Systemic Inflammation Response Index Is a Predictor of Poor Survival in Locally Advanced Nasopharyngeal Carcinoma: A Propensity Score Matching Study

Introduction Nasopharyngeal carcinoma (NPC) is a common malignancy in China and known prognostic factors are limited. In this study, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune inflammation index (SII), and systemic inflammation response index (SIRI) were evaluated as prognostic factors in locally advanced NPC patients. Materials and Methods NPC patients who received curative radiation or chemoradiation between January 2012 and December 2015 at the Second Xiangya Hospital were retrospectively reviewed, and a total of 516 patients were shortlisted. After propensity score matching (PSM), 417 patients were eventually enrolled. Laboratory and clinical data were collected from the patients’ records. Receiver operating characteristic curve analysis was used to determine the optimal cut-off value. Survival curves were analyzed using the Kaplan-Meier method. The Cox proportional hazard model was used to identify prognostic variables. Results After PSM, all basic characteristics between patients in the high SIRI group and low SIRI group were balanced except for sex (p=0.001) and clinical stage (p=0.036). Univariate analysis showed that NLR (p=0.001), PLR (p=0.008), SII (p=0.001), and SIRI (p<0.001) were prognostic factors for progression-free survival (PFS) and overall survival (OS). However, further multivariate Cox regression analysis showed that only SIRI was an independent predictor of PFS and OS (hazard ratio (HR):2.83; 95% confidence interval (CI): 1.561-5.131; p=0.001, HR: 5.19; 95% CI: 2.588-10.406; p<0.001), respectively. Conclusion Our findings indicate that SIRI might be a promising predictive indicator of locally advanced NPC patients.


INTRODUCTION
Nasopharyngeal carcinoma (NPC) is a malignancy arising from the epithelium of the nasopharynx with a high incidence in endemic regions such as Southern China and Southeast Asia (1). More than 60% of patients are diagnosed at a locally advanced stage due to the lack of early symptoms and appropriate screening tools, and the prognosis remains poor (2). Induction chemotherapy combined with concurrent chemoradiation is the preferred treatment modality for locally advanced NPC (3). However, approximately 14% of patients relapse and 21% report metastasis (4). However, there is a persisting lack of prognostic biomarkers, and exploring prognostic factors is required for better patient stratification and treatment optimization.
There is increasing evidence that demonstrates inflammation to be one of the hallmarks of cancer, and it is closely related to cancer development (5). Activated inflammatory cells can promote cancer progression by inducing DNA damage or interfering with DNA repair systems (6). Recently, an increasing number of studies have demonstrated the value of inflammatory response biomarkers as predictive markers for prognosis in cancers. It has been shown that the neutrophil-tolymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune inflammation index (SII) can predict the prognosis in various types of cancers (7)(8)(9). The systemic inflammation response index (SIRI) is a new systemic inflammatory response biomarker based on peripheral blood cells counts, and it was demonstrated to be effective in predicting the prognosis of esophagogastric junction adenocarcinoma (10), esophageal cancer (11) and cervical cancer (12). There is minimal evidence of SIRI as a prognostic marker in NPC from a previous study (13).
In this study, we aimed to evaluate the prognostic value of NLR, PLR, SII, and SIRI in a retrospective cohort of 417 locally advanced NPC patients.

Patient Selection
A cohort of patients diagnosed with NPC at the Second Xiangya Hospital, Central South University, from January 2012 to December 2015 was retrospectively analyzed. The inclusion criteria were as follows: (1) diagnosis of pathologically proven poorly differentiated nasopharyngeal squamous cell carcinoma, (2) stage III-IVa according to the 8th edition of the American Joint Committee on Cancer (AJCC) Staging System for NPC, (3) receiving radiotherapy or chemoradiotherapy in the Department of Oncology, the Second Xiangya Hospital, Central South University, with complete follow-up data available. The exclusion criteria were as follows: (1) history of chronic inflammatory diseases such as inflammatory bowel disease, (2) history of autoimmune diseases, and (3) acute infectious diseases within 4 weeks. All patients were followed up after completion of treatment at a pre-defined frequency of once every 3 months in the first 2 years, once every 6 months from the third to the fifth year, and once yearly thereafter. The last follow-up date was April 1, 2020. Relapse or metastasis of the disease was diagnosed on contrast-enhanced magnetic resonance imaging or computed tomography.
A total of 516 patients with NPC were shortlisted. To reduce patient selection bias, we used the propensity score matching (PSM) technique (14). PSM was developed using age, sex, stage, treatment mode, chemotherapy agent dose, chemotherapy agent type, etc. After PSM, 417 patients were finally included in this study. This study was conducted according to the Helsinki Declaration of 1975, revised in 2008, and approved by the ethics committee of the Second Xiangya Hospital, Central South University. And the written consent was waivered.

Data Collection
Patients' clinical information, including that on age, sex, Eastern Cooperative Oncology Group performance status (ECOG PS) scores, T stage, N stage, clinical stage, treatment mode, chemotherapy agent dose, and chemotherapy agent type, was collected, and routine blood results within 1 week before therapy were also collected. The NLR, PLR, SII, and SIRI were calculated using the following formula: NLR = neutrophil count/lymphocyte count, PLR = platelet count/lymphocyte count, SII = platelet count × neutrophil count/lymphocyte count, SIRI = neutrophil count × monocyte count/lymphocyte count. Overall survival (OS) was calculated from the date of diagnosis to the date of death due to any cause or to the date of the last follow-up; progression-free survival (PFS) was calculated from the date of diagnosis to the date of disease progression or death.

Statistical Analysis
SPSS was used for data analysis (version 22.0; SPSS Inc., Chicago, IL, USA). Chi-square test was used to analyze the relationship between NLR, PLR, SII, SIRI, and clinicopathological features in locally advanced NPC patients. Receiver operating characteristic (ROC) curves were used to calculate the cut-off values for NLR, PLR, SII, and SIRI. When applying the ROC curves, the optimal cut-off value was defined as the value with the maximum Youden index (15). The Kaplan-Meier method was used to calculate the survival curves. Multivariate Cox hazard regression analysis was performed on the factors that were found to be significant in the univariate analysis. A two-sided p value of <0.05 was considered statistically significant.

Patient Characteristics
The clinicopathological features of the 417 locally advanced NPC patients are shown in Table 1

Association Between NLR, PLR, SII, SIRI, and Clinicopathological Features
The association between NLR, PLR, SII, SIRI, and clinicopathological features in locally advanced NPC patients is shown in Table 2

DISCUSSION
NPC is a malignancy with ethnic and geographical distribution preferences (16). Most patients have locally advanced disease with poor prognosis at time of diagnosis. Therefore, there is an urgent need to identify new prognostic factors for NPC patients. In the present study, we evaluated the prognostic value of inflammatory response biomarkers, NLR, PLR, SII, and SIRI in a retrospective cohort of 417 locally advanced NPC patients. The results showed that high NLR, PLR, SII, and SIRI contributed to significantly unfavorable PFS and OS. Furthermore, SIRI was an independent predictor of PFS and OS.
Recent studies have found that inflammation is one of the hallmarks of cancer and is involved in promoting cancer processes. Inflammation associated with cancer development is triggered by a variety of blood immune cells, including neutrophils, macrophages, dendritic cells, and T and B lymphocytes (17). Increasing evidence has shown that systemic immune response markers are promising prognostic biomarkers for various cancers. The combined indicators of neutrophils, lymphocytes, monocytes, and platelets, such as NLR (18,19), PLR (20), SII (21,22) and SIRI (23,24), have been reported to be predictive of cancer prognosis. SIRI is a new systemic inflammatory response biomarker based on neutrophil, monocyte, and lymphocyte counts. Neutrophils aid cancer cells to escape immune surveillance (25). Tumor-associated macrophages, which can promote cancer development and migration, are derived from peripheral monocytes (26). Lymphocytes are major mediators of host anti-cancer immunity. Reduction of peripheral lymphocytes impairs the host's anticancer immunity and accelerates the progression of   cancers. SIRI combines the above cell types and reflects the tumor microenvironment. The prognostic value of NLR, PLR, and SII has been reported in many types of cancers, including NPC. Pan et al. (27) conducted a retrospective study in stage II NPC patients and found that NLR was an independent prognostic biomarker in stage II NPC patients; NLR≥2.92 was associated with poorer 5-year OS (84.3% vs. 97.4%, p=0.001). Another study in NPC patients without distant metastasis reported that NLR≥ 2.28 and PLR≥174 were significantly associated with a shorter OS (p<0.05), and NLR≥2.28 was associated with a shorter PFS (p<0.05) (28). For NPC patients receiving intensitymodulated radiotherapy, Oei et al. (29) reported that SII was an independent prognostic factor for OS (p=0.003), PFS (p=0.002), and distant metastasis-free survival (p=0.002). Our results were consistent with the above findings, indicating that NLR, PLR, and SII may act as prognostic biomarkers for locally advanced NPC.
SIRI is a novel systemic inflammatory response biomarker that is valuable for predicting the prognosis of cancers. Qi Q et al. (30) conducted a cohort study of patients with advanced pancreatic carcinoma who received palliative chemotherapy, and found that SIRI≥1. 8     with SIRI >2.80 had a 2.89 times higher risk (95% CI: 1.86-4.42; p=0.0001), SIRI was an independent predictor of disease-specific survival (31). SIRI was also investigated in patients with NPC. In a cohort of 285 patients with NPC, ROC curves showed that the AUC obtained with SIRI was superior to the AUC of other parameters such as NLR or PLR, and SII (p <0.001) were significantly associated with PFS and OS (13). These results were consistent with the results of our study, indicating that SIRI acts as a superior prognostic factor for locally advanced NPC patients. The present study has some inherent limitations. First, it was a single-center retrospective study with a comparatively small sample size, and no validation group was used to confirm the results. Second, the inflammatory response biomarkers NLR, PLR, SII, and SIRI could be affected by various factors such as inflammation and infection, which may have biased the results. Third, the prognosis of patients may be affected by other factors, including EBV-DNA (32), LDH (33), CRP (34), and D-dimer (35). However, in the present study, due to incomplete data, these factors were not considered for evaluation, and this may have biased the results. Finally, the cut-off value for SIRI varied in prior studies, and the optimal cut-off value still needs further investigation. Thus, the results should be interpreted with caution.
In summary, the present study showed that SIRI was an independent predictor of PFS and OS in locally advanced NPC patients. It is a convenient and easy-to-use biomarker that may help in better patient stratification and treatment optimization. Early intervention for system inflammation may be a promising strategy to improve the prognosis of locally advanced NPC patients, warranting further investigation.

DATA AVAILABILITY STATEMENT
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

ETHICS STATEMENT
The studies involving human participants were reviewed and approved by the ethics committee of the Second Xiangya Hospital, Central South University. Written informed consent to participate in this study was waivered by the ethics committee.

AUTHOR CONTRIBUTIONS
TH developed the idea for the study, analyzed and interpreted the patient data, and revised the manuscript. YF collected the patient data and was a major contributor in writing the draft of manuscript. SW, WZ, YH, JAM, and PL collected and cured the data. XL and CH interpreted the data and supervised the research. All authors contributed to the article and approved the submitted version.

FUNDING
This research was supported by the Natural Science Foundation of Hunan Province (2020JJ5807).