Gastric cancer (GC), a significant global public health burden, is among the top-ranked cancers for causing significant levels of mortality and disability (1). Globally, as per the estimated data for the year 2019, GC is the fifth most diagnosed cancer, fourth leading cause of cancer-associated mortalities and contributes to 1.7 million disability-adjusted life years (2-4). GC can be difficult to detect in its initial stages due to mild or absent symptoms, and is usually diagnosed at the advanced disease stage (5). GC requires a multidisciplinary approach to treatment, involving gastroenterologists, surgeons, medical oncologists and radiation oncologists (6,7). Advances in surgical techniques, chemotherapy, targeted therapy and immunotherapy have improved GC treatment outcomes, but early detection and timely treatment remain critical targets to improve the prognosis of the disease (8,9).

Despite advances in the diagnosis and treatment of GC, patients with advanced disease stages face a poor prognosis with a 5-year overall survival (OS) rate of <5% (10,11). This highlights the need for improved prognostic indices to guide clinical decision-making and improve patient outcomes. Systemic inflammatory responses contribute to the tumor microenvironment, promoting angiogenesis, tumor development and metastasis (12,13). Neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, lymphocyte-monocyte ratio and systemic immune-inflammation index (SII) have shown promise as prognostic markers in patients with specific types of cancer, such as metastatic non-small cell lung cancer, testicular germ cell tumor and rectal cancer (14-16). Moreover, the levels of these markers can be measured from routine blood tests, making them easily accessible and relatively inexpensive.

The SII has demonstrated its prognostic value in various types of tumor, such as urological cancers, including prostate cancer, small cell lung cancer and esophageal cancer (17-21), and is used to assess and quantify the systemic inflammatory response. It is a composite index that takes into account blood-based markers, such as neutrophil count, lymphocyte count and platelet count [SII=(platelet count x neutrophil count)/lymphocyte count]. It can be easily and inexpensively measured using blood samples and, therefore, has the potential to be adopted in everyday clinical practice for personalized treatment planning. It may also be used in combination with other clinical and pathological variables, such as tumour size, differentiation, clinical stage, vascular or lymphatic invasion, distant metastasis or abnormal carcinoembryonic antigen (CEA), to improve prognostic accuracy and guide treatment decisions for patients with GC. To the best of our knowledge, only two meta-analyses have focused on SII: One including eight studies and the other including 11 studies (22,23). The meta-analysis by Qiu et al showed that a high pretreatment SII is associated with poorer OS, but not poor disease-free survival (DFS) in patients with GC (22). By contrast, the analysis by Fu et al showed that higher SII levels are associated with poorer OS and DFS (23). The present study was designed to update the analysis with the data from new publications and evaluate the association of SII with OS or RFS in patients with GC.

The present study included data from 30 studies in this analysis (27-56). Fig. 1 presents the process of the study selection. The majority of studies (n=24) were conducted in China (Table I); two studies were conducted in Japan and four in Turkey. Except for one study that had a prospective cohort design, all studies had a retrospective cohort design. In 24 studies, the main GC management strategy was gastrectomy, whereas in the remaining six studies, non-surgical management strategies included immune checkpoint inhibitors, combination of chemotherapy and radiotherapy, anti-programmed death 1 treatment and a combined immune- and chemo-therapy (Table I). The study sample sizes ranged from 45 to 2,257 participants, with 19 studies having <500 participants and 11 studies having ≥500 participants. The follow-up periods varied from 15.5 to 65.6 months. Quality scores on the NOS ranged from 6 to 9, with a mean score of 7.53, indicating overall acceptable study quality (Table I).

Patients with high SII levels had poor OS (HR, 1.53; 95% CI, 1.34-1.75; n=27; I²=72.4%), compared with patients with low SII levels (Fig. 2). Egger's test (P=0.01) and funnel plots (Fig. S1) indicated the presence of publication bias. Patients with high SII levels had poorer OS, irrespective of whether they had received surgical or non-surgical management, whether they were part of sample sizes <500 or >500, or the cut-offs used to define high and low SII (<600 and ≥600 x10⁹ cells/l) (Table II). Notably, the elevated risk of poorer OS associated with a high SII level was statistically significant in studies conducted in China (HR, 1.53; 95% CI, 1.34-1.75; n=21; I²=73.7%), but not in studies conducted in other settings (Table II).

The present meta-analysis revealed that high SII levels were associated with poor OS and RFS in patients with GC irrespective of the sample size, treatment received or cut-offs used to define high and low SII levels.

A meta-analysis by Qiu et al demonstrated a significant correlation between high SII levels and unfavorable OS outcomes (22). However, this study revealed no significant associations with the RFS (22). Another review by Fu et al that included 11 studies with ~7,000 patients with GC revealed that a higher SII is associated with an ~53% increase in the risk of death and a 57% increase in the risk of disease recurrence or progression (23). Studies have also shown that a high SII is associated with unfavorable survival outcomes in patients with solid tumors, hepatocellular cancer, urological cancers, small cell lung cancer and esophageal squamous cell cancer (19,57-59). The findings from these meta-analyses indicate that SII may serve as a reliable marker of prognosis in various cancer types and could provide valuable information for clinical decision-making and patient management.

Systemic inflammatory responses are involved in cancer progression (12,13,60,61). SII is a commonly used systemic inflammation marker. A high SII score has been associated with poor prognosis in different types of cancers, such as hepatocellular, prostate, renal cell and non-small cell lung cancers (19,58). One potential explanation for the observed association may be the involvement of lymphocytes, specifically tumor-infiltrating lymphocytes, which inhibit the increases in the number of cancer cells (62,63). Thus, low lymphocyte counts, contributing to high SII scores, may indicate a weakened immune response favoring cancer cell survival and growth (64,65). Another hypothesis involves the role of neutrophils, which are capable of secreting various growth factors and interleukins that stimulate tumor cell growth. These neutrophils could enhance tumor progression (66,67) by promoting tumor angiogenesis and invasion, and releasing proteases that degrade the extracellular matrix and facilitate cancer cell migration (67). Thus, high neutrophil counts, which contribute to high SII scores, may be indicative of inflammatory environments supporting tumor growth and metastases (68,69). Finally, elevated platelet counts have been shown to increase SII scores and may be indicative of tumor microenvironments that support the survival and spread of cancer cells (70,71). Taken together, increased SII scores may reflect the presence of prevailing pro-tumor microenvironments, which could contribute to poor prognosis for patients with GC.

The findings of the present study may be used for improving clinical practice, since they support the use of SII as a potentially valuable prognostic tool that can lead to more personalized treatment strategies. By modifying prognostic criteria to incorporate SII, clinicians could improve the prediction of outcomes and tailor treatment plans, ultimately leading to improved patient care and timely monitoring. Incorporation of SII in the panel of prognostic indicators for GC may foster multidisciplinary collaboration among healthcare professionals, particularly oncologists, hematologists and immunologists. The present study also provided incentive to conduct further research into the underlying mechanisms connecting high SII levels to adverse outcomes.

The present meta-analysis has some limitations. First, all included studies were conducted in Asian countries, mostly in China, and this may complicate the generalizability of the findings. The significant association of SII with poor OS and RFS in the Chinese studies and the lack thereof in studies conducted outside of China may be attributed to the considerably larger number of studies from China, which could have increased the statistical power of the analysis. Conversely, the limited number of studies from non-Chinese countries may have underpowered the analysis. As a result, statistical significance may have remained undetected, even if it genuinely existed. Second, the selected studies used diverse thresholds to categorize patients into high and low SII groups, leading to discrepancies in the interpretation of SII levels and subsequent outcomes. Third, most of the included studies were retrospective in nature, which may have introduced various selection and misclassification biases. Fourth, the heterogeneity among the included studies was significant, and the specific reasons for this heterogeneity remain unclear. Finally, the present study found evidence of publication bias in the analysis for the overall survival outcome, which may have influenced the results.

In conclusion, high pretreatment SII levels were associated with poor OS and RFS in patients with GC. SII levels, therefore, may serve as a potential prognostic marker. However, the present study has limitations, such as the lack of diversity in patient ethnicity, the variability in cut-off values and the reliability on retrospective studies. Thus, larger studies with a prospective design are needed to confirm the findings.