrence events (n = 39), represents another constraint. Although multivariate logistic regression identified CEA and AFP as independent risk factors, the relatively low events-per-variable ratio increases the likelihood of model overfitting and may reduce the stability and external validity of the regression coefficients. Larger, prospective multicenter studies are therefore required to validate these findings with greater statistical power. Second, although no significant differences were found in baseline characteristics between groups, the influence of unmeasured confounding factors—such as detailed chemotherapy response and specific genetic mutations—cannot be fully excluded. Third, biomarker measurements were performed at fixed postoperative intervals; a more continuous monitoring strategy could provide a finer depiction of biomarker dynamics preceding clinical recurrence.

CONCLUSION

In summary, postoperative serum levels of CEA and AFP in patients with gastric cancer showed dynamic changes that were negatively correlated with recurrence timing. Continuous monitoring of these markers may enable earlier detection of recurrence and guide timely clinical intervention, thereby improving postoperative management and patient outcomes.