Impact of sintilimab with first-line therapy on tumor marker response in advanced gastric cancer

Abstract

BACKGROUND

Advanced gastric cancer (GC) remains a significant cause of cancer-related mortality worldwide, with limited therapeutic options and poor prognosis. Combining immune checkpoint inhibitors with chemotherapy has shown promise for improving outcomes; however, its impact on tumor marker responses remains underexplored. Therefore, we hypothesized that sintilimab combined with S-1 plus oxaliplatin/xeloda plus oxaliplatin (SOX/XELOX) regimens could enhance tumor marker response in patients with advanced GC.

AIM

To investigate the impact of sintilimab plus SOX/XELOX regimen on tumor markers in advanced GC.

METHODS

This randomized controlled trial enrolled 60 patients (2019-2025) treated at our hospital. The patients received sintilimab plus SOX/XELOX or chemotherapy alone. Serum carcinoembryonic antigen, carbohydrate antigen (CA) 19-9, and CA72-4 levels were assessed at baseline and 12 weeks. Response rates (objective response rate and disease control rate) were compared, and Spearman correlation analyzed the relationship between tumor marker reduction and shrinkage.

RESULTS

Compared with the control group, the combination therapy group demonstrated significantly greater reductions in tumor marker levels post-treatment (P < 0.05), with significantly higher tumor marker response rates (P < 0.01). This study demonstrated that the combination therapy group achieved significantly better objective response rate (40.00% vs 13.33%) and disease control rate (70.00% vs 46.67%) than the control group and the tumor shrinkage rate in the combination therapy group was significantly higher (P < 0.05). Spearman’s correlation analysis revealed that after 12 weeks of treatment, tumor shrinkage rates showed significant positive correlations with Δ carcinoembryonic antigen % (r = 0.642), ΔCA19-9% (r = 0.587), and ΔCA72-4% (r = 0.613) (P < 0.05).

CONCLUSION

Sintilimab plus SOX/XELOX regimen reduced tumor markers in advanced GC, correlated with tumor shrinkage, and may serve as an efficacy indicator for this regimen.

Key Words: Sintilimab; S-1 plus oxaliplatin regimen; Capecitabine plus oxaliplatin regimen; Advanced gastric cancer; Tumor markers; Carcinoembryonic antigen; Carbohydrate antigen 19-9; Carbohydrate antigen 72-4

Core Tip: This study demonstrated that sintilimab plus S-1 plus oxaliplatin/xeloda plus oxaliplatin regimen therapy significantly enhanced the reduction in tumor markers and improved tumor marker response rates in patients with advanced gastric cancer. The early and profound decrease in these markers showed a significant positive correlation with objective tumor shrinkage, highlighting their potential as valuable dynamic indicators for evaluating the efficacy of this immunochemotherapy combination.

INTRODUCTION

Gastric cancer (GC) remains a common malignant tumor worldwide, ranking fifth in cancer-related mortality[1]. Recently, the application of surgical procedures and anticancer agents has improved the overall prognosis of patients with GC. However, the 5-year survival rate of patients with advanced GC remains < 30%[2], because of the lack of highly effective treatment methods. Currently, gastrointestinal endoscopy is the standard method for GC screening in clinical practice. However, detecting occult gastric tumors requires biomarkers with higher sensitivity and specificity[3]. Therefore, an in-depth investigation of the factors influencing tumor markers in patients with GC is crucial in enhancing treatment efficacy. With the continuous advancement of cancer treatment technologies, Xu et al[4] reported that using cetuximab improved overall survival compared to placebo in patients with GC or gastroesophageal junction cancer, with a stratified hazard ratio of 0.77 (95%CI: 0.63-0.94), P = 0.009. Zeng et al[5] reported that a combination with sintilimab demonstrated significant efficacy and tolerable toxicity in patients with advanced liver cancer. Sintilimab, a novel programmed death 1 antibody, modulates immunity and enhances antitumor activity. Wei et al[6] suggested that sintilimab combined with concurrent chemoradiotherapy offers good controllability and safety in treating adenocarcinomas, indicating the positive significance of sintilimab for cancer survival rates and treatment outcomes. The S-1 plus oxaliplatin (SOX) regimen is commonly used for treating advanced GC. Liu et al[7] indicated that an adjuvant SOX chemotherapy regimen yielded better outcomes in patients with GC undergoing radical laparoscopic D2 gastrectomy. Qiu et al[8] proposed that the xeloda plus oxaliplatin (XELOX) regimen (capecitabine combined with oxaliplatin) effectively improved disease control in metastatic rectal cancer, suggesting that SOX/XELOX chemotherapy may be an effective tumor marker response in advanced GC. However, the effects of sintilimab combined with the SOX/XELOX regimen on the treatment efficacy in patients with advanced GC remain unknown. Therefore, this study aimed to investigate the changes in the expression of tumor markers in patients with advanced GC treated with sintilimab plus SOX/XELOX therapy, thereby providing new perspectives for GC diagnosis and treatment.

MATERIALS AND METHODS

General data

This study enrolled 60 patients with advanced GC who underwent treatment at our hospital between March 2019 and June 2025. They were randomly assigned to the combination therapy (sintilimab + SOX/XELOX) or control groups (SOX/XELOX) (n = 30 per group). In the combination therapy group, the male-to-female ratio was 25:5; age range was 36-82 years, with a mean age of 66.57 ± 11.59 years; and number of patients with moderately differentiated, poorly differentiated, mucinous adenocarcinoma, and signet ring cell carcinoma were 16, 10, 2, and 2, respectively. In the control group, the male-to-female ratio was 25:5; age range was 46-83 years, with a mean age of 67.21 ± 10.12 years; and number of patients with moderately differentiated, poorly differentiated, mucinous adenocarcinoma, and signet ring cell carcinoma were 17, 10, 1, and 2, respectively. No significant differences were observed in the general characteristics of the two groups (P > 0.05), indicating comparability. The inclusion criteria were as follows: (1) Meeting the diagnostic criteria for GC outlined in the relevant literature[9]; (2) Pathologically confirmed diagnosis with clinical stage IV; (3) Disease progression, recurrence, or failure of first-line chemotherapy, with the ability to tolerate intensity-modulated radiation therapy and apatinib treatment; (4) Life expectancy > 3 months; and (5) Informed consent obtained from the patients and their families. The exclusion criteria were as follows: (1) Eastern Cooperative Oncology Group Performance Status score > 2[10]; (2) Complicated by severe infection, major gastrointestinal bleeding, or other malignancies; (3) Presence of factors affecting oral drug absorption, such as intestinal obstruction, nausea and vomiting, or dysphagia; (4) Presence of psychiatric or behavioral abnormalities with low treatment compliance; and (5) Presence of central nervous system metastasis.

Methods

The control group received either the SOX or XELOX chemotherapy regimen. The SOX regimen was as follows; oxaliplatin (135 mg/m²) was administered via intravenous drip on day 1 of each cycle; concurrently, tegafur, gimeracil, and oteracil potassium (S-1) was administered orally twice daily from days 1-14, with the dose adjusted according to body surface area (BSA) (60 mg/dose for BSA > 1.5 m²; 40 mg/dose for BSA ≤ 1.5 m²). The XELOX regimen was as follows; oxaliplatin (135 mg/m²) was administered via intravenous drip on day 1 of each cycle, combined with capecitabine (1000 mg/m²), administered orally once daily from days 1-14. The combination therapy group received the same SOX/XELOX chemotherapy as the control group with the addition of sintilimab. Sintilimab (200 mg) was administered via intravenous infusion on day one of each cycle. All treatment regimens were administered in three-week cycles. Both groups continued treatment for 12 weeks, completing four cycles.

Observation indicators

Peripheral venous blood samples (approximately 5 mL) were collected from all patients after fasting before treatment and at 12 weeks (after completion of 4 treatment cycles) after initiating treatment. This 12-week time point corresponds to the completion of the first planned treatment phase (four cycles of three-week regimens), allowing for a standardized assessment of the initial therapeutic response while minimizing potential bias from early, unstable fluctuations, or late, confounding factors, such as disease progression or treatment discontinuation. The serum was obtained by centrifugation. Serum levels of carbohydrate antigen (CA) 19-9 (CA19-9), carcinoembryonic antigen (CEA), and CA72-4 were measured using a Cobas E601 electrochemiluminescence fully automated immunoassay system and corresponding kits (Roche, Switzerland), employing a double-antibody sandwich enzyme-linked immunosorbent assay method. The response rate for each tumor marker was calculated after 12 weeks of treatment (post-cycle 4). Tumor marker response was defined as a decrease of ≥ 50% from baseline levels or normalization of the marker level. Clinical efficacy was evaluated after 12 weeks of treatment. The assessment criteria[11] were as follows: (1) Complete disappearance of tumor cells in the body with the effect maintained for ≥ 4 weeks was defined as complete response (CR), a reduction of > 50% in the maximum volume of the lesion for > 4 consecutive weeks without the appearance of new lesions was defined as partial response (PR); (2) A change in tumor volume within a 25% range (either increase or decrease) without the appearance of new lesions was defined as stable disease; and (3) An increase in tumor volume > 25% or the emergence of new lesions was defined as progressive disease. The objective response rate (ORR) was calculated as (CR + PR)/total number of cases × 100%, whereas the disease control rate (DCR) was calculated as (CR + PR + stable disease)/total number of cases × 100%. All patients underwent contrast-enhanced computed tomography or magnetic resonance imaging before and after treatment. Radiological evaluation was performed using a Siemens Somatom Definition Flash second-generation dual-source, high-speed multi-slice spiral computed tomography scanning system. Before examination, patients fasted for 8 hours. Additionally, 10 mg of anisodamine hydrochloride was administered intramuscularly 10 minutes before the scan, followed by the oral administration of a gas-producing agent (4.5 g). During the scan, patients were placed in the supine position with the scanning range set from the diaphragm dome to the pelvic floor. The procedure sequentially included non-contrast scanning and triple-phase dynamic-enhanced scanning. A nonionic contrast agent, iohexol (300 mg/mL), was administered at 90 mL via the elbow vein channel at a flow rate of 3.0 mL/second. Subsequent scans were performed at 35 seconds and 70 seconds after completing the injection to obtain arterial-phase and venous-phase images, respectively. The scanning parameters were set as follows; tube voltage was set at 100 kVp and 140 kVp Sn, and the slice thickness was set at 5 mm. During image reconstruction, portal venous phase images were selected and processed to a slice thickness of 1 mm at 1 mm interval. Multiplanar reconstruction technology was used for image processing. In measuring the largest tumor diameter and volume, efforts were made to avoid areas of liquefaction and necrosis caused by chemotherapy. The measurements were repeated thrice, and the average values were calculated. The tumor reduction rate was calculated using the formula: (V0 - Vx)/V0 × 100%, in which V0 represents the tumor volume before treatment and Vx represents the tumor volume upon re-examination after treatment.

Statistical analysis

Data analysis was performed using SPSS version 27.0 software. Measurement data conforming to a normal distribution were expressed as mean ± SD and compared between groups using the t-test. Count data are expressed as n (%) and compared between groups using the χ² test. Non-normally distributed data were expressed as mean (interquartile range) and analyzed using the rank-sum test (Mann-Whitney U test), with the statistic denoted as the Z value. Correlations between variables were analyzed using Spearman’s rank correlation analysis. The test level α was set at 0.05, and statistical significance was set at P < 0.05.

RESULTS

Tumor marker levels

After 12 weeks of treatment, the combination therapy group showed significantly lower post-treatment levels of CEA (4.27 ± 1.61 U/mL vs 5.75 ± 1.70 μg/mL, P = 0.001), CA19-9 (32.07 ± 10.61 U/mL vs 38.25 ± 9.10 U/mL, P = 0.019), and CA72-4 (6.24 ± 1.27 U/mL vs 7.39 ± 1.65 U/mL, P = 0.004) compared to the control group (Table 1).

Table 1 Comparison of tumor marker levels, mean ± SD.

Group	Carcinoembryonic antigen (μg/mL)		CA19-9 (U/mL)			CA72-4 (U/mL)
	Pre-treatment	12 weeks	Pre-treatment	12 weeks	Pre-treatment	12 weeks
Control (n = 30)	8.85 ± 2.26	5.75 ± 1.70a	74.85 ± 12.26	38.25 ± 9.10a	12.68 ± 3.60	7.39 ± 1.65a
Combination (n = 30)	8.90 ± 2.28	4.27 ± 1.61a	69.80 ± 10.28	32.07 ± 10.61a	12.20 ± 3.57	6.24 ± 1.27a
t value	0.085	3.462	1.729	2.422	0.519	3.025
P value	0.932	0.001	0.089	0.019	0.606	0.004

^aP < 0.05 vs pre-treatment in the same group.

CA: Carbohydrate antigen.

Tumor marker response rate

After treatment, the tumor marker response rates for CEA (63.33% vs 36.67%, P = 0.039), CA19-9 (63.33% vs 36.67%, P = 0.039), and CA72-4 (53.33% vs 26.67%, P = 0.035) were significantly higher in the combination therapy group than those in the control group (Table 2).

Table 2 Comparison of tumor marker response rate, n (%).

Group	Tumor marker response rate (%)
	Carcinoembryonic antigen	CA19-9	CA72-4
Control (n = 30)	11 (36.67)	11 (36.67)	8 (26.67)
Combination (n = 30)	19 (63.33)	19 (63.33)	16 (53.33)
χ2 value	4.267	4.267	4.444
P value	0.039	0.039	0.035

CA: Carbohydrate antigen.

Therapeutic efficacy and tumor reduction rate comparison

The combination therapy group showed significantly better ORR (40.00% vs 13.33%, P = 0.020) and DCR (83.33% vs 46.67%, P = 0.003) than the control group. Furthermore, the median tumor reduction rate in the combination therapy group was significantly higher than that in the control group [67% (52%-78%) vs 19% (5%-32%), P < 0.001; Tables 3 and 4].

Table 3 Comparison of therapeutic efficacy, n (%).

Group	Complete response	Partial response	Stable disease	Progressive disease	Objective response rate	Disease control rate
Control (n = 30)	0 (0.00)	4 (13.33)	10 (33.33)	16 (53.33)	4 (13.33)	14 (46.67)
Combination (n = 30)	0 (0.00)	12 (40.00)	13 (43.33)	9 (30.00)	12 (40.00)	25 (83.33)
χ2 value	-				5.455	8.865
P value	-				0.020	0.003

Table 4 Comparison of tumor reduction rate, mean (interquartile range).

Group	Tumor reduction rate
	Pre-treatment (V0) (mm³)	Post-12-week (V1) (mm³)	Tumor reduction rate (ΔV%)
Control (n = 30)	41032 (12342, 134726)	33216 (6759, 73546)	19 (5, 32)
Combination (n = 30)	40321 (13452, 123492)	13246 (4358, 43667)	67 (52, 78)
Z value	0.125	2.894	5.672
P value	0.901	0.004	< 0.001

Spearman rank correlation analysis of the relationship between the maximum percentage reduction in tumor markers and reduction rate after treatment completion

Spearman correlation analysis revealed that at 12 weeks post-treatment, the tumor reduction rate was significantly positively correlated with ΔCEA% (r = 0.642), ΔCA19-9% (r = 0.587), and ΔCA72-4% (r = 0.613) (P < 0.05; Table 5).

Table 5 Relationship between the maximum percentage reduction in tumor markers and the tumor reduction rate after treatment completion.

Parameter	Tumor reduction rate (%)
	r value	P value
Δ Carcinoembryonic antigen %	0.642	0.004
ΔCA19-9%	0.587	0.025
ΔCA72-4%	0.613	0.003

CA: Carbohydrate antigen.

DISCUSSION

China has a high incidence of GC. Relevant data indicate that Brazil accounts for approximately 50% of the world’s new GC cases and deaths annually[12]. Approximately 80% of GC cases in China are diagnosed at an advanced stage, with most patients losing the opportunity to undergo radical surgery[13]. Clinically, the efficacy of traditional first-line chemotherapy regimens, such as SOX/XELOX, has reached a plateau, with a median overall survival of ≤ 13 months and generally poor prognosis[14]. Immunotherapy with sintilimab has opened new avenues for the treatment of advanced GC. This study compared the tumor marker responses between patients with advanced GC treated with sintilimab combined with the SOX/XELOX regimen and those treated with the SOX/XELOX regimen alone. These findings indicate that sintilimab plus SOX/XELOX can effectively reduce tumor marker levels in patients with advanced GC, providing theoretical support for the optimization of clinical treatment strategies.

Zheng et al[15] indicated that CA72-4, a GC-specific marker, showed decreased levels, reflecting the enhanced clearance capacity of the combination regimen against tumor cells expressing the TAG-72 antigen. The study results demonstrated that compared to the control group, the combination therapy group exhibited a more significant reduction in the post-treatment levels of tumor markers (CEA, CA19-9, and CA72-4). This suggests that the addition of sintilimab can effectively enhance the efficacy of SOX/XELOX chemotherapy in treating advanced GC. The underlying mechanism may be attributed to the oxaliplatin in the SOX/XELOX regimen, which induces immunogenic cell death in tumor cells. This leads to the exposure of calreticulin on the cell membrane and release of danger signals, such as HMGB1, thereby initiating a specific T-cell immune response and resulting in the direct killing of GC cells expressing CEA[16]. Moreover, sintilimab may further block the programmed death 1/programmed death ligand-1 signaling pathway. This alleviates the functional suppression of T cells within the tumor microenvironment and creates a synergistic antitumor effect, thereby reducing tumor marker levels[17]. Furthermore, this study revealed that the combination therapy group achieved significantly higher response rates for CEA, CA19-9, and CA72-4 after treatment, demonstrating a synergistic effect between sintilimab and the SOX/XELOX regimen in treating advanced GC, with the combination therapy showing distinct advantages. The underlying mechanism for CA19-9 response may be twofold. First, the combined regimen directly eliminates tumor cell subpopulations expressing the CA19-9 antigen through oxaliplatin. Second, the T-cell immune response activated by sintilimab clears surviving CA19-9-positive cells via the Fas/FasL pathway, thereby significantly improving the response rate among CA19-9-positive patients[18]. Simultaneously, sintilimab restores T-cell function, which enables immune recognition of the TAG-72 antigen for the specific clearance of tumor cells expressing CA72-4[19]. Additionally, it activates cytotoxic T cells to effectively eliminate adenocarcinoma cell populations with high CEA expression via the perforin-granzyme pathway[20]. The improved CA72-4 response rate suggests an enhanced immune response against GC-specific antigens, which may translate into a better long-term prognosis[21], offering new strategies for precision treatment in patients with advanced GC. The study by Cai et al[20] highlighted the significant role of sintilimab in improving T-cell immune function and maintaining immune balance in patients with advanced GC, which aligns with the study conclusions. Compared to the SOX/XELOX chemotherapy regimen alone, the control group is clinically well established and demonstrates faster efficacy in patients with prominent symptoms; however, it carries a high risk of inducing drug resistance[22]. Contrastingly, the addition of sintilimab could establish sustained immune surveillance, significantly mitigating the development of drug resistance.

The study by Zhang et al[23] indicated in the overall survival analysis of patients with GC that sintilimab (hazard ratio = 0.95, 95%CI: 0.91-0.99) suggests its certain value in prolonging patient survival. The study results showed that the ORR and DCR in the combination therapy group were significantly higher than those in the control group, which is consistent with previous findings. Moreover, after 12 weeks of treatment, the maximum percentage reduction in CEA, CA19-9, and CA72-4 levels positively correlated with the tumor reduction rate, indicating that the combination therapy possessed stronger antitumor activity and more reliable disease control capability in patients with advanced GC. This may be due to sintilimab maintains the sustained activation state of effector T cells and promotes the generation of memory T cells, establishing long-term immune surveillance and effectively clearing residual micro-metastases after chemotherapy[24]; oxaliplatin in the SOX/XELOX regimen induces immunogenic cell death in tumor cells, leading to calreticulin exposure on the cell membrane and release of danger signals such as HMGB1, directly causing apoptosis in cell populations expressing specific tumor markers[25]. Hence, the combined chemotherapy regimen further modulates the tumor microenvironment by reducing immunosuppressive components, such as myeloid-derived suppressor cells, thereby maintaining sustained immune function and significantly enhancing anti-tumor efficacy[26]. This synergistic effect enables more patients to achieve significant tumor burden reduction, which accelerates the regression of tumor lesions and effectively restrains tumor progression, thereby providing patients with longer progression-free survival and increased duration of disease stability[27]. Consistent with the findings of Liu et al[28], immune-related factors were closely associated with progression-free survival in patients with GC. However, despite its established clinical application and comprehensive management strategies for treatment-related adverse events, using SOX/XELOX regimen alone lacked long-term protective effects. Disease recurrence often occurs upon the discontinuation of therapy[29]. Conversely, sintilimab activates the corresponding immune cells to establish long-term protective immunity.

This study has several limitations that should be considered in interpreting the results. First, the small sample size (n = 60) may have limited the statistical power and increased the risk of type I/II errors. Second, the single-center design may restrict the generalizability of our findings to broader patient populations with different ethnic backgrounds or healthcare settings. Third, the assessment of tumor marker response at 12 weeks, although practical for evaluating early efficacy, may not reflect long-term dynamics or correlations with survival outcomes. These limitations suggest that our findings regarding the superior efficacy of combination therapy should be viewed as preliminary and hypothesis generating. They highlighted the need for cautious interpretation and the necessity for validation in larger multicenter trials with longer follow-up periods.

CONCLUSION

Sintilimab plus SOX/XELOX regimen therapy reduces the levels of CEA, CA19-9, and CA72-4 more effectively in patients with advanced GC and is associated with higher tumor marker response rates. Furthermore, after 12 weeks of treatment, the maximum percentage reduction in CEA, CA19-9, and CA72-4 levels showed a positive correlation with the tumor reduction rate, suggesting a potential theoretical basis for clinically improving tumor marker levels in patients with advanced GC. However, this study has certain limitations, including a small sample size and an overly concentrated selection range, which may introduce bias into the results. Future studies should expand the sample size and conduct multicenter studies to validate these findings.