Prognostic factors and optimal timing for initiating adjuvant chemotherapy in stage IIIC gastric cancer

Abstract

BACKGROUND

Gastric cancer (GC) is a highly aggressive malignant tumor. Radical surgery combined with postoperative adjuvant chemotherapy (AC) is the mainstay treatment for stage III GC. Although current guidelines recommend similar AC strategies for all patients with stage III GC, stage IIIC GC is associated with markedly inferior long-term survival compared to stages IIIA and IIIB. Furthermore, the optimal timing for initiating AC after radical surgery remains uncertain. Therefore, clarifying the aggressive pathological characteristics, identifying key prognostic factors, and evaluating the optimal timing for initiating AC in stage IIIC GC are extremely important for developing individualized postoperative therapeutic strategies.

AIM

To investigate the aggressive pathological characteristics, key prognostic factors and optimal timing for initiating AC in stage IIIC GC.

METHODS

We retrospectively analyzed 122 patients with stage IIIB (n = 60) or IIIC (n = 62) GC who underwent radical surgery followed by AC with S-1 plus oxaliplatin (SOX) or capecitabine plus oxaliplatin regimens. Disease-free survival (DFS) was estimated using the Kaplan-Meier method. Univariate and multivariate analyses were performed using Cox proportional hazards models to identify prognostic factors.

RESULTS

Age ≥ 60 years, carcinoembryonic antigen (CEA) ≥ 5.0 μg/L, metastatic lymph node ratio (MLR) ≥ 0.5, and the time interval (TI) from surgery to initiation of AC were independent risk factors for recurrence and metastasis after radical surgery of stage IIIC GC. Within stage IIIC cohort, age ≥ 60, CEA ≥ 5.0 μg/L, and MLR ≥ 0.5 predicted shorter DFS. Regarding TI cut offs, 3-year DFS did not differ at < 4 weeks vs ≥ 4 weeks, but was higher at < 6 weeks vs ≥ 6 weeks and < 8 weeks vs ≥ 8 weeks in stage IIIC. In the SOX subgroup, initiating AC within 6 weeks or 8 weeks improved 3-year DFS; however no significant TI effect was observed in the capecitabine plus oxaliplatin subgroup.

CONCLUSION

Age ≥ 60 years, CEA ≥ 5.0 μg/L, MLR ≥ 0.5, and TI are independent risk factors for postoperative recurrence and metastasis in stage IIIC GC. For patients with stage IIIC GC, the optimal time window for initiating postoperative AC is within 6 weeks. Crucially, the SOX regimen exhibits significant time-sensitivity, with an optimal window of within 6 weeks. In contrast, the XELOX regimen did not show this phenomenon.

Key Words: Gastric cancer; Chemotherapy; Disease-free survival; Prognosis; Time factors

Core Tip: We identified age ≥ 60 years, carcinoembryonic antigen ≥ 5.0 μg/L, metastatic lymph node ratio ≥ 0.5 and time interval (TI) from surgery to initiation of adjuvant chemotherapy are independent risk factors for postoperative recurrence. Crucially, our findings demonstrate that initiating adjuvant chemotherapy within 6 weeks of surgery significantly improves disease-free survival in stage IIIC patients. Notably, the S-1 plus oxaliplatin regimen exhibits significant time-sensitivity, with an optimal window of within 6 weeks. Whereas the capecitabine plus oxaliplatin regimen does not. These insights provide a rationale for optimizing individualized therapeutic strategies for this high-risk subgroup.

INTRODUCTION

Gastric cancer (GC) is a highly aggressive malignant tumor that ranks fifth worldwide in both incidence and mortality[1]. Despite continuous advances in treatment strategies, the prognosis of GC remains poor, as most patients are diagnosed at an advanced stage[2]. Currently, the tumor-node-metastasis (TNM) staging system serves as the cornerstone for prognostic prediction and therapeutic decision-making in GC[3]. According to the 8^th edition (2017) of the American Joint Committee on Cancer TNM classification system, stage III GC is subdivided into stages IIIA, IIIB, and IIIC. Data from the Japanese GC Association indicate that the 5-year overall survival (OS) rates for stage IIIA and IIIB patients are 59.3% and 45.6%, respectively. In contrast, the 5-year OS for stage IIIC patients is only 29.9%, which is markedly lower than that of the other subgroups[4]. Although current guidelines recommend similar adjuvant chemotherapy (AC) strategies for all stage III patients, stage IIIC GC is associated with markedly inferior long-term survival compared to stages IIIA and IIIB[5]. Furthermore, the optimal timing for initiating AC after radical surgery remains uncertain[5,6]. Therefore, this study aims to clarify the aggressive pathological characteristics, identify key prognostic factors, and evaluate the optimal timing for initiating postoperative AC in stage IIIC GC, thereby providing evidence for individualized postoperative therapeutic strategies.

MATERIALS AND METHODS

Data

This retrospective study included 122 patients with pathologically confirmed stage IIIB or IIIC primary GC who were treated at the Gastrointestinal Cancer Center of the First Affiliated Hospital of Xiamen University between February 2017 and August 2023.

Inclusion criteria: (1) Pathologically confirmed primary gastric adenocarcinoma; (2) Underwent radical gastrectomy with D2 lymph node dissection; (3) Achieved R0 resection; (4) Pathological TNM stage IIIB or IIIC; (5) Received postoperative AC with either the S-1 plus oxaliplatin (SOX) or capecitabine plus oxaliplatin (XELOX) regimen; and (6) Complete clinicopathological and follow-up data available.

Exclusion criteria: (1) Synchronous or metachronous malignancies in other organs; (2) Severe comorbid diseases of the circulatory, respiratory, neurological, or hematological systems significantly affecting prognosis; (3) Postoperative pathological confirmation of distant metastasis; (4) Patients who received neoadjuvant chemotherapy or radiotherapy of surgery; and (5) Loss to follow-up due to accidental death.

This study was approved by the Ethics Committee of the First Affiliated Hospital of Xiamen University, approval No. (2024) Scientific Research Ethics Review (014).

Observation variables

The following variables were collected: Gender, age, body mass index, primary tumor location, atrophic gastritis, preoperative tumor markers [carcinoembryonic antigen (CEA), carbohydrate antigen 19-9, and carbohydrate antigen 125], platelet-to-lymphocyte ratio, defined as the peripheral platelet count divided by the peripheral lymphocyte count; neutrophil-to-lymphocyte ratio, defined as the peripheral neutrophil count divided by the peripheral lymphocyte count, histological differentiation, tumor size (maximum diameter), Borrmann classification [polypoid (type I), fungating (type II), ulcerated (type III) and flat/diffusely infiltrative (type IV)], lymphatic and/or blood vessel invasion (LBVI) status, pathological T (pT) stage (T3, T4a, T4b), pathological N (pN) stage (N2, N3a, N3b), metastatic lymph node ratio (MLR), calculated as the number of metastatic lymph nodes divided by the total number of dissected lymph nodes, human epidermal growth factor receptor-2 status, pathological Ki-67 index, Epstein-Barr virus-encoded small RNA status, mismatch repair status (proficient mismatch repair or deficient mismatch repair), and the AC regimen (SOX or XELOX). The time interval (TI) between radical surgery and the initiation of AC was calculated as the number of days from the surgery date to the date of the first AC administration. Each chemotherapy cycle lasted 21 days. The Ki-67 index was recorded as the percentage of positive tumor cells. For analytical purposes, Ki-67 expression was categorized as: < 10% (negative), 10%-29% (+), 30%-49% (++), and ≥ 50% (+++). In addition, p53, human epidermal growth factor receptor-2, and Ki-67 were grouped into low-expression (negative, +, ++) and high-expression (+++) categories.

AC regimens

SOX regimen: S-1 [dose according to body surface area (BSA): BSA < 1.25 m², 40 mg/dose; BSA 1.25-1.50 m², 50 mg/dose; BSA ≥ 1.50 m², 60 mg/dose], administered orally twice daily on days 1-14 of each 3-week cycle, plus oxaliplatin (130 mg/m²) administered intravenously on day 1 of each cycle. XELOX regimen: Capecitabine (1000 mg/m²), administered orally twice daily on days 1-14 of each 3-week cycle, plus oxaliplatin (130 mg/m²) administered intravenously on day 1 of each cycle.

Follow-up

Patients were followed up every 3 months on average via outpatient visits or telephone contact to obtain postoperative survival and recurrence information. The last follow-up date was July 1, 2025. Freedom from recurrence or metastasis was defined as the absence of any evidence of tumor progression from the date of surgery to the last follow-up. Recurrence or metastasis was defined as the reappearance of tumor growth after a disease-free interval. Disease-free survival (DFS) was defined as the interval from surgery to the first documented tumor recurrence or metastasis, the occurrence of a new primary malignancy, or death due to tumor progression. Disease-specific survival was defined as the interval from surgery to death attributable to GC. Recurrence and metastasis were determined based on comprehensive evaluation of chest computed tomography (CT), contrast-enhanced abdominal CT, serum gastrointestinal tumor markers, positron emission tomography-CT, and/or pathological biopsy.

Statistical analysis

All statistical analyses were performed using SPSS software (version 29.0). Continuous variables with a normal distribution were compared using the independent-samples t-test. Unordered categorical variables were compared using the χ² test, while ordinal categorical variables and non-normally distributed continuous variables were analyzed using the Mann-Whitney U test. Multivariate analysis was performed using Cox proportional hazards regression models. DFS and survival curves were estimated with the Kaplan-Meier method, and intergroup comparisons were conducted using the log-rank test. A two-sided P value < 0.05 was considered statistically significant.

RESULTS

Comparison of clinicopathological characteristics

The study cohort included 122 patients, stratified into stage IIIB (n = 60) and stage IIIC (n = 62) groups. Univariate analysis revealed that stage IIIC tumors exhibited significantly more aggressive pathological features compared to stage IIIB. Specifically, the stage IIIC group had a higher prevalence of LBVI, larger maximum tumor diameters, poorer histological differentiation, a higher proportion of Borrmann type IV classification, a higher MLR, and more advanced pathological T and pN stages (all P < 0.05), as illustrated in Table 1.

Table 1 Comparison of clinicopathological characteristics between stage IIIB (n = 60) and stage IIIC (n = 62) gastric cancer patients, n (%).

Variable	Stage IIIB	Stage IIIC	P value
Gender
Female	15 (25.0)	20 (32.3)	0.376
Male	45 (75.0)	42 (67.7)
Age (years)
< 60	27 (45.0)	27 (43.5)	0.872
≥ 60	33 (55.0)	35 (56.5)
Tumor location
Upper	25 (41.7)	24 (40.2)	0.864
Middle	7 (11.7)	9 (13.1)
Lower	28 (46.6)	29 (46.7)
Atrophic gastritis
No	45 (75.0)	42 (67.7)	0.376
Yes	15 (25.0)	20 (32.3)
CEA (μg/L)
< 5	47 (78.3)	44 (71.0)	0.350
≥ 5	13 (21.7)	18 (29.0)
CA19-9 (kU/L)
< 37	45 (75.0)	43 (69.4)	0.487
≥ 37	15 (25.0)	19 (30.6)
CA125 (kU/L)
< 35	58 (96.7)	62 (100)	0.147
≥ 35	2 (3.3)	0 (0.0)
PLR
< 154	21 (35.0)	23 (37.1)	0.809
≥ 154	39 (65.0)	39 (62.9)
NLR
< 2.15	27 (45.0)	29 (46.8)	0.844
≥ 2.15	33 (55.0)	33 (53.2)
pT stage
T3	20 (33.3)	8 (12.9)	0.014
T4a	37 (61.7)	50 (80.6)
T4b	3 (5.0)	4 (6.5)
Pathological Ki-67
Low	14 (23.3)	15 (24.2)	0.911
High	46 (76.7)	47 (75.8)
HER-2
Low	52 (86.7)	59 (95.2)	0.101
High	8 (13.3)	3 (4.8)
EBER
Negative	52 (86.7)	57 (91.9)	0.346
Positive	8 (13.3)	5 (8.1)
P53
Low	33 (55.0)	35 (56.5)	0.872
High	27 (45.0)	27 (43.5)
pMMR
No	2 (3.3)	5 (8.1)	0.463
Yes	58 (96.7)	57 (91.9)
LVI
No	18 (30.0)	7 (11.3)	0.010
Yes	42 (70.0)	55 (88.7)
Tumor size (cm)
< 5	36 (60.0)	22 (35.5)	0.007
≥ 5	24 (40.0)	40 (64.5)
Histological differentiation
Others	20 (33.3)	1 (1.6)	< 0.001
Poorly-differentiated	40 (66.7)	61 (98.4)
Borrmann classification
Type I	6 (10.0)	3 (4.8)	0.014
Type II	42 (70.0)	36 (58.1)
Type III	9 (15.0)	9 (14.5)
Type IV	3 (5.0)	14 (22.6)
MLR
< 0.5	52 (86.7)	18 (29.0)	< 0.001
≥ 0.5	8 (13.3)	44 (71.0)
pN stage
2	2 (3.3)	0 (0.0)	< 0.001
3a	58 (96.7)	1 (1.6)
3b	0 (0.0)	61 (98.4)
Cycle (week)
6	34 (56.7)	28 (45.2)	0.071
8	23 (38.3)	22 (35.5)
12	3 (5)	12 (19.3)
TI (week)
< 4	9 (15)	13 (21.0)	0.055
< 6	26 (43.3)	28 (45.2)
< 8	9 (15)	1 (1.6)
≥ 8	16 (26.7)	20 (32.2)

CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9; CA125: Carbohydrate antigen 125; PLR: Platelet-to-lymphocyte ratio; NLR: Neutrophil-to-lymphocyte ratio; pT: Pathological T; EBER: Epstein-Barr virus-encoded small RNA status; HER-2: Human epidermal growth factor receptor-2; pMMR: Proficient mismatch repair or deficient mismatch repair; LVI: Lymphatic and/or blood vessel invasion status; MLR: Metastatic lymph node ratio; pN: Pathological N; TI: Time interval.

Prognostic factors for recurrence and metastasis in stage IIIC GC

In the univariate analysis of the stage IIIC cohort, age ≥ 60 years, CEA ≥ 5.0 μg/L, MLR ≥ 0.5, the number of chemotherapy cycles, and the TI from surgery to AC initiation were identified as significant risk factors (all P < 0.05). These variables were entered into a multivariate Cox proportional hazards regression model. The analysis confirmed that age ≥ 60 years [hazard ratio (HR) = 4.917, 95% confidence interval (CI): 2.226-10.861, P < 0.001], CEA ≥ 5.0 μg/L (HR = 2.942, 95%CI: 1.506-5.747, P = 0.003), MLR ≥ 0.5 (HR = 2.770, 95%CI: 1.193-6.432, P = 0.018), and TI (HR = 1.002, 95%CI: 1.000-1.005, P = 0.046) were independent risk factors for recurrence and metastasis after radical resection of stage IIIC GC, as demonstrated in Table 2.

Table 2 Univariate and multivariate analyses of clinicopathologic factors for disease-free survival of patients with stage IIIC gastric cancer.

Variable	Univariate analysis		Multivariate analysis
	HR (95%CI)	P value	HR (95%CI)	P value
Gender	1.170 (0.594-2.305)	0.649	-	-
Age (years)	4.776 (2.253-10.126)	< 0.001	5.151 (2.200-12.060)	< 0.001
Tumor location	0.815 (0.581-1.142)	0.234	-	-
BMI	0.841 (0.489-1.448)	0.532	-	-
Atrophic gastritis	0.985 (0.514-1.888)	0.965	-	-
CEA (μg/L)	2.833 (1.486-5.401)	0.002	2.997 (1.404-6.400)	0.005
CA19-9 (kU/L)	1.682 (0.875-3.232)	0.119	-	-
PLR	0.954 (0.502-1.812)	0.886	-	-
NLR	1.726 (0.909-3.278)	0.095	-	-
pT stage	1.119 (0.564-2.221)	0.748	-	-
Ki-67	0.993 (0.485 2.031)	0.984	-	-
HER-2	0.043 (0.001-7.247)	0.230	-	-
EBER	1.494 (0.530-4.213)	0.448	-	-
P53	0.825 (0.440-1.545)	0.548	-	-
pMMR	0.380 (0.091-1.583)	0.184	-	-
Vascular invasion	0.980 (0.383-2.507)	0.966	-	-
Nerve invasion	0.798 (0.284-2.247)	0.670	-	-
Tumor size (cm)	0.718 (0.380-1.353)	0.305	-	-
Histological differentiation	0.283 (0.037-2.144)	0.222	-	-
Borrmann classification	1.185 (0.855-1.642)	0.309	-	-
MLR	2.481 (1.094-5.624)	0.030	2.404 (1.048-5.519)	0.039
TI	1.014 (1.006-1.021)	< 0.001	1.002 (1.000-1.005)	0.046
Cycle	0.355 (0.211-0.597)	< 0.001	0.667 (0.372-1.195)	0.174

HR: Hazard ratio; CI: Confidence interval; BMI: Body mass index; CEA: Carcinoembryonic antigen; CA19-9: Carbohydrate antigen 19-9; PLR: Platelet-to-lymphocyte ratio; NLR: Neutrophil-to-lymphocyte ratio; pT: Pathological T; EBER: Epstein-Barr virus-encoded small RNA status; HER-2: Human epidermal growth factor receptor-2; pMMR: Proficient mismatch repair or deficient mismatch repair; MLR: Metastatic lymph node ratio; TI: Time interval.

Survival analysis

The cumulative survival rate of the stage IIIC group was significantly lower than that of the stage IIIB group (χ² = 5.138, P = 0.023) (Figure 1). Within the stage IIIC cohort, stratification by risk factors revealed significantly lower survival rates for patients with age ≥ 60 years (P < 0.001), CEA ≥ 5.0 μg/L (P = 0.001), and MLR ≥ 0.5 (P = 0.022) compared to their respective lower-risk counterparts (Figure 2).

Figure 1 Kaplan-Meier survival curves comparing cumulative survival rates after radical gastrectomy between stage IIIB and stage IIIC gastric cancer. DFS: Disease-free survival.

Figure 2 Kaplan-Meier survival curves of prognostic factors following radical gastrectomy in stage IIIC gastric cancer. A: Age ≥ 60 vs age < 60 years, P < 0.001; B: Carcinoembryonic antigen ≥ 5.0 μg/L vs carcinoembryonic antigen < 5.0 μg/L, P < 0.001; C: Metastatic lymph node ratio ≥ 0.5 vs metastatic lymph node ratio < 0.5 P = 0.007. CEA: Carcinoembryonic antigen; MLR: Metastatic lymph node ratio; DFS: Disease-free survival.

Impact of the TI from surgery to chemotherapy initiation

To determine the optimal therapeutic window, DFS in stage IIIC GC was further analyzed using TI cut-offs of 4 weeks, 6 weeks, and 8 weeks.

The 4 weeks: There was no significant difference in 3-year DFS between patients with TI < 4 weeks and those with TI ≥ 4 weeks.

The 6 weeks: The 3-year DFS of patients with TI < 6 weeks was significantly higher than that of those with TI ≥ 6 weeks (χ² = 4.384, P = 0.036) (Figure 3A).

Figure 3 Kaplan-Meier survival curves for stage IIIC gastric cancer stratified by adjuvant chemotherapy regimen and initiation timing. A: All patients: < 6 weeks vs ≥ 6 weeks; B: All patients: < 8 weeks vs ≥ 8 weeks; C: S-1 plus oxaliplatin subset: < 6 weeks vs ≥ 6 weeks; D: S-1 plus oxaliplatin subset: < 8 weeks vs ≥ 8 weeks. DFS: Disease-free survival.

The 8 weeks: The 3-year DFS of patients with TI < 8 weeks was significantly higher than that of those with TI ≥ 8 weeks (χ² = 20.290, P < 0.001) (Figure 3B).

In regimen-stratified analyses, among SOX-treated patients, initiating AC within 6 weeks after surgery resulted in a significantly higher 3-year DFS than initiation at ≥ 6 weeks (χ² = 10.823, P = 0.001) (Figure 3C), and initiation within 8 weeks was superior to ≥ 8 weeks (χ² = 9.381, P = 0.002) (Figure 3D). No significant TI effect was observed in the XELOX subgroup.

Follow-up outcomes

The mean follow-up time for all patients was 31.0 ± 25.3 months. In the stage IIIC group, 22 patients (35.5%) remained free of recurrence and metastasis, with a mean 3-year DFS of 23.7 ± 11.9 months. Patients who were > 60 years old and had both CEA > 5 μg/L and MLR > 0.5 had a 3-year recurrence rate of 100%, with a mean 3-year DFS of only 8.5 ± 3.6 months.

DISCUSSION

Despite the application of current standard therapy - radical surgery combined with AC - the prognosis of stage IIIC GC remains substantially worse than that of stage IIIB disease, suggesting that the therapeutic benefit of this approach has reached a plateau in this subset. The necessity of postoperative AC for stage IIIC GC is well recognized. However, the optimal timing for initiating AC remains unclear, and current clinical guidelines do not provide explicit recommendations[5,6]. A TI that is too short may compromise wound healing and increase the risk of complications such as anastomotic leakage, bleeding, and infection, whereas an excessively prolonged TI may allow micrometastases to progress, thereby increasing the risk of recurrence[6]. Evidence indicates that early initiation of AC improves survival in GC, whereas delayed AC is associated with poorer outcomes[7-10]. A meta-analysis of 34 studies involving 141853 patients found that delayed initiation of chemotherapy (TI > 6-8 weeks) significantly increased mortality risk in GC[10]. Other studies have suggested that starting AC within 8 weeks of surgery improves OS[8,9]. Additionally, studies using a 4-week cutoff also reported survival benefits associated with early initiation of AC. For instance, Ahn et al[11] showed that patients who commenced AC within 4 weeks after radical resection had longer DFS than those who started later. However, these studies analyzed GC patients as a whole without further stratification, and specific investigations focusing exclusively on stage IIIC disease remain lacking.

Our study identified the TI from surgery to initiation of AC were independent risk factors for recurrence and metastasis after radical surgery of stage IIIC GC. Further stratification revealed that 3-year DFS was significantly better in the TI < 6 weeks and TI < 8 weeks groups than in their respective control groups, whereas no significant difference was observed between the TI < 4 weeks and TI ≥ 4 weeks groups. These findings suggest that excessively early initiation of chemotherapy may not confer additional benefit, whereas starting treatment within 6 weeks provides a clear survival advantage. Therefore, a window of 4 weeks to 6 weeks appears to strike the best balance between postoperative recovery and tumor suppression.

Crucially, we further found that the timing of chemotherapy initiation exhibited regimen-specific sensitivity. Patients treated with SOX showed a pronounced survival benefit when therapy began within 6 weeks. In contrast, the XELOX regimen did not demonstrate this time-dependency in our cohort. The reasons for this discrepancy are uncertain. Possible explanations include the role of chance due to the limited sample size. Nevertheless, if confirmed in larger cohorts, our data suggest that SOX could be prioritized in patients who are likely to recover sufficiently to begin AC within 6 weeks, while XELOX might be considered for those in whom postoperative complications or frailty make early initiation less feasible. These hypotheses warrant prospective validation.

With regard to tumor biological behavior, stage IIIC GC exhibits highly malignant characteristics. In our cohort, most of stage IIIC GC were poorly differentiated or undifferentiated adenocarcinomas. Such tumors are characterized by loss of differentiation, high proliferative activity, and strong invasive capacity, making them prone to local infiltration and distant metastasis, and are widely recognized as markers of high-grade malignancy in GC[12]. Moreover, the proportion of Borrmann type IV tumors was significantly higher in the stage IIIC group than in the stage IIIB group. Even after achieving R0 resection, these patients remain at high risk of local recurrence and distant metastasis and generally have an extremely poor prognosis[13]. In addition, the incidence of LBVI (+) in stage IIIC GC was significantly higher than in stage IIIB disease. LBVI (+) indicates that tumor cells have entered the vascular and/or lymphatic systems, suggesting a high likelihood of hematogenous or lymphatic dissemination. It is widely regarded as a precursor to distant metastasis and an independent prognostic factor[14].

Lymph node metastasis is one of the key determinants of prognosis in GC[15-17]. At present, there is no consensus on the optimal cutoff value of MLR in patients with GC. Some studies have used the median MLR as the cutoff[18]. Chen et al[19] used the X-tile software and based on OS, identified optimal MLR thresholds of 0.2 and 0.5. Drawing on these prior findings, our study adopted 0.5 as the MLR cutoff[19,20]. Our findings highlight the central role of MLR in predicting prognosis in stage IIIC GC. Survival analysis showed that patients with MLR ≥ 0.5 had significantly worse outcomes than those with MLR < 0.5. As an index that simultaneously reflects the extent of lymph node dissection and the metastatic burden, MLR more accurately represents the degree of lymphatic involvement and the invasive potential of the tumor than pN stage alone, thereby providing superior prognostic value[21,22].

Our multivariate analysis identified age ≥ 60 years, CEA ≥ 5 μg/L, and MLR ≥ 0.5 as independent risk factors for postoperative recurrence and metastasis, providing a basis for risk stratification and individualized treatment planning in stage IIIC GC. Previous studies have suggested that combining multiple prognostic indicators can enhance prediction accuracy for advanced GC. For example, Zhai et al[23] reported that the 5-year survival of patients with Borrmann type III tumors accompanied by LBVI (+) was similar to that of patients with Borrmann type IV tumors. In our cohort, patients who were > 60 years old and had both CEA > 5 μg/L and MLR > 0.5 experienced a 3-year recurrence or and metastasis rate of 100% and a mean 3-year DFS of only 8.5 months, underscoring the need for more intensive or innovative treatment strategies in this high-risk population.

CONCLUSION

Stage IIIC GC is a distinct clinical entity characterized by prominent aggressive pathological characteristics and poor outcomes. Age ≥ 60 years, CEA ≥ 5.0 μg/L, MLR ≥ 0.5, and TI as independent risk factors for postoperative recurrence and metastasis in stage IIIC GC. We further demonstrate that initiating postoperative AC within 6 weeks is critical for improving prognosis in stage IIIC GC, particularly when the SOX regimen is utilized. Whereas such time-sensitivity was not observed for the XELOX regimen. These findings provide a rationale for developing individualized adjuvant treatment strategies in stage IIIC GC.

Given that this was a single-center retrospective study with a limited sample size, selection bias cannot be excluded. In addition, some emerging biomarkers were not included in our analysis despite our efforts to comprehensively collect clinicopathological data. Future prospective, multicenter, large-scale studies integrating genomic, transcriptomic, and other multi-omics data are warranted to construct more precise prognostic models and ultimately achieve individualized precision therapy for stage IIIC GC.

ACKNOWLEDGEMENTS

We are grateful to Fan Li, Shi-Dian Wang, Yu-Kun Guo, Bing-Huang Li, Xin Zhou, Guo-Qiang Su, Chuan-Hui Lu for useful feedback and discussions.