Association of carcinoembryonic antigen/carbohydrate antigen 19-9 with gastric cancer recurrence and chemotherapy toxicities

Abstract

BACKGROUND

Gastric cancer is a major global health burden and ranks among the most common and deadly cancers in China and worldwide. Tumor markers, particularly carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9), are vital for diagnosis, prognosis, and monitoring. Elevated CEA and CA19-9 levels are correlated with advanced disease, high recurrence risk, and poor survival. However, their specific utility in predicting recurrence during adjuvant chemotherapy and association with chemotherapy-induced toxicities require further exploration. This study aimed to analyze the correlation among CEA/CA19-9 levels, postoperative recurrence, and chemotherapy-related toxicities in gastric cancer to develop personalized treatment strategies.

AIM

To identify the correlation of serum CEA and CA19-9 levels with postoperative recurrence and chemotherapy toxicity in patients with gastric cancer to guide treatment.

METHODS

We enrolled 74 patients with gastric cancer who underwent radical resection and adjuvant S-1 and oxaliplatin chemotherapy between January 2022 and December 2023. All the patients completed six chemotherapy cycles. They were categorized into the recurrence and non-recurrence groups based on 1-year postoperative follow-up. We compared CEA and CA19-9 levels and adverse gastrointestinal reactions. The patients were also stratified by elevated (> 37 U/mL) or normal (≤ 37 U/mL) CA19-9 levels to compare recurrence rates and recurrence-free survival (RFS). Finally, we analyzed the correlation of CEA and CA19-9 levels with postoperative recurrence, RFS, and gastrointestinal toxicities.

RESULTS

The mean postoperative serum CEA (59.58 ± 11.95) ng/mL and CA19-9 (104.25 ± 28.64) U/mL levels (averaged from three time-point measurements) in the recurrence group were significantly higher than that in the non-recurrence group (44.33 ± 8.39 ng/mL, 40.81 ± 12.47 U/mL) (P < 0.05). Patients with elevated mean postoperative CA19-9 levels (70.00%, 6.25 ± 0.85 months) had a significantly higher recurrence rate and shorter mean RFS than those with normal levels (7.41%, 9.83 ± 0.97 months) (P < 0.05). The recurrence group experienced significantly more severe gastrointestinal adverse reactions [mild (33.33%), moderate (44.44%), and severe (22.22%)] than the non-recurrence group [mild (58.93%), moderate (37.50%), and severe (3.57%)] (P < 0.05). CEA and CA19-9 levels increased significantly with the severity of adverse gastrointestinal reactions (P < 0.05). CEA and CA19-9 levels correlated positively with the recurrence and severity of adverse gastrointestinal reactions (P < 0.05) and negatively with RFS (P < 0.05).

CONCLUSION

Serum CEA and CA19-9 levels could serve as effective prognostic indicators in gastric cancer. Postoperative monitoring of these markers could detect potential recurrence, assess gastrointestinal toxicity, and predict RFS, thereby guiding clinical decision-making.

Key Words: Gastric cancer; Carcinoembryonic antigen; Carbohydrate antigen 19-9; Gastrointestinal adverse reactions; Recurrence; Recurrence-free survival; Correlation

Core Tip: This study included patients with stage II-III gastric cancer who received six cycles of the S-1 and oxaliplatin chemotherapy regimen postoperatively, measured serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels, and conducted a 1-year follow-up to explore the predictive value of these markers for cancer recurrence, chemotherapy-related gastrointestinal adverse reactions, and recurrence-free survival. CEA and CA19-9 could be reliable tools for guiding individualized treatment plans in patients with gastric cancer, highlighting their practical clinical value.

INTRODUCTION

Gastric cancer is a globally recognized malignancy with among the highest incidence rates. Recent epidemiological data have revealed that despite a notable decline in the overall incidence of gastric cancer in many regions, it remains the fifth most common cancer worldwide[1]. In China, gastric cancer accounts for 6.8% of all confirmed malignancies, and is a major contributor to cancer-related mortality, ranking second only to lung cancer[2]. Carcinoembryonic antigen (CEA), a glycoprotein involved in cell adhesion, is frequently elevated in various epithelial cancers, including prognosis and recurrence. Among them, CEA and carbohydrate antigen 19-9 (CA19-9) are two of the most glycoprotein synthesized and secreted by epithelial malignancies. CEA, a glycoprotein involved in cell adhesion, is frequently elevated in various epithelial cancers, including gastric cancer. CA19-9, a sialylated Lewis antigen, is a cell-surface glycoprotein synthesized and secreted by epithelial tissues. Although normally present at low levels in serum, its concentration increases significantly during malignancy owing to the overactivation of genes regulating mucin secretion[3,4]. Both markers have established prognostic values; elevated preoperative or postoperative levels are consistently associated with a more advanced disease stage, higher recurrence risk, and poorer survival outcomes in patients with gastric cancer[5,6]. However, the pathogenesis of gastric cancer remains unclear, although studies have suggested a multifactorial etiology. Although the role of CEA and CA19-9 in diagnosis and prognosis is recognized, their utility in predicting gastric cancer recurrence in the context of adjuvant chemotherapy, their correlation with chemotherapy-related gastrointestinal toxicities, and their combined predictive value for recurrence-free survival (RFS) warrant further investigation[7,8]. Therefore, this study aimed to analyze the correlation of CEA and CA19-9 levels with postoperative recurrence and chemotherapy-related toxicities in gastric cancer to provide a basis for individualized clinical treatment.

MATERIALS AND METHODS

Participants

A total of 74 patients with gastric cancer who underwent radical resection and completed six cycles of S-1 and oxaliplatin (SOX) adjuvant chemotherapy between January 2022 and December 2023 were retrospectively enrolled. The cohort comprised 19 women and 55 men, aged between 53 and 88 years (mean: 69.3 ± 11.2 years). Based on postoperative pathological tumor-node-metastasis staging, 38 patients had stage II disease and 36 had stage III disease. Tumor differentiation was classified as poor in 47 patients, moderate in 16, and well in 11. The study was approved by the hospital’s ethics committee. Written informed consent was obtained from all patients or their families. Consecutive patients who met the inclusion criteria during the study period were initially considered. The inclusion criteria were as follows: (1) Diagnosis of gastric adenocarcinoma in accordance with the Standardization for Diagnosis and Treatment of Gastric Cancer (2022 edition)[9]; (2) Age ≥ 18 years; (3) History of radical (R0) gastrectomy; (4) Planned completion of six cycles of SOX adjuvant chemotherapy; (5) Availability of complete clinical and follow-up data; and (6) Good treatment compliance (defined as receiving ≥ 80% of the planned chemotherapy dose intensity). The exclusion criteria were: (1) Lack of a definitive postoperative pathological diagnosis; (2) Known allergy to SOX; (3) Poor treatment compliance; (4) Pregnancy or lactation; (5) Severe hematopoietic system diseases; (6) Karnofsky performance status score < 70; (7) Presence of synchronous or metachronous other malignancies; (8) Incomplete postoperative tumor marker data; or (9) Loss to follow-up within 1 year. A total of 92 patients were initially screened, and 18 were excluded (8 because of incomplete marker data, 6 because of poor compliance/treatment discontinuation, and 4 because of loss to follow-up), resulting in the final cohort of 74 patients.

Chemotherapy regimen

All patients received the SOX regimen, and the oral dose of S-1 (tegafur, gimeracil, and oteracil potassium) was calculated based on the body surface area (BSA) and administered twice daily on days 1-14. The dosing schedule was as follows: 40 mg twice daily for BSA < 1.25 m²; 60 mg in the morning and 40 mg in the evening for BSA 1.25-1.5 m²; 60 mg twice daily for BSA ≥ 1.5 m². Oxaliplatin (85-100 mg/m²) was administered intravenously on day 1 of each 21-day cycle. Patients completed a total of six cycles. For patients aged > 70 years, the dose was reduced by 25%. A triple antiemetic regimen, comprising dopamine receptor antagonists, 5-hydroxytryptamine 3 receptor antagonists, and dexamethasone, was administered to prevent chemotherapy-induced nausea and vomiting.

Serum CEA and CA19-9 level tests

To obtain a more stable and representative measurement, serum CEA and CA19-9 levels were assessed at three postoperative time points: On the first postoperative day (before chemotherapy initiation), 1 month postoperatively (prior to the second chemotherapy cycle), and 3 months postoperatively (after completion of two chemotherapy cycles). At each time point, 3 mL of peripheral blood was collected from the elbow vein. The samples were centrifuged to isolate serum for analysis. Serum CEA and CA19-9 levels were measured using an automated chemiluminescence immunoassay analyzer. For each patient, the three measured values for CEA and CA19-9 were averaged to calculate the mean postoperative level, which was used for subsequent group stratification and correlation analyses. Patients were stratified into elevated (mean CA19-9 > 37 U/mL) and normal (mean CA19-9 ≤ 37 U/mL) groups based on their averaged postoperative CA19-9 levels.

Recurrence assessment

Patients were followed up for 1 year postoperatively through regular clinical visits and imaging examinations (contrast-enhanced computed tomography or magnetic resonance imaging every 3-6 months). Clarifying the study’s analytical logic is important. Recurrence status was determined as the outcome at the end of the 1-year follow-up period. Subsequently, patients were retrospectively categorized into two groups: The recurrence group (those who experienced recurrence within 1 year) and the non-recurrence group (those who remained recurrence-free throughout the follow-up period). Recurrence was defined as the identification of new masses in the surgical bed, regional lymph node metastasis, or distant metastases (e.g., liver, lungs, or peritoneum) via imaging and clinical assessment. Patients showing no evidence of recurrence at the end of the follow-up were classified into the non-recurrence group. RFS was defined as the time from the date of surgery to the date of confirmed disease recurrence or last follow-up without recurrence (censored).

Evaluation of gastrointestinal adverse reactions

Adverse gastrointestinal reactions (nausea, vomiting, diarrhea, and anorexia) during the six chemotherapy cycles were graded (I-IV) according to the Common Terminology Criteria for Adverse Events version 5.0[10]. The highest grade experienced by each patient was recorded and classified as mild (grades I and II), moderate (grade III), or severe (grade IV).

Statistical analysis

Data were analyzed using the SPSS 19.0 software. Continuous data are expressed as means ± SDs. Student’s t-test was used to compare continuous variables between groups, and categorical data are expressed as n (%). The χ² test was used to compare categorical variables. Correlations were assessed using Spearman’s rank correlation coefficient. Significance was set at P < 0.05.

RESULTS

The baseline patient characteristics are summarized in Table 1. The recurrence and non-recurrence groups showed no statistically significant differences in age, sex, differentiation grade, tumor-node-metastasis stage, or metastatic status (P > 0.05).

Table 1 Baseline patient characteristics, mean ± SD/n (%).

Characteristics	Recurrence group (n = 18)	Non-recurrence group (n = 56)	χ²/t/Z value	P value
Sex
Men	14 (77.8)	41 (73.2)	0.006	0.940
Women	4 (22.2)	15 (26.8)
Age (years)	70.61 ± 10.87	68.82 ± 11.32	0.589	0.558
Tumor differentiation
Poorly differentiated	14 (77.8)	33 (58.9)	2.419	0.298
Moderately differentiated	3 (16.7)	13 (23.2)
Well-differentiated	1 (5.6)	10 (17.9)
TNM stage
Stage II	6 (33.3)	32 (57.1)	3.091	0.079
Stage III	12 (66.7)	24 (42.9)
Lymph node metastasis
Present	4 (33.3)	20 (42.9)	1.132	0.287
Absent	14 (66.7)	36 (57.1)

TNM: Tumor-node-metastasis.

The serum CEA and CA19-9 levels are summarized in Table 2. On the first day, 1 month postoperatively, and 3 months postoperatively, serum CEA and CA19-9 levels were significantly higher in the recurrence group than in the non-recurrence group (P < 0.001). The mean postoperative serum CEA (59.58 ± 11.95) ng/mL and CA19-9 (104.25 ± 28.64) U/mL levels (averaged from three time-point measurements) in the recurrence group were significantly higher than that in the non-recurrence group (44.33 ± 8.39 ng/mL, 40.81 ± 12.47 U/mL) (P < 0.05).

Table 2 Postoperative serum carcinoembryonic antigen and carbohydrate antigen 19-9 levels, mean ± SD.

Group	n	First postoperative day		1 month postoperatively		3 months postoperatively		Average value
		CEA (ng/mL)	CA19-9 (U/mL)	CEA (ng/mL)	CA19-9 (U/mL)	CEA (ng/mL)	CA19-9 (U/mL)	CEA (ng/mL)	CA19-9 (U/mL)
Recurrence group	18	62.15 ± 12.84	110.47 ± 31.25	59.33 ± 11.02	105.82 ± 27.19	57.26 ± 12.08	96.45 ± 28.94	59.58 ± 11.95	104.25 ± 28.64
Non-recurrence group	56	46.21 ± 9.14	43.56 ± 13.89	44.87 ± 8.02	41.73 ± 12.05	41.92 ± 8.01	37.15 ± 11.46	44.33 ± 8.39	40.81 ± 12.47
t value		6.842	13.005	6.334	13.415	6.571	12.880	6.017	13.246
P value		< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001	< 0.001

CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9.

The postoperative recurrence and RFS rates are summarized in Table 3. Patients with elevated mean postoperative CA19-9 levels (70.00%, 6.25 ± 0.85 months) had a significantly higher recurrence rate and shorter mean RFS than those with normal levels (7.41%, 9.83 ± 0.97 months) (P < 0.05).

Table 3 Recurrence rates and recurrence-free survival in the elevated and normal carbohydrate antigen 19-9 groups, mean ± SD/n (%).

Group	n	Recurrence rate (%)	Mean RFS
Elevated	20	14 (70.00)	6.25 ± 0.85
Normal	54	4 (7.41)	9.83 ± 0.97
χ²/t value		27.756	14.606
P value		< 0.001	< 0.001

RFS: Recurrence-free survival.

The gastrointestinal adverse reaction grades are summarized in Table 4. The recurrence group experienced significantly more severe gastrointestinal adverse reactions [mild (33.33%), moderate (44.44%), and severe (22.22%)] than the non-recurrence group [mild (58.93%), moderate (37.50%), and severe (3.57%)] (P < 0.05).

Table 4 Gastrointestinal adverse reaction grades, n (%).

Group	n	Mild	Moderate	Severe
Recurrence group	18	6 (33.33)	8 (44.44)	4 (22.22)
Non-recurrence group	56	33 (58.93)	21 (37.50)	2 (3.57)
Z value		23.970
P value		< 0.001

CEA and CA19-9 levels across gastrointestinal adverse reaction grades are summarized in Table 5. CEA and CA19-9 levels increased significantly with the severity of adverse gastrointestinal reactions (P < 0.05).

Table 5 Carcinoembryonic antigen and carbohydrate antigen 19-9 levels across gastrointestinal adverse reaction grades, mean ± SD.

Gastrointestinal reaction adverse grades	n	Mean CEA (ng/mL)	Mean CA19-9 (U/mL)
Mild	39	39.87 ± 5.96	38.44 ± 17.27
Moderate	29	54.41 ± 5.27a,1	68.14 ± 26.95a,1
Severe	6	70.34 ± 10.74a,1,2	114.44 ± 42.08a,1,2
F value		8.931	32.216
P value		< 0.001	< 0.001

^aP < 0.05.

¹P vs mild group.

²P vs moderate group.

CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9.

The correlation analysis of CEA and CA19-9 levels with prognosis is summarized in Table 6. CEA and CA19-9 levels correlated positively with the recurrence and severity of adverse gastrointestinal reactions (P < 0.05) and negatively with RFS (P < 0.05).

Table 6 Correlation analysis of carcinoembryonic antigen and carbohydrate antigen 19-9 levels with prognosis.

Indicators	CEA		CA19-9
	r value	P value	r value	P value
Recurrence	0.655	< 0.001	0.702	< 0.001
RFS	-0.704	< 0.001	-0.681	< 0.001
Gastrointestinal adverse reaction grade	0.518	< 0.001	0.597	< 0.001

CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9; RFS: Recurrence-free survival.

DISCUSSION

In China, the incidence of gastric cancer has increased significantly among individuals aged ≥ 50 years. Gastric cancer typically presents with nonspecific symptoms such as epigastric discomfort, abdominal pain, bloating, and melena that emerge relatively late in the disease course. Consequently, diagnosis often occurs at an intermediate or advanced stage, when the optimal window for curative resection has passed, making chemotherapy a primary alternative treatment[11]. During chemotherapy, nearly all patients experience toxicities of varying intensity, most notably gastrointestinal symptoms, which often necessitate dose reduction or treatment delays[12]. Previous studies have confirmed that chemotherapy causes gastrointestinal discomfort; however, symptom severity is also closely related to the disease stage[13]. Specifically, patients with advanced malignancies often require higher doses and prolonged chemotherapy durations, which can further aggravate gastrointestinal toxicity[14].

CEA, an acidic glycoprotein, and CA19-9, a mucin-type glycosphingolipid antigen, are broad-spectrum tumor markers expressed in multiple epithelial malignancies, with the latter exhibiting robust diagnostic accuracy for gastric cancer[15]. Patients who experienced recurrence had significantly higher CEA and CA19-9 levels than those who remained recurrence-free, suggesting that elevated levels of these markers may be associated with diminished chemotherapy efficacy and accelerated disease progression. CEA overexpression disrupts intercellular recognition, inducing tumor cells to form clusters, detach from their original sites, and evade immune surveillance. Conversely, CA19-9 binds to endothelial selectins, anchoring tumor cells to the vascular wall. This interaction facilitates extravasation and promotes distant metastasis. Elevated levels of either marker reflect a large tumor burden and high malignancy; such lesions are often less sensitive to cytotoxic drugs and prone to drug resistance, resulting in poor therapeutic responses and a high risk of recurrence[5].

Moreover, patients with elevated postoperative CA19-9 levels had a significantly higher recurrence rate and shorter RFS than those with normal levels, suggesting that postoperative CA19-9 levels reflect the biological behavior and prognosis of the tumor, providing a basis for clinical risk assessment. While chemotherapy inhibits tumor growth and prolongs survival, its efficacy correlates significantly with the patient’s overall condition, and chemotherapy efficacy is lower in patients with lymph node metastasis than in those without metastasis[16,17]. Serum molecular markers influence the therapeutic outcomes and may serve as predictive indicators.

This study demonstrated that patients with gastric cancer experienced varying degrees of gastrointestinal adverse reactions during postoperative antitumor therapy. Patients in the recurrence group exhibited the most severe gastrointestinal adverse reactions; those with severe toxicity had significantly elevated serum CEA and CA19-9 levels. Elevated levels of these markers typically reflect a greater tumor burden, higher malignancy, and stronger invasive and metastatic potential. These aggressive malignancies trigger systemic low-grade inflammation, releasing large amounts of tumor necrosis factor-α, interleukin-1β, interleukin-6, and other cytokines that induce a pro-inflammatory state[18]. In patients with systemic inflammation, chemotherapy amplifies intestinal mucosal injury and the accompanying inflammatory response, creating an additive effect that manifests as severe gastrointestinal toxicity. Patients with a heavy tumor burden often present with malnutrition, muscle atrophy, and reduced hepatic reserve. These factors render the gastrointestinal mucosal barrier more vulnerable to cytotoxic injury and impair hepatic drug metabolism, thereby elevating serum drug concentrations and increasing the risk of toxicity[19].

Correlation analysis confirmed that serum CEA and CA19-9 levels correlated positively with postoperative recurrence and the severity of gastrointestinal adverse reactions, and negatively with RFS. These findings suggest a vicious cycle: A higher tumor burden and invasiveness lead to elevated CEA and CA19-9 levels while simultaneously aggravating chemotherapy-induced toxicity, which often necessitates dose reduction or premature termination of treatment, leading to inadequate tumor control, early recurrence, and shortened survival.

This study had some limitations. First, the sample size (n = 74) was relatively small, which may have limited the statistical power and generalizability of the findings. Second, the follow-up duration was only 1 year, which is relatively short for assessing the long-term recurrence and survival outcomes of gastric cancer. A longer follow-up period would provide more robust data regarding the prognostic value of these markers. Third, the study design was retrospective and conducted at a single center, which may have introduced a selection bias. Lastly, although we measured tumor markers at three time points to obtain a mean value, a more frequent or dynamic monitoring scheme may capture fluctuations with greater sensitivity. Future prospective multicenter studies with larger cohorts, longer follow-up periods, and serial marker measurements are warranted to validate these findings and explore the potential of combining CEA/CA19-9 with other novel biomarkers for improved risk prediction.

CONCLUSION

Elevated serum CEA and CA19-9 levels may indicate an increased risk of postoperative recurrence. Higher levels of these markers are also associated with severe gastrointestinal adverse reactions and may predict early recurrence and reduced survival. Therefore, we recommend dynamic monitoring of postoperative CEA and CA19-9 levels in patients with gastric cancer. Patients with persistently high markers should receive intensified supportive care, close surveillance, and individualized treatment strategies.