Abstract
Background/Aim: Systemic immune-inflammation index (SII) was developed and evaluated for various malignancies. This study evaluated the clinical impact of the SII in patients with gastric cancer (GC) who received curative treatment. Patients and Methods: Patients who underwent curative resection for GC at Yokohama City University between 2005 and 2020 were chosen consecutively based on their medical records. SII was calculated as follows: platelet (cell/mm3 ×103)× neutrophil (cell/mm3)/lymphocyte (cell/mm3). Three measurements were obtained preoperatively. Results: In total, 258 patients were enrolled in this study. Based on the 3- and 5-year survival rates and previous studies, we set the cutoff value of the SII to 550. The 258 patients were classified into the SII-low (n=152) and SII-high (n=106) groups, respectively. The 3- and 5-year overall survival (OS) rates were 82.6% and 78.7%, respectively, in the SII-low group and 74.5% and 61.9%, respectively, in the SII-high group. There were significant differences between the two groups (p<0.001). In the multivariate analysis of factors associated with OS, the SII was identified as an independent prognostic factor (hazard ratio=1.816; 95% confidence interval=1.075-3.069, p=0.026). Similar results were observed for recurrence-free survival. In addition, the incidence of postoperative surgical complications was 30.9% in the SII-low group and 45.2% in the SII-high group (p=0.019). Conclusion: The SII was an independent prognostic factor for GC. Thus, the SII may be a promising biomarker for the treatment and management of GC.
Gastric cancer (GC) is the fifth most common cancer and the fourth leading cause of cancer-related death worldwide (1, 2). Standard treatment of resectable GC is curative gastrectomy with or without perioperative adjuvant treatment (3, 4). Even though GC patients receive curative treatment, almost half of GC patients experience recurrence, and the prognosis after recurrence is poor (5, 6). To date, various prognostic and predictive factors have been developed and evaluated to improve patient survival (7-10). Some studies have reported that perioperative host immune and inflammatory responses involving neutrophils, lymphocytes, and platelets affect the perioperative clinical course and response to chemotherapy. Several inflammation indices have been developed and introduced for the treatment of various malignancies (11-13).
Recently, the systemic immune-inflammation index (SII) was developed and evaluated for various malignancies (14-16). The SII is calculated using the combination of neutrophils, lymphocytes, and platelets. Although each factor reflects inflammation, a combined assessment might more effectively assess host immune and inflammatory responses. The prognostic and predictive value of the SII has been reported in hepatocellular carcinoma and pancreatic cancer. However, few studies have evaluated the clinical impact of the SII in patients with GC. If the SII is a promising prognostic and predictive factor for GC, patients with GC will be able to receive more aggressive treatment and optimal care based on the SII. Therefore, in the present study, we evaluated the clinical impact of the SII in patients with GC who received curative treatment.
Patients and Methods
Patients. The study population included GC patients who received curative resection at Yokohama City University from 2005 to 2020. Consecutive patients were selected according to their medical records. Patients who met all of the following criteria were included in the study: histologically diagnosed adenocarcinoma; a clinical stage of I-III (15th edition of the general rules of the Japanese Gastric Cancer Association) (17); received gastrectomy with curative intent as the primary treatment for GC; and the achievement of complete resection (defined as R0) with radical lymph node dissection.
Surgery and adjuvant treatment. In all cases, the primary treatment was gastrectomy with either D1+ or D2 nodal dissection. S-1-based adjuvant chemotherapy was administered for pathological stage I or II disease (18, 19).
Systemic immune-inflammation index. The systemic immune-inflammation index was calculated using the following formula: platelet count (cell/mm3 ×103) × neutrophil count (cell/mm3)/lymphocyte count (cell/mm3). Three measurements were performed preoperatively.
Follow-up. Every three months, for a total of five years, patients underwent hematological tests (including tumor marker measurements) and physical examinations at outpatient clinics. In addition, for the first three years postoperatively, CT examinations were conducted every three months. CT examinations were then performed every six months until five years postoperatively.
Statistical analysis. The chi-squared test was used to analyze differences between the SII and clinicopathological factors. Overall and recurrence-free survival were analyzed using the Kaplan–Meier method. Univariate and multivariate Cox proportional hazards analyses were conducted. A p<0.05 was considered to indicate statistical significance. All of the statistical analyses were conducted using SPSS (v27.0 J Win; IBM, Armonk, NY, USA).
Ethical approval. The present study received ethical approval from the institutional review board of Yokohama City University.
Results
Patient background. The present study enrolled a total of 258 patients (male, n=182; female, n=76; median age, 70 years). The comparison of overall survival (OS) according to individual clinicopathological factors revealed statistically significant differences in age, T status, lymphovascular invasion status, lymph node metastasis status, postoperative surgical complications, pathological type, and SII (Table I). We set the cutoff value of the SII as 550 based on the 3- and 5-year survival rates and previous studies. Using this cutoff value, 152 of the 258 patients were classified into the SII-low group, while 106 were classified into the SII-high group. There were no significant differences between the SII-low and SII-high groups in age, sex, pathological type, T status, or lymph node metastasis.
Comparison of survival rates stratified by patient characteristics.
Survival analysis. The 3- and 5-year OS rates were 82.6% and 78.7%, respectively, in the SII-low group, and 74.5% and 61.9% in the SII-high group (both p<0.001) (Figure 1). The univariate analysis of factors associated with OS identified age, T status, lymphovascular invasion, lymph node metastasis, pathological type, postoperative surgical complications, and the SII as significant prognostic factors (Table II). In the multivariate analysis, the SII showed an independent association with OS [Hazard ratio (HR)=1.816, 95% confidence interval (CI)=1.075-3.069, p=0.026].
Overall survival of gastric cancer patients in the systemic immune-inflammation index (SII)-high and SII-low groups.
Uni and multivariate Cox proportional hazards analysis of clinicopathological factors for overall survival.
The 3- and 5-year recurrence-free survival (RFS) rates were 78.9% and 77.8%, respectively, in the SII-low group, and 69.4% and 56.5% in the SII-high group (both p<0.001) (Figure 2). The univariate analysis of factors associated with RFS identified T status, lymphovascular invasion, lymph node metastasis, postoperative surgical complications, and the SII as prognostic factors (Table III). In the multivariate analysis for RFS, the SII remained a marginally significant prognostic factor (HR=1.943, 95%CI=1.207-3.129, p=0.006).
Recurrence-free survival of gastric cancer patients in the systemic immune-inflammation index (SII)-high and SII-low groups.
Uni and multivariate Cox proportional hazards analysis of clinicopathological factors for recurrence-free survival.
The comparison of sites of recurrence between the two groups revealed that the rate of peritoneal recurrence in the SII-high group (17.9%) was significantly higher than that in the SII-low group (7.9%) (p=0.015) (Table IV).
Patterns of recurrence according to systemic immune-inflammation index (SII).
Postoperative clinical course. Significant differences were observed in the postoperative surgical complications of the SII-low and SII-high groups. Postoperative surgical complications occurred in 30.9% of the patients in the SII-low group and 45.2% of the patients in the SII-high group (p=0.019). Furthermore, there were marginally significant differences in the individual postoperative complications in each group. The incidence of pneumonia was 3.3% in the SII-low group and 8.5% in the SII-high group (p=0.070). The incidence of anastomotic leakage was 6.6% in the SII-low group and 12.3% in the SII-high group (p=0.115). The incidence of pancreatic fistula was 4.6% in the SII-low group and 9.4% in the SII-high group (p=0.124). With regard to adjuvant chemotherapy, although a marginally significant difference in the rate at which adjuvant chemotherapy was required (was observed between the SII-low and SII-high groups (35.5% vs. 46.2%, respectively, p=0.084), the rate at which adjuvant chemotherapy was actually introduced did not differ to a statistically significant extent between the SII-low and SII-high groups (59.2% vs. 57.1%, respectively, p=0.829).
Discussion
This study aimed to clarify the prognostic impact of the SII in GC patients who received curative treatment. The major finding is that the SII is an independent prognostic factor for patients with GC. In addition, the SII affects postoperative surgical complications, including pneumonia, anastomotic leakage, and pancreatic fistula. Therefore, the SII may be a promising biomarker for the treatment and management of GC.
In the present study, we demonstrated that the SII is an independent prognostic factor, and the HR of the SII for GC patients was 1.816 (95%CI=1.075-3.069, p=0.026). Similar results and HRs have been reported in previous studies. Zhaojun et al. clarified the prognostic impact of the SII in 771 GC patients who underwent curative resection (20). They divided GC patients into SII-low (n=531) and SII-high (n=240) groups using the cutoff value of 489.52. The median survival time was 73 months in the SII-low group and 28 months in the SII-high groups. In addition, the 3- and 5-year OS rates were 81.0% and 67.9%, respectively, in the SII-low group and 39.8% and 28.9% in the SII-high group. In the multivariate analysis for OS, the SII was identified as an independent prognostic factor (HR=2.707, 96%CI=2.074-3.533, p<0.001). Similar results were observed after propensity score matching. They concluded that the SII, which remains simple, universal, noninvasive, cheap, and reproducible, is an index for assessing the prognosis of GC patients. Inoue et al. evaluated the clinical impact of the SII in 447 GC patients who received gastrectomy (21). They divided GC patients into SII-low (n=167) and SII-high (n=280) groups using a cutoff value of 395. The five-year OS rate was 92.7% in the SII-low group and 80.0% in the SII-high group. In the multivariate analysis for OS, the SII was identified as an independent prognostic factor (HR=2.95, 96%CI=1.49-6.39, p=0.001). Similar results were observed in RFS. The five-year RFS rate was 90.2% in the SII-low group and 77.7% in the SII-high group. In the multivariate analysis for RFS, the SII was identified as an independent prognostic factor (HR=2.36, 95%CI=1.31-4.48, p=0.004). In addition, similar to our study, peritoneal recurrence was more frequent in the SII-high group than in the SII-low group (p=0.028). They concluded that the preoperative SII could be a useful predictor of postoperative survival outcomes in patients with GC. According to the present study and previous studies, the SII might have a clinical impact on the survival of patients with GC.
Why does the preoperative SII status affect survival in GC patients? There are several possible explanations for this finding. First, the SII status affects postoperative surgical complications. In the present study, we demonstrated that the SII status was correlated with postoperative surgical complications, such as pneumonia, anastomotic leakage, and pancreatic fistula. Similar results have been reported previously. Xiaowei et al. evaluated the predictive value of the SII for predicting postoperative pulmonary complications in 204 lung cancer patients who underwent lung resection (22). They divided lung cancer patients into SII-low and SII-high groups using a cutoff value of 320.22. The incidence of pulmonary complications was significantly higher in the SII-high group than in the SII-low group. In a multivariate analysis, the SII was identified as an independent predictive factor for lung complications (odds ratio=2.773, 95%CI=1.075-7.159, p=0.035). Moreover, Xu et al. reported that the SII status predicted postoperative acute kidney injury in 479 patients with hepatocellular carcinoma after hepatectomy (23). The patients were divided into SII-low (n=360) and SII-high (n=119) groups using a cutoff value of 547.84. The rate of acute kidney injury was 0.6% in the SII-low group and 41.2% in the SII-high group. In a multivariate analysis, the SII was identified as an independent predictive factor for acute kidney injury (odds ratio=15.723, 95%CI=3.595-68.766, p=0.001). Recent studies have demonstrated that postoperative complications affect long-term oncological outcomes (24, 25). The SII status was associated with the occurrence of postoperative complications, which might have resulted in a worse prognosis in patients with GC. Furthermore, SII may affect the response to chemotherapy. Liu et al. evaluated the clinical relationship between the pretreatment SII status and the neoadjuvant chemotherapy response in 210 patients with cervical squamous carcinoma (26). They divided the patients into SII-low and SII-high groups using a cutoff value of 568.7. The pathological complete response was 23.5%-27.9% in the SII-low group and 2.9%-7.3% in the SII-high group (p=0.005). In the multivariate analysis, the SII was identified as an independent predictive factor for a pathological complete response (odds ratio=3.897, 95%CI=1.359-11.174, p=0.001). In the present study, almost half of the patients received postoperative chemotherapy, and the SII status was associated with a poor response to adjuvant chemotherapy, which might have resulted in a worse prognosis in patients with GC.
To utilize the SII for the treatment and management of GC in daily clinical practice, it will be necessary to set the optimal cutoff value. Previous studies set various cutoff values: 556 in the study of Gu et al. (27), 369.2 in the study of Wang et al. (28), 489.9 in the study of Wang et al. (29), and 508.3 in the study of He et al. (30). These differences might be due to differences in patient background factors, patient numbers, treatment methods, or the methods used to determine the cutoff value of the SII. Thus, further studies are needed to determine the optimal cutoff value for SII. Considering these findings, our study needs to be validated in a larger cohort.
In conclusion, the SII is an independent prognostic factor for GC. Moreover, the SII was significantly correlated with postoperative surgical complications. Therefore, the SII may be a promising biomarker for the treatment and management of GC.
Acknowledgements
This study was supported in part by the nonprofit organization of the Yokoyama Surgical Research Group (YSRG).
Footnotes
Authors’ Contributions
TA and YM contributed substantially to the concept and study design. TA, IH, YM, MN, AY, NY, AS, YR, TO, MN, and HC made substantial contributions to the data acquisition, analysis, and interpretation. TA, MN, AS, TA, KS, TO, NY, and YR were involved in drafting and critically revising the manuscript for important intellectual content. TA and YM approved the final version of the manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest in association with the present study.
- Received April 18, 2024.
- Revision received May 14, 2024.
- Accepted May 15, 2024.
- Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
