Gastric cancer is a highly prevalent malignant tumor, characterized by inherently high aggressiveness. The tumor is accompanied by common presentations, such as stomach discomfort, indigestion, acid reflux, and retrosternal burning, during the initial stage. However, the lack of distinct clinical manifestations is the prime reason for delayed diagnosis of the cancer, causing most patients to miss the golden window of early-stage detection. By the time significant symptoms such as increased pain, gastrointestinal bleeding, and weight loss start to manifest, the disease has often progressed to the middle and advanced stages, during which the malignancy can hardly be cured. The five-year overall survival of patients with advanced gastric cancer is reportedly lower than 30%. In the event of metastasis, gastric cancer patients would have a worse prognosis, with a median overall survival of only one year [1].

Currently, multiple therapeutic approaches are employed for the treatment of advanced gastric cancer, including local palliative surgery, systemic chemotherapy, radiotherapy, immunotherapy, and targeted therapy. In addition, the prognosis of patients with gastric cancer has been shown to improve with the administration of successive lines of treatment. According to findings from a clinical trial published in Japan [2], patients with advanced gastric cancer who had undergone first-line therapy exhibited a median survival time of 234 days. This median survival was increased by an additional 166 days following second-line treatment and was further extended by 151 days after the implementation of third-line therapy [2]. There are many first-line and second-line treatment options, such as trastuzumab, 5-fluorouracil, irinotecan, capecitabine, tegafur, platinum compounds, and docetaxel. However, therapeutic options become markedly limited beyond the third-line setting following treatment failure, preventing some patients with advanced gastric cancer from receiving comprehensive care and ultimately adversely affecting their overall survival outcomes.

In this study, baseline and clinical information was collected from patients with advanced gastric cancer who received third-line treatment at Zhongshan Hospital, Fudan University, Shanghai, China. In addition, the third-line treatment regimens were evaluated as a whole based on factors such as efficacy, tolerability, and cost. This investigation aimed to enhance our understanding third-line treatment regimens for advanced gastric cancer in a of real-world setting, with the goal of improving therapeutic efficacy.

According to the findings of several randomized clinical trials, third-line therapies improve the survival rate of patients with advanced gastric cancer. In Western countries, the overall acceptance rate for third-line treatment remains relatively low. However, in Japan, the vast majority of patients with advanced gastric cancer receive second-line therapy, and over half proceed to third-line treatment. This approach has significantly improved the survival rate for these patients, and the national treatment guidelines explicitly recommend specific third-line treatment strategies. Despite the high incidence of gastric cancer in China, at present, comprehensive and systematic assessments regarding the efficacy of third-line therapeutic interventions for advanced gastric cancer remain limited. This study was designed and conducted to explore the various critical aspects of third-line treatment regimens—including efficacy, safety, and cost—in Chinese patients with advanced gastric cancer.

This study retrospectively analyzed the third-line treatment regimens received by patients with advanced gastric cancer. A sample of 145 patients with advanced gastric cancer was included in this study, including 45 in the chemotherapy-alone group, 58 in the immunotherapy/targeted therapy group, and 42 in the chemotherapy + immunotherapy/targeted therapy group. No significant differences were observed among the three groups before receiving third-line treatment. Variables such as prior treatment regimens, height, weight, medical history, surgical status, and Lauren classification were comparable across the groups. The results of this study showed that both the chemotherapy + immunotherapy/targeted therapy and immunotherapy/targeted therapy regimens significantly improved the prognosis and prolonged overall survival compared with chemotherapy-alone regimen. The aforementioned article has pointed out that in the overall study population, irinotecan or docetaxel monotherapy had no significant overall survival benefits in patients who had received second-line treatment (HR: 0.812, 95% CI: 0.450–1.464) [5], consistent with the conclusions of this study. Immunotherapy has also been regarded as one of the most important treatment strategies for cancer patients in the future and has achieved great clinical success [6]. Despite the survival benefit of immunotherapy/targeted therapy regimen, resistance to these treatments should not be overlooked, as it may result in treatment failure. The underlying resistance mechanisms are highly heterogeneous and include loss of neoantigens, defects in antigen presentation and interferon signaling, upregulation of immune inhibitory molecules, and exclusion of T cells. Further efforts are warranted to determine strategies to overcome resistance to immunotherapy/targeted therapy.

Furthermore, there are many reports on the influencing factors of treatment prognosis in patients with advanced gastric cancer. For example, Zhou et al. [7] conducted a prognostic model analysis involving 112 patients with advanced gastric cancer treated with first-line therapy between July 2013 and September 2019. Their univariate analysis identified several factors significantly associated with survival prognosis, including the Eastern Cooperative Oncology Group (ECOG) performance status, presence of peritoneal metastasis, hemoglobin levels, serum lactate dehydrogenase (LDH), carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9). Cox regression analysis showed that peritoneal metastasis, hemoglobin 90 g/L, serum LDH $\ge$225 U/L, and CEA and CA19-9 levels exceeding three times the normal range were independent prognostic factors [7]. Moreover, in a clinical trial, Catalano et al. [8] identified five categories of indicators that adversely influence the prognosis of patients undergoing second-line treatment for advanced gastric cancer, including the ECOG performance status score, CEA expression levels, hemoglobin levels, duration of disease progression, and the number of metastatic lesions. The univariate analysis findings of the current study indicate that the patient’s gender, age, weight, body surface area, and history of gastric cancer surgery were significantly associated with the prognosis of third-line treatment. The results of multivariate analysis also showed that only the history of gastric cancer surgery was an independent influencing factor for the prognosis of patients with advanced gastric cancer treated with third-line therapy. The findings are summarized as follows: (1) There is no unified conclusion on the impact of age on the prognosis of gastric cancer patients. For example, it has been reported that gastric cancer patients over 60 years old have a better prognosis than other age groups [9]. In addition, it is believed that in some certain malignant tumors (such as breast cancer and gastric cancer), compared to middle‑aged and elderly patients, adolescents and young adult patients may exhibit a worse prognosis after treatment, due to the higher aggressiveness of malignant tumor cells and increased susceptibility to recurrence [10, 11]. Reports suggest that contemporary young people are more health-conscious, an attitude that facilitates earlier disease detection, thereby improving survival rates and prolonging their survival [12]. In addition, Kim et al. [13] found that there was no significant difference in the prognosis of elderly patients after radical resection of gastric tumors when compared with their younger counterparts. The analysis of prognostic factors in this study suggests that elderly patients with third-line treatment for advanced gastric cancer have a better prognosis, and there is no definitive conclusion at present. (2) Weight loss has been identified as a prognostic factor for numerous malignant tumors, including colon cancer [14] and advanced lung cancer [15], with patients experiencing weight loss associated with poor prognosis. However, Lin et al. [16] contend that although patients with weight loss tended to have poorer post-surgery prognosis, the difference was not statistically significant. This outcome may be attributed to the limited duration of the follow-up period. A meta-analysis revealed that weight loss during chemotherapy is an adverse risk factor affecting the prognosis of advanced gastric cancer patients (HR: 0.72, 95% CI: 0.63–0.82) [17], aligning with the results of this study. The findings of the present study indicate that patients with advanced gastric cancer who have undergone radical or local palliative surgery exhibit a better prognosis than patients with advanced gastric cancer who have not undergone surgical treatment (HR: 0.639, 95% CI: 0.431–0.948). Correspondingly, evidence from a related investigation into surgical outcomes demonstrates that the median survival duration of patients with advanced gastric cancer treated with surgery following chemotherapy is significantly prolonged relative to patients receiving chemotherapy alone [18]. Yoshida et al. [19] also found that patients with a prior gastrectomy history had a better prognosis than those who had undergone either palliative or radical surgery (9.7 vs. 7.6 months), consistent with the results of the current study.

Finally, the chemotherapy + immunotherapy/targeted therapy group exhibited the highest incidence rate of adverse events, reaching 90.5%. Likewise, a study evaluating nivolumab as a third-line treatment for advanced gastric cancer demonstrated a favorable safety profile for immunotherapy/targeted therapy; among patients in the treatment group who achieved a complete or partial response, 87% survived for at least 1 year and 61.3% survived for 2 years. The overall median survival was 26.6 months, and the incidence of adverse events was 43%, with the occurrence of grade 3 to 4 adverse events being less than 10%. These findings lend credence to the safety of immunotherapy under the premise of drug effectiveness [20]. Furthermore, our analysis of adverse event data identified cytopenia as the most prevalent drug-related toxicity, encompassing myelosuppression affecting platelets, neutrophils, and trilineage cells. The second most common adverse reactions involved the gastrointestinal system, primarily manifesting as nausea and vomiting. These findings are corroborated by a study conducted by Kang et al. [5] on third-line treatment using irinotecan or similar agents, which indicates that bone marrow suppression is the principal adverse drug reaction, with neutropenia occurring in over 15% of patients, negatively impacting disease progression.

Several limitations of our study should be acknowledged. First, the retrospective nature of the data collection may have introduced selection and information biases. Second, the overall sample size was relatively small (n = 145). Following patient categorization based on treatment type, the sample size in each group (especially the combination therapy group, n = 42) became much more limited, which may have reduced the statistical power and robustness of the findings. Third, all data were sourced from a single institution (Zhongshan Hospital, Fudan University), limiting the generalizability of the results to the broader Chinese population or to patients treated in other healthcare settings with different practices and from other demographic groups. Fourth, there were limitations associated with the cost analysis. While costs were adjusted using a benchmark interest rate, the analysis did not account for other economic factors such as inflation, changes in drug pricing, or variations in insurance reimbursement policies over the study period (2016–2022), potentially affecting the accuracy and comparability of the cost data. Fifth, the presence of missing data, particularly for survival status (6 patients) and cost information (41 patients), may have introduced bias and compromised the completeness of the survival and economic analyses. Sixth, there was substantial heterogeneity in the treatment regimens. The immunotherapy/targeted therapy group likely comprised a variety of specific agents and the aggregation of different drugs into broad categories may have obscured clinically meaningful differences in efficacy and toxicity among individual agents. Finally, there was a lack of patient-reported outcomes. This study did not assess quality of life or other patient-reported outcomes. Therefore, the impact of these treatments on patients’ overall well-being and daily functioning remains unknown. Further prospective studies are warranted to verify the results of our study.

The survival analysis of this study demonstrates that gastric cancer patients receiving chemotherapy combined with immunotherapy or targeted therapy as the third-line treatment achieved the longest MST; however, this regimen is also associated with a higher incidence of adverse events and overall treatment costs. In addition, multivariate analysis identifies the absence of prior gastric cancer surgery as an independent prognostic factor for outcomes in patients with advanced gastric cancer receiving third-line treatment.

• This study aimed to retrospectively evaluate the therapeutic efficacy, safety, and costs of different third-line treatment regimens for treating advanced gastric cancer, thereby providing a theoretical basis to guide the selection of third-line treatment regimens.

• A total of 145 patients were included and divided into three groups: 45 patients in the chemotherapy-alone group, 58 patients in the immunotherapy/targeted therapy group, and 42 patients in the chemotherapy + immunotherapy/targeted therapy group.

• Survival analysis revealed a median survival time (MST) of 7.7 months (95% CI: 6.8–8.5) for the overall cohort, with the chemotherapy + immunotherapy/targeted therapy group exhibiting the longest MST (MST: 10.5 months; 95% CI: 8.9–12.1), followed by the immunotherapy/targeted therapy group (MST: 8.5 months; 95% CI: 7.1–9.9).

• Regression analysis showed that a history of gastric surgery was an independent prognostic factor (hazard ratio [HR] = 0.639; 95% CI: 0.431–0.948; p = 0.026) for outcomes in gastric cancer patients receiving third-line treatment.

• The chemotherapy + immunotherapy/targeted therapy group exhibited the highest incidence of adverse events (90.5%), followed by the chemotherapy-alone group (75.6%).

• The cost analysis showed that the chemotherapy + immunotherapy/targeted therapy group incurred the highest treatment costs, and both the total treatment costs and anti-tumor drug-related costs were significantly and positively correlated with patient survival (r² = 0.2656 and 0.3081).

The data that support the findings of this study are available from the corresponding authors upon reasonable request.

SY, CWZ, and TSL made substantial contributions to study conception and design. XLZ performed the acquisition and analysis of data. SY drafted the manuscript. All authors contributed to the important editorial changes in the manuscript. All authors gave final approval of the version to be published. All authors have participated sufficiently in the work to take public responsibility for appropriate portions of the content and agreed to be accountable for all aspects of the work.

This study was approved by the Ethics Committee of Zhongshan Hospital, Fudan University (Approval No.: B2020-253R2). All procedures were performed in compliance with the Good Clinical Practice guidelines and the Declaration of Helsinki. Written informed consent was acquired from all patients before any research procedures were undertaken.

The authors would like to sincerely thank Dr. Qing Liu and Dr. Xueyi Weng from Zhongshan Hospital, Fudan University, for their critical review and valuable methodological insights during the preparation of this article. Gratitude is also extended to all of the patients and their families for their cooperation and support.

This research received no external funding.

The authors declare no conflict of interest.

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/BJHM50918.