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-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune inflammation index (SII) can predict the prognosis in various types of cancers (7–9). 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.

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 intensity-modulated 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 had a shorter time to progression (HR: 2.348; 95% CI: 1.559-3.535; p=0.003) and shorter OS (HR: 2.789; 95% CI: 1.897-4.121; p <0.001). In patients with head and neck squamous cell carcinomas, research showed that compared with SIRI<1.1, patients with SIRI between 1.10 and 2.80 had a 1.92 times higher risk of disease-specific death (95% CI: 1.33‐2.82; p=0.001), and patients 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.

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

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.

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.

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

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.