Abstract
Background/Aim: The systemic immune-inflammation index (SII) has been developed and reported to be a useful prognostic factor in various malignancies. The aim of the present study was to evaluate the clinical impact of the SII as a prognostic factor for esophageal cancer recurrence after esophagectomy.
Patients and Methods: We retrospectively reviewed the medical records and collected data from consecutive patients with recurrent EC who received any treatment after recurrence at Yokohama City University from 2005 to 2022.
Results: Ninety-four patients were included in this study. The median age was 69 years. The study included 83 men and 11 women. The median overall survival (OS) was 11.2 months. According to previous studies and 1- and 3-year OS rates, we set the cutoff value of the SII at 500 in the present study. Ninety-four patients were divided into an SSI-low group (n=36) and an SSI-high group (n=58). The 1- and 3-year OS rates were 84.9% and 44.7%, respectively, in the SSI-low group and 28.8% and 13.1%, respectively, in the SSI-high group. There were significant differences between the two groups (p<0.001). In the univariate and multivariate analyses, the SII was selected as an independent prognostic factor (hazard ratio=2.833, 95% confidence interval=1.555-5.161, p<0.001). The rate of first-line treatment introduction was 86.1% (31/36) in the SII-low group and 63.8% (37/58) in the SII-high group (p=0.019). In addition, the patients did not continue first-line chemotherapy because of disease progression, which was marginally significantly higher in the SII-high group than in the SII-low group.
Conclusion: The SII was an independent prognostic factor. In addition, the SII affects the clinical course of treatment after recurrence. Therefore, physicians might have a chance to make better decisions for treatment and management of recurrent EC using the SII.
Introduction
Esophageal cancer ranks eighth in global cancer incidence and sixth in cancer-related mortality (1, 2). The standard treatment for recurrent esophageal cancer after esophagectomy is chemoradiation therapy and/or chemotherapy (3-5). Survival of patients with recurrent esophageal cancer is gradually improving due to early detection using imaging diagnosis techniques, the development and introduction of immune checkpoint inhibitors, and supportive care after recurrence (6-8). However, the prognosis of patients with esophageal cancer recurrence is still limited, with a prognosis of less than 12 months. To improve the survival of patients with recurrent esophageal cancer after esophagectomy, it is necessary to identify prognostic factors in patients with recurrent esophageal cancer.
To date, several studies have demonstrated that pretreatment of the immune and inflammatory status affects long-term oncological outcomes (9-12). The pretreatment immune and inflammation status also affects the introduction of chemotherapy, continuation of chemotherapy, and occurrence of adverse events in chemotherapy. Recently, the systemic immune-inflammation index (SII) was developed and reported to be a useful prognostic factor in various malignancies, including esophageal cancer (13-15). The SII is calculated using a combination of neutrophils, lymphocytes, and platelets. Although the neutrophil, lymphocyte, and platelet count individually reflect the inflammation status of the patients, a combined assessment might more effectively assess the host immune and inflammatory responses. However, there is limited evidence on the association between SII and recurrence of esophageal cancer.
The aim of the present study was to evaluate the clinical relationship between the SII and the prognosis of patients with esophageal cancer and to clarify the clinical impact of the SII as a prognostic factor for these patients.
Patients and Methods
Patients. We retrospectively reviewed the medical records and collected data from consecutive patients with recurrent EC who received any treatment (including best supportive care) after recurrence at Yokohama City University from 2005 to 2022. Patients included in this study met the following criteria: diagnosis of esophageal adenocarcinoma, adenosquamous carcinoma, or squamous cell carcinoma based on a histological examination, and stage IV diagnosed by imaging examinations [8th edition of the Tumor-Node-Metastasis classification (Union for International Cancer Control)] (16).
Treatment after recurrence. In principle, patients with recurrent EC receive the same treatment. First-line treatment included 5-fluorouracil (800 mg/m2, days 1-5) and cisplatin (80 mg/m2, day 1) before February 2022, with patients receiving 5-fluorouracil (800 mg/m2, days 1-5), cisplatin (80 mg/m2, day 1), and immune checkpoint inhibitors (nivolumab or pembrolizumab) after March 2022. In the second-line treatment setting, patients received paclitaxel or docetaxel treatment or immune checkpoint inhibitor monotherapy when they did not receive immune checkpoint inhibitors as first-line treatment.
Systemic immune-inflammation index. The SII was calculated using the following formula: platelet count (cells/mm3×103) × neutrophil count (cells/mm3)/lymphocyte count (cells/mm3). Three measurements were performed at the time of the diagnosis of recurrent disease.
Adverse events evaluation. Adverse events were assessed in all patients who received at least one dose of the assigned treatments throughout the treatment and follow-up periods. Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0 (17).
Statistical analysis and ethical approval. The chi-square test was used to analyze the differences between the SII and clinicopathological factors. Overall survival (OS) was calculated from the date of the imaging examination that confirmed recurrence to the date of death from any cause or the last follow-up examination. OS was analyzed using the Kaplan–Meier method. Univariate and multivariate Cox proportional hazards analyses were performed. Statistical significance was set at p<0.05. All statistical analyses were conducted using SPSS (v27.0 J Win; IBM Corp., Armonk, NY, USA). This study received ethical approval from the institutional review board of Yokohama City University.
Results
Patient background. In total, 198 patients underwent curative esophagectomy between 2008 and 2022. Of these, 94 were eligible for inclusion in the present study. The median age of the patients was 69 years (range=37-83 years). The study included 83 men and 11 women. The median OS was 11.2 months [95% confidence interval (CI)=5.2-17.2 months] (Figure 1). According to previous studies and the 1- and 3-year OS rates, we set the cutoff value of the SII at 500 in the present study (Table I). Ninety-four patients were divided into an SSI-low group (n=36) and an SSI-high group (n=58). When comparing the patient backgrounds between the SSI-high and SSI-low groups, there were significant differences in the pretreatment body mass index, pretreatment serum albumin level, and pathological type (Table II). The number of patients with a poor nutritional status was significantly higher in the SSI-high group than in the SSI-low group. In contrast, the first recurrence site, age, and sex were similar between the two groups (Table III).
Overall survival of patients with recurrent esophageal cancer after esophagectomy.
Comparison of survival rates stratified by patient characteristics.
Comparison of patient characteristics according to systemic immune-inflammation index (SII).
Patterns of recurrence according to systemic inflammation index (SII).
Survival analysis. The 1- and 3-year OS rates were 84.9% and 44.7%, respectively, in the SSI-low group and 28.8% and 13.1% in the SSI-high group (Figure 2). There were significant differences between the two groups (p<0.001). In the univariate analyses, the neoadjuvant chemotherapy status, serum albumin level, and SII were identified as significant prognostic factors. In the multivariate analysis, the SII was identified as an independent prognostic factor [hazard ratio (HR)=2.833, 95%CI=1.555-5.161, p<0.001] (Table IV).
Overall survival of patients with recurrent esophageal cancer 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.
Comparison clinical course after recurrence. When comparing the treatment clinical course between the SSI-low and SII-high groups, there was a significant difference in the rate of first-line treatment introduction, which was 86.1% (31/36) in the SII-low group and 63.8% (37/58) in the SII-high group (p=0.019). In addition, the patients did not continue first-line chemotherapy because of disease progression, which was marginally significantly higher in the SII-high group than in the SII-low group. The failure of first-line treatment due to disease progression was 32.2% (10/31) in the SII-low group and 48.6% (18/37) in the SII group (p=0.171). In contrast, the rate of second-line treatment introduction was similar between the two groups, which was 74.2% (23/31) in the SII-low group and 64.9% (24/37) in the SII-high group (p=0.407).
Discussion
The aim of the present study was to evaluate the clinical relationship between the SII and recurrent EC and to clarify the prognostic impact of the SII on recurrent EC. The major finding was that the SII was an independent prognostic factor. In addition, the SII affects the clinical course of treatment after recurrence. Therefore, the SII is a promising prognostic factor for patients with recurrent EC.
First, we wanted to discuss the prognostic impact of the SII in patients with recurrent EC. In the present study, we demonstrated that SII levels affect OS, and that a higher SII level leads to poor survival. Although there have been no reports evaluating the prognostic impact of SII for recurrent EC, there are limited studies evaluating the clinical impact of SII on resectable EC. Esashi et al. evaluated the clinical impact of the SII in 180 resectable EC patients (18). They set the cutoff value of the SII at 500 based on the 3- and 5-year OS rates. A total of 180 patients were divided into SII-low (n=80) and SII-high (n=100) groups. The 5-year OS rates were 75.0% and 54.0% in the SII-low and SII-high groups, respectively. There were significant differences between the groups (p=0.001). Univariate and multivariate analyses showed that the SII was an independent prognostic factor (HR=2.333, p<0.001). The SII status also reflects the preoperative nutritional treatment status. Zhang et al. clarified the predictive value of the SII in 82 patients with locally advanced esophageal squamous cell carcinoma who received neoadjuvant radiation therapy between 2011 and 2017 (19). The patients were divided into SII-low (n=62) and SII-high (n=20) groups using a cutoff value of 916.6. They set the cutoff value using the Cutoff Finder software program. The median OS and 3-year OS rates were 55 months and 60.5%, respectively, in the SII-low group and 16 months and 27.5% in the SII-high group. There were significant differences in the median OS and the 3-year OS rates. Univariate and multivariate analyses showed that the SII was an independent prognostic factor (HR=2.665, p=0.040). Considering the present and previous studies, the SII might have some clinical impact on survival in both unresectable and resectable EC.
Second, we wanted to discuss the mechanism by which the SII status affects survival of patients with EC. The first possible explanation is that the SII status affected the introduction of the first-line treatment after recurrence. In the present study, we first found that the introduction rates were significantly different between the SII-high and SII-low groups. Although there have been no reports demonstrating that the SII status affects the introduction of chemotherapy, previous studies have demonstrated that some nutritional and inflammatory markers affect the introduction of chemotherapy. For example, we previously evaluated the clinical impact of the C-reactive protein-to-albumin ratio (CAR) in 481 gastric cancer patients who received curative treatment (20). Among 481 patients, 381 were categorized into the CAR-low group and 100 were categorized into the CAR-high group using a cutoff value of 0.05. The rate of adjuvant chemotherapy refusal was 29.7% in the CAR-high group and 14.6% in CAR-low group (p=0.049). Poor nutritional and/or high inflammation status might affect the introduction of chemotherapy, resulting in poor survival. The second possible explanation is that the SII status affected the chemotherapy response. In the present study, the patients did not continue first-line chemotherapy because of disease progression, the rate of which was marginally significantly higher in the SII-high group than in the SII-low group. Similar results were observed in a previous study. Chen et al. evaluated the clinical impact of nutritional status, such as hemoglobin level and body mass index (BMI) status, and the immune checkpoint inhibitor response in 354 patients with advanced EC (21). They found that there was a significantly worse immune checkpoint inhibitor response in patients with low hemoglobin (cutoff value, 11.9 g/dl) and low BMI (cutoff value, 20.56). In the hemoglobin-low group, the complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) rates were 0.8%, 24.8%, 49.6%, and 24.8%, respectively, and the objective response rate (ORR) was 25.6%. In the hemoglobin-high group, the CR, PR, SD, and PD rates were 0.0%, 45.7%, 40.7%, and 13.6, respectively, while the ORR was 45.7% (p< 0.001). Moreover, in the BMI-low group, the CR, PR, SD, and PD rates were 0.0%, 29.4%, 47.4%, and 23.2%, respectively, while the ORR was 29.4%. In the BMI-high group, the CR, PR, SD, and PD rates were 0.6%, 46.3%, 40.7%, and 12.4%, respectively, and the ORR was 46.9% (p= 0.001). Considering the present and previous studies, the nutritional and inflammatory statuses might affect the chemotherapy response.
Study limitations. First, it is a retrospective, single-institution study. In addition, the number of patients was less than 100. Therefore, there may have been a selection bias. Second, the optimal cutoff value for the SII is unclear. In the present study, we set the cutoff value of the SII according to 1- and 3-year OS rates. However, previous studies set the cutoff value using other methods, such as ROC curves or the Cutoff Finder software program (18, 19). To introduce the SII in daily clinical practice, it is necessary to establish the optimal cutoff value of the SII. Third, there may have been a time bias. This study included patients treated between 2005 and 2022. During this period, standard treatments for metastatic EC changed. Considering these limitations, we suggest the following points for future research: first, the SII needs to be evaluated as a prognostic or predictive factor in a prospective study; second, it is necessary to examine whether the SII reflects the therapeutic effects of nutrition and inflammation.
In conclusion, the SII is an independent prognostic factor. In addition, the SII affects the clinical course of treatment after recurrence. Therefore, physicians might have a chance to make better decisions for treatment and management of recurrent EC using the SII.
Acknowledgements
This study was supported in part by the nonprofit organization of Yokoyama Surgical Research Group (YSRG).
Footnotes
Authors’ Contributions
TA and YM contributed substantially to the concept and study design. TA, IH, SY, RE, KK, AT, FM, NK, JM, NO, and AS made substantial contributions to data acquisition, analysis, and interpretation. TA, YM, HS, HC, AS, and NY 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.
Artificial Intelligence (AI) Disclosure
No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.
- Received March 27, 2025.
- Revision received April 10, 2025.
- Accepted April 11, 2025.
- Copyright © 2025 The Author(s). Published by the International Institute of Anticancer Research.
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).
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