The prognostic role of radiotherapy in non-surgical gastric cancer: a retrospective cohort study in the SEER database

Introduction

Gastric cancer (GC) remains a significant global public health challenge, ranking as the fifth most common malignancy worldwide and the third leading cause of cancer-related mortality (1). Although radical surgery (R0 resection, indicating complete microscopic resection) remains the primary curative approach for localized GC (2,3), epidemiological data reveal that approximately 35% of patients with surgical indications in the United States ultimately do not undergo surgery (4). Even among those receiving surgery, the risk of recurrence remains high, resulting in suboptimal long-term survival rates (5), underscoring the urgent need to optimize non-surgical therapeutic strategies.

In systemic therapy, the cornerstone role of chemotherapy is well-established—neoadjuvant chemotherapy improves resection rates (6). However, the therapeutic value of radiotherapy (RT) remains highly controversial. International guidelines reflect divergent perspectives: The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for Gastric Cancer recommend systemic therapy, chemoradiation, and/or optimal supportive care for all patients with unresectable or metastatic disease (2), whereas the European Society for Medical Oncology (ESMO) and Japanese Gastric Cancer Association (JGCA) guidelines advocate for systemic chemotherapy as the preferred treatment option (7,8). This discrepancy stems from conflicting clinical evidence: the landmark INT0116 trial established the practice of adjuvant chemoradiation in North America (9), but subsequent ARTIST trials failed to demonstrate its benefits in patients undergoing D2 lymphadenectomy (10). Recent studies, such as the CRITICS trial, showed no survival improvement with chemoradiation (11), while a meta-analysis by Li et al. [2018] suggested potential benefits in specific subgroups (12). These discrepant findings may be attributed to several factors, including the evolution of surgical techniques (e.g., the adoption of D2 lymphadenectomy), improvements in systemic therapy regimens, and advancements in RT technology. The heterogeneity of patient populations across studies further complicates interpretation. The most critical issue is the low utilization rate of RT among non-surgical GC patients, which has resulted in a severe shortage of dedicated research focusing specifically on this population.

Notably, the rapid development of immunotherapy [e.g., pembrolizumab (13)] and targeted therapies [e.g., trastuzumab (14)] has further complicated RT’s role in multimodal treatment. The emergence of conversion therapy has enabled surgical resection in select metastatic patients (15). The role of RT in inoperable patients remains unclear. Evidence for its efficacy, especially in palliative settings, remains scarce.

While randomized controlled trials provide the highest level of evidence, they often include selected patient populations. Large, population-based databases like the Surveillance, Epidemiology, and End Results (SEER) program offer complementary real-world evidence that can describe treatment patterns and associated outcomes in broader, unselected cohorts, such as patients with non-surgical GC. This can help contextualize the efficacy of RT as it is applied in routine clinical practice. The aim of this study was to explore the prognostic role of RT in patients with non-surgical GC, as well as to identify potential factors influencing overall survival (OS) in this patient population. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1177/rc).

Methods

Study population

We conducted a retrospective cohort study using data from the SEER database [2004–2021]. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Since the database contains de-identified public information, this study was exempt from ethics approval.

Inclusion and exclusion criteria

Patients were included if they met the following criteria: (I) diagnosed with primary GC between 2004 and 2021; (II) age at diagnosis ≥18 years; (III) histological confirmation of adenocarcinoma (ICD-O-3 histology codes: 8140-8147, 8210-8211, 8220-8221, 8255-8263, 8310, 8323, 8480-8481, 8490); (IV) no surgical resection of the primary tumor. We excluded patients with: (I) survival time of less than 2 months post-diagnosis, to mitigate immortal time bias; (II) unknown RT status; (III) receipt of non-external beam RT (e.g., radioisotopes or brachytherapy). The detailed patient selection flowchart is presented in Figure 1.

Figure 1 Flowchart of the study cohort. GC, gastric cancer; NOS, not otherwise specified; RT, radiotherapy; SEER, Surveillance, Epidemiology, and End Results.

Follow-up and outcome measurement

The primary outcome of this study was OS. OS was defined as the duration from the date of GC diagnosis to the date of death from any cause. Patients who were still alive at the last follow-up date were censored. The survival time and vital status data were provided directly by the SEER database.

Statistical analyses

Multivariable Cox proportional hazards regression was used to assess the independent association between RT and OS, after adjusting for pre-specified potential confounders. The model included the following covariates: age (categorized as <65 vs. ≥65 years), sex, year of diagnosis (2004–2009, 2010–2015, 2016–2021), race (White, Black, other), marital status (married, unmarried, other), tumor site (cardia, fundus/body, antrum/pylorus, overlapping/other), grade (I/II, III/IV, unknown), stage (localized, regional, distant), and chemotherapy status (yes/no).The cumulative death rates were compared using Kaplan-Meier curves, and the RT and non-RT patient groups were compared using the log-rank test. While accounting for confounding factors, subgroup analyses were conducted to further examine the relationship between RT and survival rates within each subgroup. This study performed a descriptive analysis of the results. Qualitative data were presented as proportions and percentages, while continuous data were reported as medians with interquartile ranges. The Chi-squared test was used to compare categorical variables, while one-way analysis of variance (ANOVA) was used for comparing continuous variables. The Kruskal-Wallis test was applied for comparisons of skewed distributions.

Statistical analyses were performed using R software (version 4.2.1; R Foundation for Statistical Computing; http://www.R-project.org), the R survey package (version 4.1-1), and Free Statistics software (version 2.0; Beijing Free Clinical Medical Technology Co., Ltd., Beijing, China). A two-sided P value of less than 0.05 was deemed statistically significant for all tests.

Sensitivity analyses

Due to baseline differences among participants, to mitigate selection bias and enhance the robustness of our findings, we employed propensity score matching (PSM).

We grouped participants according to whether they had RT. Confounders identified through existing literature and clinical judgment were included in the analysis. The covariates included in the PSM were age, sex, year of diagnosis, marital status, race, tumor site, grade, tumor stage and chemotherapy. A one-to-one nearest neighbor matching technique was employed. The statistical method enabled comparisons between participants who received RT and those who did not, both prior to and following PSM. The degree of PSM was assessed using the standardized mean difference (SMD), with a threshold of less than 0.1 considered acceptable. However, the SEER database lacks critical clinical variables such as symptom burden (e.g., bleeding, obstruction), performance status, and detailed tumor biology, which may introduce residual confounding. Despite PSM adjustment for some variables, unmeasured factors (e.g., disease severity) could still bias the observed association between RT and survival. It is important to note that the non-RT group is clinically heterogeneous, potentially encompassing patients receiving best supportive care, chemotherapy alone, or other non-radiotherapeutic interventions, which could differentially impact prognosis.

Results

The selection of participants

Between 2004 and 2021, we included 115,992 patients with GC conditions from the SEER database who met the inclusion criteria. We first excluded individuals with incomplete or inadequate diagnoses, surgical resection, or initial malignant primary conditions that did not meet the inclusion criteria. Secondly, we also excluded patients with survival durations of less than 3 months, as evaluating survival efficacy for such cases is not feasible. A total of 30,265 eligible patients were included in the cohort. Patients who underwent unspecified radiation treatment, radioisotope therapy, or implantation were excluded from the study. The analysis included 29,923 patients from the final study cohort. Figure 1 illustrates the study enrollment process.

Baseline clinical characteristics

The baseline clinical characteristics of the included patients are presented in Table 1. Among the total cohort, 6,629 individuals (22.2%) underwent RT, while 23,294 (77.8%) did not receive RT. The average survival duration for the study population was 19.6 months. The groups differed significantly in age, sex, year of diagnosis, race, marital status, tumor site, grade, stage, and chemotherapy status (all P<0.001) according to the status of RT treatment.

Survival analysis

Figure 2 depicts the association between RT and OS in GC patients. The median OS for the entire cohort was 10.5 months, regardless of whether they received RT (P<0.001). After three years, the survival rate was 12.4% for the RT group and 17.8% for the non-RT group. Most patients experienced death within 36 months of starting treatment (Figure 2A). After PSM was performed, survival rates at 3-year were 11.90% for patients receiving RT and 13.8% for those who did not (Figure 2B).

Figure 2 Overall survival curves of cases with non-surgical GC according to RT (A), RT after PSM (B), and the year of diagnosis (C). GC, gastric cancer; PSM, propensity score matching; RT, radiotherapy.

Univariate OS analyses

Table 2 shows that mortality was significantly higher in patients who received RT [hazard ratio (HR), 1.13; 95% confidence interval (CI): 1.09–1.16; P<0.001] and in those who received chemotherapy (HR, 1.24; 95% CI: 1.21–1.27; P<0.001). Age (≥65 years: HR, 1.15; 95% CI: 1.12–1.18) demonstrated an inverse relationship with OS. This study observed variations in mortality based on sex (male HR, 1.17; 95% CI: 1.14–1.2), race (other-race HR, 0.93; 95% CI: 0.91–0.96), or marital status (other HR, 0.97; 95% CI: 0.95–1.0). OS was significantly improved in patients with cancer diagnosed between 2010–2015 (HR, 0.9; 95% CI: 0.87–0.93) and 2016–2021 (HR, 0.77; 95% CI: 0.75–0.8) compared with patients treated between 2004–2009. Patients with grade III/IV disease had a higher risk of mortality compared to those with grade I/II disease (HR, 1.54; 95% CI: 1.49–1.59). In this study, individuals with a tumor site defined as “antrum/pylorus” (HR, 0.97; 95% CI: 0.94–1.01) have a better OS than those whose tumor site is cardia. Patients with regional (HR, 1.71; 95% CI: 1.63–1.79) or distant disease (HR, 2.29; 95% CI: 2.20–2.38) had worse outcomes compared to those with localized disease, with the poorest prognosis observed in patients with distant-stage disease.

Multivariate OS analyses

As shown in Table 2, Multivariate analysis suggested that RT was associated with worse OS (HR, 1.11; 95% CI: 1.07–1.15; P<0.001). In contrast, chemotherapy was associated with improved outcomes (HR, 0.79; 95% CI: 0.76–0.81) compared to patients who were not treated with chemotherapy. Additionally, individuals aged 65 years and older had a significantly higher risk of mortality (HR, 1.3; 95% CI: 1.27–1.33; with age <65 years as the reference). Compared with patients treated between 2004–2009, patients with cancer diagnosed between 2010–2015 (HR, 0.89; 95% CI: 0.86–0.92) and 2016–2021 (HR, 0.84; 95% CI: 0.81–0.87) have a longer survival, and patients with cancer diagnosed between 2016–2021 have the best prognosis. The proportion of deaths in patients with grade III/IV disease (HR, 1.44; 95% CI: 1.39–1.49 was higher compared to those with grade I/II disease. Patients with regional (HR, 1.73; 95% CI: 1.65–1.82) or distant disease stage (HR, 2.6; 95% CI: 2.49–2.71) was linked to poorer outcomes than those with stage localized disease, and distant disease stage patients have the worst prognosis.

Subgroup analyses

Subgroup analysis examined the relation between RT and overall OS based on various factors, including age, sex, year of diagnosis, marital status, tumor site, grade, and chemotherapy (Figure 3). We assessed the consistency of the RT-OS relationship within the chemotherapy subgroup using three different models, with all results showing consistency (Table 3). Furthermore, a subgroup analysis was performed based on the year of diagnosis, categorizing patients into three groups, followed by Kaplan-Meier survival analysis for those who received RT (Figure 2C). The 1-year survival rates were 39.1% [2004–2009], 44.7% [2010–2015], and 49.5% [2016–2021]. The 3-year survival rates were 13.8%, 15.7%, and 19.8% (P<0.001), and the 5-year survival rates were 9.7%, 10.9%, and 14.6% (P<0.001). The median OS was 9.0, 10.5, and 12 months, respectively.

Figure 3 The association between radiotherapy and mortality based on baseline characteristics, before and after PSM. Each stratification was adjusted for potential confounders (i.e., age, sex, year of diagnosis, marital status, race, grade, tumor site, stage, and chemotherapy), excluding the stratification factor itself. CI, confidence interval; OR, odds ratio; PSM, propensity score matching.

Sensitivity analyses

PSM analysis was used to balance differences in baseline medical and demographic characteristics. Table 1 shows that after PSM, there were no significant differences between the two groups. After adjusting for relevant variables, the administration of RT was negatively associated with survival (P<0.001) (Figure 2B). Multivariate analysis confirmed these findings, indicating a higher HR for patients undergoing RT compared to those receiving non-RT treatment (HR, 1.1; 95% CI: 1.06–1.15; P<0.001) (Table 2). Additionally, Various statistical methods were applied to adjust for propensity scores, and the HR remained consistent (HR, 1.11; 95% CI: 1.07–1.15; P<0.001) (Table 4).

Discussion

This large-scale analysis revealed an association between RT and reduced survival in non-surgical GC. However, substantial residual confounding, particularly by unmeasured treatment intent (e.g., palliative vs. curative), precludes any causal inference. Our findings highlight the critical need for future studies and detailed data collection that can adequately account for treatment intent and symptom burden to clarify the role of RT in this population.

Current research for treatment of non-surgical GC is focused on conversion therapy (15,16). The possibility of surgery is evaluated after a combination of RT, chemotherapy, and immunotherapy to further decide whether to operate.

Combinations of therapies, including radiation, chemotherapy, and immunotherapy, are demonstrating safety (13,17,18). Trastuzumab in combination with chemotherapy also shows positive effects in human epidermal growth factor receptor 2 (HER2) positive advanced GC (14). Another review has systematically summarized the preclinical research and clinical progress of chimeric antigen receptor (CAR-T) cell therapy in the field of GC, evaluating its therapeutic potential and safety profile (19). New biomarkers and novel approaches to detecting recurrence are also being investigated (20,21). The significance of the integrated therapy method is garnering heightened attention. A study also found that 31% (42/136) of patients with stage IV GC underwent surgery and had an R0 resection rate of 90.5% (38/42) after immune checkpoint inhibitors and chemotherapy (22). A new biological classification category is proposed to address the possibility of translational therapy for stage IV GC (8). However, it must also be acknowledged that a majority of patients remain unable to attain conversion surgery following neoadjuvant therapy. Nonetheless, most of the studies are stuck at the drug treatment stage, and the impact of RT on GC survival deserves further consideration.

Cytotoxic agents such as fluoropyrimidine, platinum compounds, taxanes, and irinotecan constitute the primary treatment for advanced GC. Fluoropyrimidine agents, including fluorouracil, capecitabine, and S-1, are typically utilized in combination with platinum as the foundational therapy in first-line treatment (23,24). The GO2 phase III trial demonstrated that administering 60% of the full chemotherapy(oxaliplatin/capecitabine) dose enhanced tolerability in elderly and frail patients (25). Li et al. (12) found that in patients with stage I–III GC who were not eligible for potentially curative surgery, those who received chemoradiotherapy (CRT) had a median survival of 12.3 months and a 2-year OS rate of 28.3%. In comparison, patients treated with chemotherapy alone had a median survival of 11.3 months and a 2-year OS rate of 21.5%. These findings suggest a potential survival benefit of CRT over chemotherapy alone in this patient population. The observed association between RT and reduced median survival with elevated mortality risk in non-surgical GC patients echoes historical findings from the Gastrointestinal Tumor Study Group (GITSG). The GITSG trial reported shorter median survival in patients receiving chemoradiation (40 weeks) compared to chemotherapy alone (76 weeks), without OS improvement (26). Our study may overestimate RT-related risks. Although we included all RT-receiving patients to minimize selection bias, RT was likely administered for palliative purposes (e.g., bleeding/obstruction control) in patients with more advanced disease (27,28). The study by Ushimaru et al. (29) demonstrated that RT achieved effective hemostasis (94.7%) with high treatment completion rates in gastric bleeding, though its survival benefits require further validation. Critical differences exist between the GITSG trial [1990] and current analyses, including advancements in RT technology [e.g., the transition from historical 2D techniques to modern precision modalities such as intensity-modulated RT (IMRT) and stereotactic body RT (SBRT)], evolution of systemic therapies (e.g., updated chemotherapy regimens and the integration of immunotherapy), and limitations in older studies regarding documentation of prognostic factors such as performance status and molecular biomarkers. More prospective studies are needed to explore the impact of RT on these patients.

Patients diagnosed with GC between 2010 and 2015, as well as those diagnosed between 2016 and 2021, show improved survival compared to those diagnosed between 2004 and 2009, with the best prognosis observed in the latter group. This finding was also confirmed in our subgroup analysis (Figure 2C). While advancements in systemic therapies, including optimized chemotherapy regimens, targeted agents, and immunotherapy (30), are likely the primary drivers of this improvement, potential contributions from modern RT techniques (e.g., IMRT and image-guided approaches) cannot be excluded. Emerging evidence suggests that precision RT may synergize with systemic therapies by enhancing local control (31) and modulating tumor immunogenicity (32). Certainly, the most recent bibliometric analysis of the scientific literature further substantiates this perspective, providing quantitative evidence (33). However, the SEER database’s lack of RT dose and technique details precludes definitive conclusions regarding its independent impact.

This study demonstrates significant strengths, particularly in terms of its high generalizability. However, it also has some limitations. First, the retrospective design of the SEER database inevitably introduces selection bias into our study, which may affect the stability of our results. Second, unobserved or unmeasured confounding variables may have a potential impact on the relationship between RT and OS. Third, the SEER database lacks certain patient-specific clinical information, such as complete blood count results, liver and kidney function, and imaging findings, all of which can significantly influence treatment decisions and patients’ willingness to continue therapy. To address these limitations of the database, we employed PSM and conducted subgroup analyses to minimize differences between the RT and non-RT groups.

Our study underscores several critical avenues for future research. First, the attenuated association between RT and OS in metastatic patients merits further investigation to determine whether it stems from the dominant prognosis of disseminated disease, differential palliative benefits, or distinct selection criteria for RT in this population. Second, the potential synergy between modern precision RT and novel systemic agents (e.g., immunotherapy) could not be assessed in our dataset but represents a compelling direction for clinical trials, given its promise for enhancing antitumor immunity. Finally, as the SEER database lacks data on toxicity and patient-reported outcomes, prospective studies are urgently needed to evaluate the impact of RT on quality of life and symptom control, which are paramount for patients with advanced disease.

Conclusions

Our study observed an association between RT and reduced survival in non-surgical GC patients within the SEER database. However, significant limitations, including the lack of data on treatment intent (curative vs. palliative), symptom burden, and RT details, prevent causal inferences. Therefore, these results should not be interpreted as evidence against the use of RT, which remains a critical modality for symptom control in advanced GC. There is currently a lack of prospective randomized controlled trials to confirm the relationship between RT and OS in non-surgical GC patients. Our findings highlight the necessity for such trials and for detailed documentation of treatment intent in future studies.

Acknowledgments

We thank Dr. Liu Jie (People’s Liberation Army of China General Hospital, Beijing, China) for helping in this revision.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1177/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1177/prf

Funding: This work was supported by Shandong Provincial Natural Science Foundation for Young Scholars (grants ZR2023QH417).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1177/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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