Clinical Features and Prognostic Analysis of Early-Onset Gastric Cancer

Clinical Features and Prognostic Analysis of Early-Onset Gastric Cancer

Xuanru Kang 1（First author），Yuanyuan Nian*2（corresponding author），Xianmei Meng2（Third author）

1. Baotou Medical College,Inner Mongolia University of Science&Technology，Baotou，014040，China
2. Department of Gastroenterology, Second Affiliated Hospital of Baotou Medical College，Baotou，014030，China

First author e-mail：13654787753@163.com

corresponding author e-mail：nianyuanyuannina@163.com

[Abstract]

Objective: To investigate the clinicopathological characteristics, recurrence patterns, and survival prognostic features of patients with early-onset gastric cancer, and to compare the prognostic differences between early-onset gastric cancer and non-early-onset gastric cancer patients, as well as the efficacy of different treatment strategies.

Methods: A retrospective study was conducted using data from the SEER database, including 814 patients with early-onset gastric cancer and 4,997 patients with non-early-onset gastric cancer, from 2010 to 2015. Descriptive statistical methods were used to analyze the clinicopathological characteristics and prognosis of the patients. Kaplan-Meier survival analysis was performed to evaluate the survival of patients with different pathological types and treatment strategies, and survival curves were plotted. The log-rank test was used to compare the results of survival analysis. Cox proportional hazards regression models were employed to analyze overall survival (OS) and identify independent prognostic factors affecting patient survival.

Results: Compared to non-early-onset gastric cancer, early-onset gastric cancer had a higher proportion of female patients (42.3%), a higher incidence of stage IV (44.3%), and a higher prevalence of T4 and M1 stages (23.6% and 44.0%, respectively). In terms of histological type, signet-ring cell carcinoma accounted for 26.8% (218 cases) in early-onset gastric cancer and 14.7% (736 cases) in non-early-onset gastric cancer, with a significantly higher proportion in early-onset gastric cancer patients (P < 0.001). There was also a significant difference in tumor location between early-onset and non-early-onset gastric cancers (P < 0.001), with early-onset gastric cancer tumors more commonly occurring in the body, fundus, and greater curvature of the stomach (10.3%, 6.02%, 5.41%). The proportion of early-onset gastric cancer patients receiving postoperative adjuvant chemotherapy was 78.9% (642 cases), significantly higher than the 68.3% (3,412 cases) in non-early-onset gastric cancer (P < 0.001). However, both early-onset and non-early-onset gastric cancer showed better outcomes with surgery compared to surgery plus chemoradiotherapy, and better outcomes with surgery alone than with radiotherapy and chemotherapy alone.

Conclusion: Patients with early-onset gastric cancer exhibit distinct clinicopathological characteristics and recurrence patterns. Surgical treatment is more effective than surgery combined with chemoradiotherapy.

[Keywords] Early-onset gastric cancer; Non-early-onset gastric cancer; Prognosis; SEER database

Gastric cancer is a common malignant tumor. Relevant statistics indicate that the overall incidence of gastric cancer has been gradually decreasing, whereas the number of cases of early-onset gastric cancer (EOGC) has been increasing [1]. Early-onset gastric cancer (EOGC) is a distinct subtype of gastric cancer, which is typically diagnosed based on age distribution [2], though no unified standard exists. Currently, there is considerable debate surrounding its diagnosis, treatment, and pathological features [3]. Studies on its specific characteristics are inconsistent [4]. Patients with early-onset gastric cancer exhibit various pathological features that may indicate poor prognosis, but it remains unclear whether these features directly contribute to poor outcomes [5]. Furthermore, research on recurrence and metastasis patterns in early-onset gastric cancer patients is relatively scarce [6]. Therefore, this study primarily analyzes the clinicopathological characteristics, recurrence patterns, and survival prognosis of early-onset gastric cancer patients, comparing the prognostic differences between early-onset and non-early-onset gastric cancer patients, as well as the efficacy of different treatment strategies, aiming to provide some reference for the clinical prevention and treatment of early-onset gastric cancer.

1. Materials and Methods
2. Data Source

A total of 11,230 patients diagnosed with gastric cancer between January 2010 and December 2015 were included from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database. The patients were divided into two groups: the early-onset gastric cancer group (patients diagnosed at age ≤ 50 years) and the non-early-onset gastric cancer group (patients diagnosed at age > 50 years). After applying the inclusion and exclusion criteria, a total of 814 patients from the early-onset gastric cancer group and 4,997 patients from the non-early-onset gastric cancer group were included. Data extraction was conducted using SEER*Stat software (version 8.4.4), with the database set to “Incidence-SEER Research Data, 8 Registries, Nov 2023 Sub [1975-2021]”. A retrospective review of patient information was conducted. The collected data included: demographic information (age, sex, race, year of diagnosis), clinical and pathological data (tumor location, histological type, grade, TNM stage, tumor size, and treatment methods), as well as prognostic information (survival time). Permission to access the SEER database was granted, and since the database is a public resource with anonymized patient data, the study was exempt from requiring ethical approval from the hospital review board or informed consent from patients.

• Inclusion and Exclusion Criteria

2.1 Inclusion Criteria

1) Grouping of Study Subjects: Early-onset gastric cancer group (gastric cancer patients diagnosed at age ≤ 50 years), non-early-onset gastric cancer group (gastric cancer patients diagnosed at age > 50 years);

2) Grouping by Treatment Method: Surgery only, radiotherapy or chemotherapy only, surgery + radiotherapy or chemotherapy;

3) Outcome Definition: Overall survival (OS) is defined as the time from the diagnosis date to death from any cause or the date of the last follow-up.

2.2 Exclusion Criteria

Age < 18 years (n=7); presence of other types of tumors (n=3073); survival months = 0 or unknown (n=204); no surgery or radiotherapy/chemotherapy received (n=2135).

3 Statistical Methods

3.1 General Characteristics and Intergroup Comparison: Normally distributed continuous variables are described by mean ± standard deviation, and t-test is used to compare differences between groups; non-normally distributed continuous variables are described by median [interquartile range], and Wilcoxon rank-sum test is used to compare differences between groups; categorical variables are described by frequency (percentage), and chi-square test or Fisher’s exact test is used to compare differences between groups.

3.2 Survival Analysis: Kaplan-Meier method was used to plot survival curves for survival analysis, and log-rank test was employed to compare differences in OS between different gastric cancer types and treatment methods. Cox proportional hazards regression models were used to analyze OS, with Model I including only the main effects and interaction terms of gastric cancer type and treatment method. Model II further adjusted for gender, age, race, marital status, tumor location, histological category, grade, and TNM stage based on Model I. Data cleaning and analysis were performed using R 4.4.1. All statistical tests were two-sided, with P < 0.05 considered statistically significant.

1. Results
2. Clinical and Pathological Features of Early-Onset Gastric Cancer

According to the inclusion and exclusion criteria, a total of 5,811 patients were included, as shown in Figure 1. Among these, 814 patients (14%) had early-onset gastric cancer, and 4,997 patients (86%) had non-early-onset gastric cancer, with the results presented in Table 1. Compared to non-early-onset gastric cancer, early-onset gastric cancer had a higher proportion of female patients (42.3%), a higher frequency of stage IV (44.3%), and a greater proportion of T4 and M1 stages (23.6%, 44.0%, respectively). In terms of histological type, the proportion of signet-ring cell carcinoma was significantly higher in early-onset gastric cancer patients than in non-early-onset gastric cancer patients (P < 0.001), with 26.8% (218 cases) of early-onset gastric cancer patients being diagnosed with signet-ring cell carcinoma, compared to 14.7% (736 cases) of non-early-onset gastric cancer patients. There was also a significant difference in tumor location between early-onset and non-early-onset gastric cancers (P < 0.001), with early-onset gastric cancer tumors being more commonly located in the body, fundus, and greater curvature of the stomach (10.3%, 6.02%, 5.41%). The proportion of early-onset gastric cancer patients receiving postoperative adjuvant chemotherapy was 78.9% (642 cases), significantly higher than the 68.3% (3,412 cases) in non-early-onset gastric cancer patients (P < 0.001). However, no statistically significant differences were observed between early-onset and non-early-onset gastric cancer patients in terms of race, N stage, or tumor size.

Figure 1 Flowchart of Inclusion and Exclusion of Study Subjects

表 1研究对象一般特征

2. Survival Analysis of Early-Onset Gastric Cancer

Survival analysis was conducted for patients with early-onset gastric cancer and non-early-onset gastric cancer, with survival curves plotted (Figures 2–5). The study of survival rates between the two groups revealed that the 2-year survival rates for the early-onset gastric cancer group and the non-early-onset gastric cancer group were 47.7% and 48.2%, respectively, while the 5-year survival rates were 31.5% and 30.9%, respectively. The log-rank test indicated that the difference in survival curves between the two groups was statistically significant (P = 0.008).

Analysis of different treatment strategies for gastric cancer patients revealed significant differences in survival outcomes. The median survival time was 99 months (95% CI: 84, 109) for the surgery-only group, 10 months (95% CI: 9, 10) for the radiotherapy/chemotherapy-only group, and 40 months (95% CI: 36, 45) for the surgery + radiotherapy/chemotherapy group, with the log-rank test showing statistically significant differences among the three groups (P < 0.001). Further analysis of early-onset and non-early-onset gastric cancer patients demonstrated consistent findings: surgery yielded better outcomes than surgery + radiotherapy/chemotherapy, which in turn was superior to radiotherapy/chemotherapy alone. For early-onset gastric cancer patients, the 2-year survival rates for surgery only and surgery + radiotherapy/chemotherapy were 85.98% and 88.65%, respectively, while the 5-year survival rates were 61.37% and 32.62%, respectively.

Figure 2 Kaplan-Meier Survival Curves for Overall Survival in Patients with Early-Onset and Non-Early-Onset Gastric Cancer

Figure 3 Kaplan-Meier Survival Curves for Different Treatment Strategies in Patients with Early-Onset and Non-Early-Onset Gastric Cancer

Figure 4 Kaplan-Meier Survival Curves for Different Treatment Strategies in Patients with Early-Onset Gastric Cancer

Figure 5 Kaplan-Meier Survival Curves for Different Treatment Strategies in Patients with Non-Early-Onset Gastric Cancer

3. Univariate and Multivariate Cox Proportional Hazards Model Analysis

The Cox proportional hazards regression model was used to analyze overall survival (OS) (Table 2). Univariate Cox regression analysis indicated that patients undergoing surgery alone had the best prognosis. Compared with this reference group, patients receiving radiotherapy/chemotherapy alone had the highest mortality risk, which was 8.74 times higher (P < 0.001), while those receiving surgery combined with radiotherapy/chemotherapy had a 2.35-fold higher mortality risk (P < 0.001). Multivariate Cox regression analysis revealed that factors such as gender, tumor location, histological type, grade, T stage, N stage, and tumor size also significantly influenced prognosis. For example, patients with signet-ring cell carcinoma (HR = 1.20), higher grades (Grade II: HR = 1.53; Grade III: HR = 1.95), advanced T stage (T4: HR = 1.26), and higher N stage (N1: HR = 1.18; N2: HR = 1.34; N3: HR = 1.96) had a higher risk of mortality. After including these factors in the model, the mortality risks for radiotherapy/chemotherapy alone (aHR = 4.59, P < 0.001) and surgery combined with radiotherapy/chemotherapy (aHR = 1.46, P = 0.008) were reduced. Notably, patients with signet-ring cell carcinoma (aHR = 1.20, P < 0.001), higher grades (Grade II: aHR = 1.53; Grade III: aHR = 1.95), and advanced T stage (T4: aHR = 1.26, P < 0.001) continued to exhibit significantly higher mortality risks.

The survival probability predictions from the model also showed similar results (Figure 6). For early-onset gastric cancer patients, the survival rate for surgery combined with radiotherapy/chemotherapy was lower than that for surgery alone, while radiotherapy/chemotherapy alone had the lowest survival rate. Conversely, for non-early-onset gastric cancer patients, the survival rate was highest for the surgery combined with radiotherapy/chemotherapy group, followed by the surgery-only group, and lowest for the radiotherapy/chemotherapy-only group. These findings suggest that combined therapy provides significant survival benefits for non-early-onset gastric cancer patients.

Figure 6 Predicted Overall Survival Rates Based on Different Treatment Strategies in Early-Onset Gastric Cancer (A) and Non-Early-Onset Gastric Cancer (B)

Table 2 Overall Survival Analysis

1. Discussion

This study explored the clinical and pathological characteristics of early-onset gastric cancer (EOGC) patients and found that, compared to non-early-onset gastric cancer, early-onset gastric cancer is more common in females. Some researchers suggest that this could be related to hormone levels and external factors. Estrogen may contribute to gastric mucosal barrier function or influence mitosis in the cell cycle, leading to carcinogenesis. Given the relatively higher estrogen levels in younger women, this may be a contributing factor to the gender disparity observed in early-onset gastric cancer. Additionally, early-onset gastric cancer is more commonly found in the body, fundus, and greater curvature of the stomach. Degenerative changes in the gastric mucosa and intestinal metaplasia typically progress from the distal stomach towards the cardia and proximal fundus. This process reduces the gastric mucosal barrier function. Chronic irritation from smoking, alcohol, gastric ulcers, or repeated gastroesophageal reflux may further increase the risk of lesions in the fundus and cardia. Therefore, it is important to pay particular attention to these high-risk populations and locations during clinical diagnosis and treatment.

In the early stages of diagnosis, early-onset gastric cancer (EOGC) patients tend to present with later-stage American Joint Committee on Cancer (AJCC) staging compared to non-early-onset gastric cancer. Pathological stage IV, T4, and M1 staging are more common. This may be related to the insidious onset of EOGC, as well as the lower degree of tumor differentiation. The Lauren classification of EOGC is predominantly diffuse type, with a higher incidence of peritoneal recurrence, while non-early-onset gastric cancer is more frequently of the intestinal type, with distant metastases being more common. This could be due to the more invasive pathological characteristics of the latter. A study by Qu et al. found that the incidence of signet ring cell carcinoma in the early-onset gastric cancer group was as high as 21.13%, significantly higher than the 8.51% in the non-early-onset gastric cancer group (P<0.001), indicating that signet ring cell carcinoma is more common in early-onset gastric cancer. Similarly, Pocurull et al.’s multicenter retrospective study revealed that the majority of tumors in early-onset gastric cancer patients were of the diffuse type, accounting for 78.3%, with most in advanced stages. Liu Jingdong et al.’s research also supports this view, noting that the proportion of poorly differentiated or undifferentiated tumors in early-onset gastric cancer was as high as 93.9%, significantly higher than the 74.5% observed in non-early-onset gastric cancer (P<0.001), which is consistent with the findings of this study. In line with these findings, this study suggests that early-onset gastric cancer patients are usually diagnosed at an advanced stage, presenting with characteristics such as a high risk of lymph node metastasis, diffuse growth, and poor differentiation. These pathological features collectively signal a poorer treatment response and survival prognosis.

Based on the overall survival analysis results of early-onset gastric cancer (EOGC) and non-early-onset gastric cancer patients, the two groups did not show significant differences in prognosis. Previous studies have also found that EOGC has a lower all-cause mortality risk compared to non-early-onset gastric cancer (HR=0.87) [10]. A domestic study based on the National Cancer Center of China showed that early-onset gastric cancer patients with pathological stage III had worse overall survival compared to non-early-onset gastric cancer patients, while those with stage I had better survival outcomes. For stage II and IV patients, there was no significant difference in overall survival between the two groups [11]. These results suggest that the prognosis of EOGC patients may be influenced by various factors, including pathological features, stage differences, and treatment strategies.

The study found that while early-onset gastric cancer (EOGC) patients showed a slight advantage in 2-year survival rates with surgery combined with chemotherapy and radiotherapy, in terms of long-term survival (5-year survival rate), EOGC patients who only underwent surgery had significantly higher survival rates compared to those who received surgery combined with chemotherapy and radiotherapy. This may be because EOGC patients typically have fewer comorbidities and postoperative complications, and they exhibit higher completion rates and better tolerance for comprehensive treatments [12]. These factors are closely related to patient prognosis [13]. Additionally, early-onset gastric cancer patients often do not have other life-threatening diseases. Surgery can effectively remove the primary tumor, reduce tumor burden, and create conditions for subsequent treatment. While surgery combined with chemotherapy and radiotherapy may improve survival rates in the short term, in the long run, this treatment approach could lead to treatment-related side effects, a decline in quality of life, or treatment resistance. Therefore, we believe that surgery for EOGC patients, along with proactive therapeutic interventions, may still lead to better prognosis. Moreover, since the recurrence pattern of EOGC tends to be localized, surgery is more effective in controlling local disease.

Zhang et al.’s study [14] also found that in resectable early-onset gastric cancer (EOGC) patients, the prognosis of surgery alone was not inferior to that of surgery combined with chemotherapy and radiotherapy. The survival time difference between surgery combined with radiotherapy or chemotherapy and surgery alone was not statistically significant (median OS: 41 months vs. 45 months, P = 0.184). Additionally, for signet-ring cell carcinoma patients, surgery alone was superior to surgery combined with radiotherapy or chemotherapy. EOGC patients may not require additional chemotherapy or radiotherapy, as surgery itself can provide a favorable prognosis, further supporting the above analysis. However, some studies suggest that EOGC patients may face a higher risk of recurrence after surgery, and surgery combined with chemotherapy may be more appropriate [15]. Therefore, future research should further explore individualized treatment regimens for EOGC patients to improve their survival rates and quality of life.

In conclusion, early-onset gastric cancer (EOGC) patients have distinct clinical and pathological features and recurrence patterns. Surgery alone yields better outcomes than surgery combined with radiotherapy or chemotherapy.

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