The current landscape of gastric cancer and gastroesophageal junction cancer diagnosis and treatment in China: a comprehensive nationwide cohort analysis

Abstract

Background

Gastric cancer is the fifth most common cancer globally and is associated with significant morbidity and mortality. Despite its alarming prevalence, limited comparative evidence exists on its treatment efficacy and prognosis across diverse China populations.

Methods

To address this, our study used a large-scale dataset from the National Cancer Information Database, including data from 220,304 patients from 53 leading hospitals across 27 provinces in China.

Results

From 2017 to 2023, early-stage (Stages I-II) gastric cancer diagnoses increased to 35.63% of all cancer cases. Our study evaluated the neoadjuvant treatment strategies, adjuvant post-operative therapy, first- and second-line management for progressive stages, alongside current gastric cancer treatment guidelines in China. Notably, immunotherapy accounted for 16.17% and 23.28% of first- and second-line treatments for late-stage gastric cancers, and 14.56% and 5.00% for neoadjuvant and adjuvant therapies, respectively. Analysis of survival rates revealed that the 1-, 2-, 3-, 4-, and 5-year survival rates were 74.07%, 54.89%, 44.21%, 37.97%, and 33.53%, respectively. The 5-year survival rates across stages I-IV were 85.07%, 49.34%, 35.56%, and 13.15%, respectively.

Conclusions

These findings offer critical insights into the current state of gastric cancer treatment in China and can inform future initiatives to improve therapeutic outcomes for patients with gastric cancer.

Background

Gastric cancer (GC) is the fifth leading cause of cancer-related mortality globally [1], with China contributing 70% and 50% of new cases of cardia and non-cardia GC, respectively [2]. The incidence of gastric cancer in China was reported at 25.41 per 100,000 people in 2022 [3]. The etiology of gastric cancer in China stems from a convergence of biological and behavioral drivers. Helicobacter pylori (H. pylori) infection, prevalent in 43-60% of the population, establishes a foundational risk by inducing chronic gastric inflammation [4,5,6]. This bacterial colonization interacts synergistically with modifiable lifestyle factors, particularly high salt intake from preserved foods, tobacco use, and alcohol consumption [7, 8]. Emerging evidence further highlights the role of metabolic disorders, particularly in genetically susceptible individuals [9, 10]. High-risk clusters persist in provinces such as Shandong, Liaoning, Fujian, and Gansu, where local dietary practices-including the consumption of nitrate-rich preserved foods-intersect with environmental factors such as soil micronutrient deficiencies [11,12,13,14]. For instance, regions with low selenium or molybdenum levels in soil demonstrate amplified cancer risks when combined with insufficient dietary vitamin C intake [15, 16].

Recently, improved living standards have reduced traditional risks-H. pylori prevalence has declined alongside reduced smoking rates and pickled food consumption [2]. However, these gains are counterbalanced by new challenges: processed food diets and sedentary lifestyles have driven an increase in proximal diffuse-type tumors, contrasting with declining rates of distal intestinal-type cancers [3, 17,18,19]. Compounding these trends, China’s rapidly aging population-projected to reach 395 million individuals over 65 by 2050-intensifies disease burden, as advanced age remains a non-modifiable risk factor [19, 20].

The prevailing standard of care for GC is a multifaceted approach involving surgery, chemotherapy, targeted therapy, immunotherapy, and radiotherapy [19]. This comprehensive regimen is tailored to the specific requirements of each patient’s unique disease stage and characteristics. Despite advancements in GC research and treatment, challenges remain in achieving optimal outcomes. The median survival of patients with advanced GC is less than one year [19].

The findings from major clinical trials, including FLOT-4, MATTERHORN, DANTE, ESOPEC, NEOAGIES, and the latest TOPGEAR trial, play a crucial role in shaping national guidelines and clinical practices [21,22,23,24]. These studies have provided robust evidence regarding perioperative and systemic treatments for gastric cancer.

In addition to these pivotal trials, real-world evidence is equally important in guiding clinical decision-making and optimizing treatment strategies. Thus, the China National Central Cancer Registry launched a hospital-based multicenter cancer registry in 2016 [25]. The objective of this registry was to gather precise and high-quality cancer data encompassing patients’ family cancer history, clinical stage at diagnosis, tumor grade, detailed treatment history, and survival rates, along with detailed clinical data captured in the participating hospitals’ electronic health record (EHR) system. This information, previously lacking in large-scale population-based studies in China, aims to enhance patient care by providing a comprehensive and dynamic foundation for clinical outcome evaluation.

To achieve this goal, this study used longitudinal data collected via the National Central Cancer Registry to understand the current treatment landscape and survival data for GC in China, including patient outcomes across specific age groups. The findings of this study can help identify the unmet needs of patients with GC in China, and inform treatment decision-making and future healthcare initiatives toward improving patient outcomes.

Methods

Study design and data sources

This retrospective study used data from the National Cancer Information Database (NCID), a comprehensive longitudinal database extracted from EHR, and part of the National Central Cancer Registry in China. This study was approved by the Ethics Committee of Peking University Cancer Hospital (2023KT42). All the participants and their legal guardians provided informed consent. The NCID dataset includes records from 53 top-tier hospitals across 27 provinces in China and contains demographic and clinical characteristics, treatment information, and details of surgery, and other clinical procedures of 4,607,844 patients with cancer as of June 2023. This database is representative of diverse geographical regions in China. Additionally, the NCID is integrated with the Chinese National Disease Surveillance Points System of the Center for Disease Control, enabling the ascertainment of survival outcomes. The data used in this study spanned from January 1, 2017, to June 30, 2023.

Study population

The study population included patients in China diagnosed with a single primary gastric adenocarcinoma between January 2017 and June 2023. Patients were eligible for study inclusion if they (1) were clinically diagnosed with primary GC by a trained physician, (2) had histologically confirmed gastric adenocarcinoma, and (3) were diagnosed between January 1, 2017, and June 30, 2023. Patients were excluded if they were: (1) diagnosed with multiple primary tumors (≥ 2); or (2) diagnosed with gastric squamous cell carcinoma, neuroendocrine carcinoma and neuroendocrine tumor, gastrointestinal stromal, and an undetermined pathological type. The study selection flowchart is shown in Fig. S1. The study cohort consisted of 220,304 eligible participants identified through this selection process. The index date for the analysis was defined as the initial diagnosis of GC. The follow-up period was defined as the time between the index date and the last follow-up date, with a median follow-up duration of 12.91 months.

Data extraction and quality control

The structured data underwent harmonization and normalization according to a standardized ontology, ensuring consistency and compatibility across datasets [25]. This data was sourced directly or from a wide table joined by multiple tables and processed using multiple preprocessing functions to implement complex preprocessing logic. Unstructured data was extracted from EHR-based digital documents using regular expressions (Regex) or pre-trained natural language processing (NLP) models. In some cases, a more complex logic was applied, involving a combination of multi-table joins, Regex, and NLP models for accurate data extraction and processing.

During stage grouping, the presence or absence of distant metastases was initially assessed, and patients with distant metastasis were classified as having stage IV disease, regardless of the T or N stage. For patients who underwent initial surgery, the cancer stage was primarily determined based on the available pathological information [25]. For patients who received initial chemotherapy, radiotherapy, or immunotherapy, the clinical stage at diagnosis was prioritized. When extracting detailed information on the therapy regimens, we searched for treatment information collected from medication prescriptions for both outpatient and inpatient cases. HER2 expression in gastric cancer was tested using two techniques: immunohistochemistry (IHC), which identifies the potential overproduction of the HER2 protein (3+, 2+, 1+, 0), and fluorescence in situ hybridization (FISH), which checks for excessive copies of the HER2 gene in patients with HER2 (2+). Additionally, Epstein-Barr Virus (EBV) status was confirmed through in situ hybridization with probes against EBER1. Mismatch Repair (MMR) status was measured via IHC analysis of the DNA mismatch repair proteins MLH1, MSH2, MSH6, and PMS2. PD-L1 expression was assessed via IHC, incorporating Tumor Proportion Score (TPS), Immune Proportion Score (IPS), and Combined Positive Score (CPS) criteria, with positivity defined as meeting any of these scoring thresholds. CLDN18.2 expression was evaluated via IHC, with positivity defined as moderate-to-strong membranous staining (2+/3+) in > 40% of viable tumor cells. NTRK fusions were detected using pan-TRK IHC (indicative of fusion) and confirmed through DNA/RNA-based next-generation sequencing (NGS).

Both manual and automated quality control measures were implemented, involving medical and statistical experts collaborating on verification rules to maintain data quality, supported by specialized training for quality control personnel. To guarantee data integrity, a standardized study protocol was instituted, detailing the data architecture, extraction methodologies, cleaning processes, staging criteria, and procedures for file transmission. Data acquisition was stringently controlled, with source information derived directly from the EHR to ensure authenticity and precision, and executed by trained technicians [25, 26]. As part of data quality control, a subset of the data was validated through the researcher’s manual review. Data integrity checks were conducted throughout the study to address missing data and anomalies. Data privacy, confidentiality, traceability, and replicability were diligently enforced and monitored. These audits assessed internal data quality as well as involved external evaluations to foster improvements, backed by detailed documentation and issue resolution processes.

Study outcomes

The primary outcome assessed in this study was overall survival (OS) (i.e., the interval between diagnosis and death from any cause or the date of the last follow-up). The median follow-up time is 12.91 months, and we have extended the observation period to 5 years to ensure sufficient long-term follow-up and capture death events in the study population. Our study recorded 51,959 deaths among 171,530 patients. Additionally, the distribution of first- and second-line treatments was assessed on January 1, 2017, and consisted of the following potential treatments for GC: chemotherapy, targeted therapy, and immunotherapy. Neoadjuvant therapy refers to systemic therapy administered before definitive surgery for patients with stage IIa-IV GC, whereas adjuvant therapy refers to treatment after curative resection to destroy any remaining cancer cells and reduce the risk of recurrence. First-line treatment was defined as the administration of systemic anticancer therapy to patients with unresectable advanced GC, while second-line treatment was defined as the subsequent treatment regimen administered when the first-line therapy failed, was not tolerated, or the disease recurred.

Statistical analysis

Patients were stratified into four age groups (0–44, 45–64, 65–74, and 75 + years) to compare clinical, pathological, molecular features, and treatment data. Additionally, sex and clinical characteristics were descriptively summarized overall and by age group. Counts and proportions were reported for categorical variables, while medians were reported for continuous variables (age and body mass index [BMI]). The relationships between age group and clinicopathological features were evaluated using the Kruskal-Wallis test.

OS was estimated using the Kaplan–Meier method and univariate Cox regression models, with 95% confidence intervals (CIs) for the median OS determined using the log-transform method. Differences in OS across groups were assessed using the log-rank test to determine P values. All P values were two-tailed, and P < 0.05 was used to define statistical significance. All statistical analyses were performed using the SAS software (version 9.4; SAS Institute, Cary, NC, US).

Results

Patient cohort and distribution

The study cohort included 220,304 eligible participants with single primary gastric adenocarcinoma (Fig. S1). Patients were distributed across 53 hospitals in 27 provinces across seven geographical regions in China (Table S1, S2). The majority were located in three regions: East China (23.64%), North China (21.59%), and Central China (18.69%), and 99.57% of patients were treated at tertiary hospitals, advanced and specialized institutions providing comprehensive treatment and surgery (Table S2). Most patients (70.7%) received care at cancer-specialized hospitals, while 29.3% were treated at general hospitals.

The clinicopathological characteristics of GC in China

The demographic and clinical characteristics of the study population are summarized in Table 1. The majority of patients were male (72.43%), with a median age of 63.0 years (interquartile range [IQR]: 55.0–69.0), and a median BMI of 22.22 (IQR: 20.03–24.51). Most tumors were in the gastric sites (61.84%), followed by the gastro-esophageal junction (38.16%). Patients aged ≤ 44 years primarily had gastric adenocarcinoma (84.30%), while there was a positive numerical trend between older age and gastroesophageal junction tumors (GEJ) (10.70% of those aged ≤ 44 years versus 47.10% of those aged 75 + years).

Table 1 Clinical, pathological, and molecular characteristics of patients with gastric cancer according to age at diagnosis

The primary histological type was poorly differentiated (poor/moderate-to-poor) GC (73.35%), especially prevalent in patients aged ≤ 44 years (91.47%). Among the study cohort, 3.62% had stage I, 32.01% had stage II, 16.28% had stage III, and 26.16% had stage IV disease, with 21.94% having missing staging data. The liver was the primary site of metastasis in patients with advanced GC (32.33%), followed by the peritoneum (16.56%), bones (11.11%), and lungs (10.85%).

The positivity rate for HER2, as determined by IHC and FISH, is 11.47%. Over one-third (38.86%) of the patients also had a comprehensive PD-L1 positivity rate, which remained consistent across various age groups. The proportions of dMMR/MSI-H GC and EBV-positive GC were 7.94% and 10.31%, respectively. CLDN18.2 immunohistochemical positivity was observed in 54.39% of tested cases, while actionable NTRK genomic alterations (including fusions and mutations) were identified in 2.44% of tumors. Concurrently, H. pylori infection status showed a positivity rate of 44.25%, reflecting its persistent role as a key etiological factor in the studied cohort. A family history of cancer was noted in 8.97% of the patients, primarily consisting of GC (42.46%), lung cancer (17.21%), and esophageal cancer (14.47%). For enhanced clarity, we present a supplementary table (Table S3) detailing key clinicopathological features across disease stages.

Significant age-related disparities in participation rates of clinical trials were observed across demographic strata (Table 1). The youngest cohort (≤ 44 years) demonstrated the highest participation rate (9.73%), whereas the oldest participants (≥ 75 years) exhibited a markedly decreased rate of 2.73%. Supplementary analyses revealed disease stage-dependent enrollment patterns (Table S3). Enrollment rates showed a positive correlation with disease progression, increasing incrementally across severity stages: Stage I (1.72%), Stage II (3.94%), Stage III (7.24%) and Stage IV (13.84%).

Perioperative treatment of GC

Among 171,972 patients with documented staging information, 3,379 (1.96%) received neoadjuvant therapy, while 50,857 (29.57%) underwent adjuvant therapy. Notably, 39,667 patients (23.07%) underwent surgery alone without receiving either neoadjuvant or adjuvant therapy, whereas 2,705 (1.57%) received both treatment modalities.

A total of 3,379 patients in the overall cohort underwent neoadjuvant therapy for GC (Table 2). The most common regimens of neoadjuvant therapy were fluorouracil- and platinum-based therapy (44.89%), followed by triplet chemotherapy (26.40%), whereas only 4.79% received taxane-based chemotherapy. Immunotherapy was administered to 14.56% of the patients, including those who participated in clinical trials. Similarly, anti-HER2 treatment was offered to 2.99% of patients participating in clinical trials.

Table 2 Therapy regimens of patients with gastric cancer according to age at diagnosis

Among the 90,292 patients who underwent surgical treatment, the proportions of patients who underwent laparoscopic surgery (49.51%) and laparotomy (47.67%) were similar (Table S4). Laparotomy was more commonly opted than laparoscopic surgery in patients aged 75 + years (55.67% vs. 41.12%, respectively). Additionally, 92.96% of patients achieved R0 resection.

A total of 50,857 patients in the cohort received adjuvant therapy, most commonly fluorouracil- and platinum-based therapy (49.53%) or fluorouracil monotherapy (22.49%) (Table 2). Lower proportions of patients received triplet chemotherapy (6.59%), taxane-based chemotherapy (5.59%), immunotherapy (5.00%), or anti-HER2 treatment (1.02%).

First and second-line treatment regimens in advanced GC

Of the 51,847 patients in the cohort who received first-line treatment for advanced GC, 4.68% received anti-HER2 therapy, and 16.17% received immunotherapy (Table 2). However, chemotherapy regimens predominated, with 31.09% receiving a combination of fluorouracil and platinum-based chemotherapy, 16.47% receiving fluorouracil monotherapy, 14.48% receiving taxane-based chemotherapy, and 6.55% receiving triplet chemotherapy regimens.

Among patients with advanced gastric cancer who received first-line therapy, 6,770 (approximately 13.06%) subsequently underwent second-line systemic treatment. The use of anti-HER2 therapy remained low (6.38%), and substantially more patients received immunotherapy (23.28%) than in the first-line setting (Table 2). Chemotherapy combined with anti-angiogenic therapies was used in 18.08% of the patients, while 7.81% used anti-angiogenic small-molecule drugs alone. Among the patients receiving chemotherapy, 27.67% received taxane-based treatments, 5.76% received a mixture of fluorouracil and platinum-based therapy, 4.59% received fluorouracil monotherapy, and 4.83% received three-drug chemotherapy regimens.

Radiotherapy utilization patterns in stage II-IV gastric Cancer

Among the 164,000 patients analyzed (stage II-IV), 12,061 (7.35%) received radiotherapy. Specifically, radiotherapy was administered to 1,062 patients (0.65%) in the neoadjuvant setting and 5,062 patients (3.09%) in the adjuvant setting. For advanced gastric cancer, 6,377 patients (3.89%) underwent radiotherapy, with 5,598 (87.78%) receiving treatment for primary lesions and 779 (12.22%) for metastatic lesions (Table S5).

Survival analysis

In total, 171,530 patients with staging information and sufficient follow-up time were included in the survival analysis (Fig. 1). The median OS was 28.68 months (95% CI: 28.32–29.08). The 1, 2, 3, 4, and 5-year survival rates, were 74.07%, 54.89%, 44.21%, 37.97%, and 33.53%, respectively (Fig. 1a; Table 3). In the analysis of OS by stage at diagnosis, compared to patients at stage I, the HRs for stage II, III, and IV were 5.84 (5.22–6.54), 7.61 (6.80–8.52), and 17.49 (15.64–19.55), respectively, indicating that earlier stage at diagnosis was significantly correlated with longer OS (P < 0.001) (Fig. 1b). The 5-year OS rates for patients diagnosed at stages I, II, III, and IV were 85.07%, 49.34%, 35.56%, and 13.15%, respectively.

Fig. 1

Kaplan–Meier survival curves of patients with gastric adenocarcinoma. The analysis of OS in the overall cohort with gastric adenocarcinoma (a) and grouped by stage at diagnosis (b)

Table 3 Overall survival of patients with gastric cancer

Subsequently, we compared survival across different age groups in stages I-IV (Fig. S2). In stages I-III, patients aged ≤ 44 years had the best prognosis, followed by those aged 45–64, then those aged 65–74, and those ≥ 75 years had the worst prognosis (P < 0.001). In stage IV, patients over 75 years of age had the least promising outlook, whereas the other three age groups had similar survival data. The analysis of the entire cohort demonstrated no statistically significant survival disparity between genders (P = 0.065) (Fig. S3). However, female patients exhibited superior survival outcomes compared to males in stages I-III (P < 0.0001) (Fig. S4).

Immune checkpoint-based immunotherapy is a standard treatment regimen for GC worldwide and is being increasingly adopted in China. Therefore, we compared the OS of patients who received immunotherapy or other therapies in first- and second-line settings (Fig. S5). The results indicated that patients receiving immunotherapy as their first-line treatment had significantly longer median OS than that of patients treated with other therapeutic options (14.32 vs. 12.71 months, respectively; HR [95% CI]: 0.89 [0.85–0.93]; P < 0.001) (Fig. S5a). A similar trend was observed in second-line treatment where the median OS of patients receiving immunotherapy was significantly longer than that of those not receiving immunotherapy (10.35 vs. 8.48 months; HR [95% CI]: 0.79 [0.74–0.85]; P < 0.001) (Fig. S5b).

Discussion

Our study represents a pioneering effort to comprehensively evaluate the age-specific burden of GC across all 27 provinces in mainland China using robust clinical data and cancer mortality statistics. Our investigation is the first to provide a holistic assessment of the GC treatment landscape on a national scale. Drawing on data from diverse multicenter hospital-based registries, this study is a thorough and current endeavor in this field.

We observed an increase in the proportion of gastroesophageal junction cancers in China from January 2017 to June 2023 (38.16%) compared to those reported in prior studies (22.3% in 1988–1992, 35.7% in 2008–2012) [27]. Younger patients (≤ 44 years) predominantly developed gastric adenocarcinoma (84.3%), while gastroesophageal junction tumors showed a striking age-dependent increase, rising from 10.7% in the youngest cohort to 47.1% in patients aged ≥ 75 years. This may be attributed to changes in diet, lifestyle choices, and the environment. The development of GEJ tumors in older populations may reflect prolonged exposure to risk factors such as chronic gastroesophageal reflux disease, obesity, and Barrett’s esophagus, which are strongly associated with GEJ adenocarcinoma and often correlate with age [1, 2]. Conversely, gastric adenocarcinomas in younger patients (< 44 years) might arise from distinct etiologies, such as genetic predisposition (e.g., CDH1 mutations), earlier H. pylori infection, or immune-related pathways [19, 28].

Our findings demonstrate significant age-related disparities in gastric cancer presentation and clinical outcomes. Poorly differentiated histology was prevalent across all age groups (73.35% overall), with the highest proportion observed in the < 45-year subgroup (91.47%). However, the youngest cohort (≤ 44 years) demonstrated the most favorable prognosis, followed by sequential reductions in survival for the 45–64, 65–74, and ≥ 75-year groups (P < 0.001). Notably, younger patients, despite presenting with more aggressive tumor features (e.g., higher rates of poorly differentiated histology), achieved superior OS compared to older cohorts. This paradox may be partially explained by treatment patterns: younger patients received more intensive therapeutic regimens, including higher utilization of triplet chemotherapy (26.40% in neoadjuvant and 6.59% in adjuvant settings) and immunotherapy (5.00% in adjuvant therapy). In advanced stages, they were also more likely to receive aggressive first-line therapies (e.g., taxane-based chemotherapy: 14.48%) and immunotherapy (16.17% first-line, 23.28% second-line), suggesting a clinical preference for intensified strategies in this demographic.

Cancer stage at diagnosis is highly prognostic of patient outcomes and has been used to explain variations in international cancer survival rates [25]. Our study observed an increase in the proportion of early-stage (I-II) GC diagnoses among Chinese patients from January 2017 to June 2023 (35.63%) compared to those reported in prior studies (25.8% in 2016–2017) [25]. This potentially signifies improvements in the screening and early identification of GC. However, China continues to face a higher incidence of late-stage GC than countries such as Japan and South Korea, where widespread implementation of endoscopic screening has contributed to lower rates of advanced-stage diagnoses [29]. Notably, in regions with high GC incidence, such as Japan and Korea, screening programs have yielded substantial reductions in gastric cancer-related mortality rates, with 5-year survival rates of > 54% [30]. China has substantially expanded its cancer screening and early detection network [28, 31]. Our findings underscore the need for enhanced screening and early detection strategies for GC in the Chinese population.

Comparative analyses reveal distinct international patterns. While China’s stage I detection rate (21.2%) now approaches that of the U.S. (23.2%), 43.3% of Chinese patients present with stage III disease versus 19.3% in the U.S [25]. Conversely, the U.S. reports higher stage IV diagnoses (42.7% vs. China’s 21.4%). This divergence suggests later clinical recognition in Western populations despite comparable early-stage diagnosis rates. A meta-analysis of 20 studies (n = 9,033) revealed significantly superior OS in Asian gastric/gastroesophageal adenocarcinoma patients compared to Western counterparts (HR = 0.76, 95% CI: 0.70–0.83) [32]. This survival advantage may be multifactorial, encompassing earlier detection, distinct tumor biology, and differential treatment responses. Notably, pooled analyses of CheckMate-649 and KEYNOTE-062 trials demonstrated enhanced immunotherapy sensitivity in Asian patients, with improved OS benefits from PD-1 inhibitors in first-line settings (HR = 0.79 vs. 0.91 in non-Asians) [33, 34].

Amplification of the HER2 (ERBB2) oncogene and overexpression of the HER2 protein is present in approximately 12-20% of patients [19]. For the first time, on a national scale with a large sample size, we validated a similar positivity rate to that seen globally [19]. The overall positivity rate for PD-L1 was 38.86%, potentially influenced by the incorporation of multiple scoring systems for PD-L1, including TPS, IPS, and CPS. Over the past three years, CPS has emerged as the primary scoring criterion, further increasing the observed positivity rate compared to that of TPS or IPS alone. Patients with dMMR accounted for 7.94% of the total, whereas those with EBV-positive infection accounted for 10.31%. While IHC remains the most accessible method for dMMR screening in China, we recognize that pathological complete response (PCR) or NGS-based MSI testing could provide complementary information. This methodological limitation inherent to retrospective studies.

The statistically significant associations observed for HER2, EBV, and PD-L1 with stage in our cohort likely reflect the large sample size, which enhances the detection of minor variations that may not signify biological relevance. Prior studies support this observation, as HER2 expression and EBV/PD-L1 status have not been consistently linked to tumor stage across malignancies [35, 36]. The rate of dMMR (deficient mismatch repair) decreases as the stage advances, with 9.02% in stage I, and 6.20% in stage IV (P < 0.0001). This finding suggests that dMMR-associated tumors are more frequently identified in earlier stages, possibly due to their distinct molecular characteristics and clinical presentation. This finding aligns with previous literature, which reports that dMMR/MSI-H GC constitutes approximately 3–5% of cases in advanced disease but is more prevalent (8–22%) in nonmetastatic tumors [37].

Preoperative chemotherapy substantially increases the likelihood of successful curative resection and eradicates the early microscopic spread of GC. Recommended regimens by China Clinical Oncology Society (CSCO) guidelines for preoperative GC chemotherapy include the combination of fluorouracil and platinum-based.

chemotherapy [38,39,40], alongside triplet chemotherapy [41, 42], and fluorouracil, leucovorin, oxaliplatin, and docetaxel protocols [43]. In this study, the most prevalent neoadjuvant therapy for GC was a combined regimen of fluorouracil and platinum, followed by triplet chemotherapy. Moreover, there have been some instances of immunotherapy, most of which are part of ongoing clinical trials. According to the KEYNOTE-585 study and two Phase II clinical trials conducted in Chinese cohorts, a remarkable increase in pCR was observed following treatment with perioperative immunotherapy combined with chemotherapy for GC, although long-term survival data are still awaited [44,45,46].

In the analysis of adjuvant therapy following GC surgery, the predominant therapy was a combination of fluorouracil and platinum (48.83%), followed by fluorouracil alone (23.46%). Taxane-based chemotherapy comprised 5.47% of the treatments, and triplet chemotherapy was administered to 6.40% of patients. Lastly, immunotherapy was used in 4.86% of the patients, most of whom were part of clinical trial studies. The ATTRACTION-5 study [47] showed no difference in centrally assessed relapse-free survival (RFS) in patients with stage III GC who underwent surgery, regardless of whether adjuvant chemotherapy was combined with nivolumab monotherapy. However, subgroup analysis demonstrated that patients with CPS ≥ 1 gained more benefits from nivolumab and chemotherapy combination therapy. Nevertheless, the efficacy of immunotherapy as an adjuvant treatment for GC requires further investigation [47].

For patients with unresectable locally advanced or metastatic gastroesophageal junction or GC, the consensus of the CSCO guidelines is to adopt a comprehensive treatment approach with systemic antitumor drug therapy as the primary component [48]. This emphasizes the need for a multi-sectoral approach to the management of advanced metastatic GC. Several clinical trials have been conducted on targeted drugs for the treatment of GC. The approved drugs targeting HER2 in GC include monotherapeutic agents such as trastuzumab from the TOGA study, its biosimilars, and antibody-drug conjugate (ADC) drugs such as disitamab vedotin [49] and fam-trastuzumab deruxtecan (T-DXd) [50]. Our study observed that anti-HER2 therapy was administered to 4.68% of first-line cases and 6.38% of second-line cases, encompassing almost all patients with HER2-positive status. Among HER2-negative patients, first-line treatment with PD-1 monotherapy combined with chemotherapy has become the new treatment standard for unresectable locally advanced or metastatic gastroesophageal junction/GC [33, 34, 51, 52]. Our study showed that 16.17% of patients received immunotherapy as a first-line treatment, while a higher proportion (23.28%) received immunotherapy as a second-line treatment. This may be attributed to a shift in immunotherapy usage from late to first-line settings.

Typically, the first-line chemotherapy regimen is based on 5-fluorouracil with combinations of platinum and/or taxanes forming a dual or triplet chemotherapy scheme [53,54,55,56]. Triplet chemotherapy has the potential to enhance survival outcomes but may also lead to adverse effects. This approach may be appropriate for patients in excellent health as well as for those with a substantial disease burden, where prompt response is crucial. Fluorouracil- and platinum-based chemotherapy was prescribed to 31.09% of patients who received only chemotherapy, with 16.47% receiving fluorouracil as a standalone therapy. Taxane-based chemotherapy and triplet chemotherapy were used in 14.48%, and 6.55% of the cases respectively.

In the context of second-line treatment, patients with GC who are suitable for chemotherapy may benefit from taxanes or irinotecan. Combination therapy with paclitaxel and ramucirumab is often preferred as second-line treatment because of improved survival outcomes. Anti-angiogenic drugs approved for advanced GC in China include ramucirumab and apatinib [57,58,59]. The treatment strategies observed in this study align well with those recommended in the clinical treatment guidelines of the CSCO [48]. Combined anti-angiogenic therapies and chemotherapy comprised 18.08% of second-line treatments, whereas anti-angiogenic small-molecule drugs alone comprised 7.81%. Among the patients who underwent chemotherapy, taxane-based treatments were predominant (27.67%).

Radiotherapy utilization remains limited in gastric cancer management, with only 7.35% of stage II-IV patients in China receiving it. Neoadjuvant radiotherapy protocols-particularly for GEJ tumors-show clear benefits. The CROSS protocol significantly improves R0 resection rates (92% vs. 69%), and long-term survival compared to surgery alone [60], supported by the POET trial’s survival trends and reduced local recurrence [61]. Additionally, the multicenter phase II RTOG-9904 trial demonstrated promising efficacy for preoperative chemoradiation in localized gastric adenocarcinoma, with a pathologic response rate of 26% and manageable toxicity [62]. For GEJ cancer (Stage III), the current recommended strategy integrates preoperative chemoradiotherapy (CRT) followed by D2 gastrectomy, as supported by these trials. For mid/distal GC, ongoing trials (e.g., TOPGEAR, CRITICS-II) are evaluating preoperative radiotherapy’s efficacy in Asian populations where D2 surgery predominates [63, 64]. Emerging evidence highlights the potential of combining immunotherapy with CRT. In China, the prospective phase II SHARED trial for locally advanced gastric/GEJ adenocarcinoma showed that sintilimab (anti-PD-1) combined with concurrent CRT followed by adjuvant immunotherapy achieved a 100% R0 resection rate, with pCR and major pathologic response (MPR) rates of 38.2% and 79.4%, respectively [65]. Conversely, a U.S. pilot study of pembrolizumab combined with the CROSS regimen in cT3NanyM0 patients showed manageable toxicity but a modest pCR rate (22.6%). These early-phase studies collectively suggest that CRT-immunotherapy combinations hold significant promise.

Post-surgery radiotherapy remains debated, particularly in Asia where advanced D2 surgery is standard. Although INT-0116 established postoperative CRT as standard after D0/D1 resection [66], Asian studies (ARTIST, ARTIST-II) in D2-resected GC showed no survival benefit despite reduced local recurrence (7% vs. 13%) [67]. The international phase III CRITICS trial further demonstrated no survival advantage for postoperative CRT over chemotherapy alone in patients with resectable gastric/GEJ cancer (Stage Ib-IVa), even after preoperative chemotherapy and adequate lymphadenectomy [68]. Thus, adjuvant CRT is not routinely recommended after D2 gastrectomy. However, in high-risk subgroups-such as those with R1 resection, inadequate margins (< 2 cm), lymphovascular/perineural invasion, N3 disease, or a high metastatic lymph node ratio (> 25%)-adjuvant CRT may be considered following full systemic therapy. For unresectable disease, radiotherapy effectively alleviates bleeding, obstruction, and pain [69] and may prolong survival when combined with chemotherapy for recurrent/oligometastatic disease [70].

Calculations of survival rates revealed a 5-year OS rate of 33.53%. Prior studies in the Chinese population, including national registry analyses, have reported 5-year OS rates for gastric cancer ranging between 25 and 28%, with variations depending on staging and regional healthcare access [3, 71, 72]. The increase in 5-year survival rates could be attributed to the refinement of cancer screening methods, integration of multidisciplinary team (MDT) approaches, the evolution of precision oncology, sustained research and breakthroughs in new drug development, improved social welfare, augmented income, and expanded access to healthcare services [73]. Additionally, this swift progression and propagation of novel drug research within clinical trials are powered by conducive government policies and rapid patient enrollment facilitated by China’s extensive population. A pivotal milestone was achieved with the approval of four domestically developed PD-1 inhibitors - troparia, sintilimab, camrelizumab, and tislelizumab - for cancer treatment by the NMPA during 2018–2019. This epoch is anticipated to ease the financial impact of cancer treatment on Chinese patients, thereby augmenting their overall well-being [74]. Nonetheless, 5-year survival rates remain lower than those in Japan and South Korea (54% and 57.9%, respectively) [30], underscoring the need for continued advancement of initiatives focused on improving the outcomes of patients with GC.

This study has several strengths. First, our analysis utilized up-to-date representative data from 53 hospitals across 27 provinces, ensuring the systematic utilization of the most current and comprehensive data available in China. Second, to the best of our knowledge, our analysis of real-world data on neoadjuvant, adjuvant, and first- and second-line treatment regimens for GC in China provides crucial evidence for policymakers to shape future GC control strategies. Third, our study is the first to estimate the survival of 171,530 individuals with GC in China based on high-quality data from hospitals with continuous surveillance, providing valuable insights into the disease trajectory. The geographic diversity of patients within the NCID contributed to the comprehensiveness and representativeness of the data, supporting the robustness of our analysis and findings.

This study has several limitations, some of which are inherent to retrospective studies that use large EHR databases. Although our multicenter design accounted for geographical variations, population density, socioeconomic status, and lifestyle, the included patients primarily originated from areas with above-average socioeconomic development. Consequently, the observed proportion of early-stage diagnoses and survival rates may be higher than the actual national figures. Further studies using nationally representative samples are warranted for a more comprehensive understanding.

China is one of 57 nations expected to face formidable challenges associated with an aging population. Therefore, accelerated efforts aimed at curbing cancer-related burdens via risk factor control are of profound importance [2]. Notably, the recently updated Healthy China Action Plan on Cancer Control (2019–2030) underscores the imperative role of bolstering cancer awareness and encouraging healthier lifestyles as pivotal components of future preventive measures and cancer control strategies within the country. The results of this analysis, therefore, have clinical implications for the treatment of GC and may inform more efficacious cancer awareness campaigns, to enhance early detection procedures, and improve access to high-quality medical interventions.

Conclusions

This study provided an in-depth analysis of the current paradigms in GC treatment across 53 hospitals in 27 Chinese provinces. Advancements in methods facilitating the early diagnosis and staging of GC, as well as the advent of novel treatments, have substantially improved the 5-year survival rate compared to earlier data. The treatment protocols for GC largely adhered to the guidelines established by the CSCO. Immunotherapy has been used to manage advanced stages of the disease but is anticipated to become more commonly adopted for neoadjuvant and adjuvant post-operative treatment. The present findings provide insights into the existing framework of GC management in China and inform and influence forthcoming treatment strategies to improve the clinical outcomes of patients with GC.