Pretreatment neutrophil to lymphocyte ratio in determining the prognosis of head and neck cancer: a meta-analysis

Head and neck cancer (HNC) is currently the fifth most common malignancy worldwide, with > 600,000 new cases and > 300,000 deaths annually [1, 2]. Despite effective surgical interventions and adjuvant therapy, the 5-year HNC survival rate of nearly 50% is still lower than that of most other cancers [3]. HNC originates in the mucosal epithelium of the oropharynx, nasopharynx, nasal and paranasal sinuses, larynx and hypopharynx. Many patients are diagnosed with HNC at an advanced stage. Data from the United States show that more than two-thirds of HNC patients present with lymph node invasion or distant metastasis at the time of diagnosis. More than half the patients need more surgery or radiotherapy because of recurrence within 2 years of initial surgery [4]. Therefore, simple, effective and economically feasible laboratory indices that can predict increased risk of recurrence, metastasis or death in HNC patients are essential for early diagnosis and improved survival in clinical practice.

Awareness of the presence of inflammation in the tumor microenvironment has spurred research on the relationship between inflammation and malignancy [5‐10]. The progression of cancer requires interactions between tumor cells and their microenvironment, including inflammatory, immune and metabolic responses to stimuli from the surrounding tissue. The systemic inflammatory response plays a key role in tumor cell invasion by promoting microvascular regeneration, tumor metastasis, and tumor cell proliferation [8, 9, 11]. Moreover, the systemic inflammatory response facilitates the differentiation of tumor cells and suppresses activity of host immune cells [6, 12‐14]. Neutrophil-to-lymphocyte ratio (NLR) is an accurate and reliable index of systemic inflammation. NLR is closely associated with prognosis of solid tumors, such as colorectal, non-small cell lung, stomach and prostate cancer [15‐19]. However, the association of NLR and prognosis of HNC remains controversial. For that reason, we conducted this meta-analysis of the prognostic value of NLR in HNC.

This study was the first to evaluate the association of NLR in peripheral blood and prognosis in HNC patients. We found that patients with elevated pretreatment NLRs had predictable decreases in OS, DSS and PFS. Also, with increasing NLR cutoff value, mortality risk had a corresponding increasing trend, and patients were increasingly prone to local recurrence and distant metastasis. Our meta-analysis was consistent with previous studies of other malignant tumors. Other meta-analyses revealed better prognosis in patients with colorectal, non-small cell lung, stomach and prostate cancer who had low pretreatment NLR compared to those who had high NLR [15‐19]. Pretreatment NLR reflects the status of systemic inflammation and the immune system. However, the cause of poor prognosis in HNC patients with elevated NLR requires further investigation.

Elevation of neutrophils reflects systemic as well as local inflammatory responses. Neutrophils provide a microenvironment conducive to the growth of tumor cells, and they promote tumor progression and invasion of malignant tumor cells [43]. Neutrophils produce and secrete tumor-promoting growth factors, such as epidermal growth factor, vascular endothelial growth factor, interleukin (IL)-6 and IL-8, that can promote tumor cell activation and facilitate tumor development, invasion and metastasis [8, 9]. In addition to producing cytokines, neutrophils secrete proteases, such as specific matrix metalloproteinases [44, 45], cysteine cathepsins [46, 47] and serine proteases [48]. These proteases can disrupt the connections between cells and degrade extracellular matrix and basement membrane proteins, thereby facilitating the migration of tumor cells [46‐49]. They also promote epithelial cell proliferation, activate dormant tumor cells, and trigger revascularization [50], forming a link between inflammation and cancer. An increase in the number of neutrophils surrounding cancerous tissue can suppress antitumor immune responses while activating T lymphocytes and natural killer (NK) cells [51]. Thus, elevation of neutrophils and release of associated cytokines play a role in tumor metastasis and indicate poor prognosis in patients with malignant tumors.

In contrast, a reduction in the number of lymphocytes reflects decreased activity of lymphokine-activated killer cells [52], with inhibition of the monitoring of the host immune response [53]. The reduction of lymphocytes includes cells of the innate immune system, such as B lymphocytes, NK cells, CD4⁺ helper T lymphocytes and CD8⁺ cytotoxic T lymphocytes, leading to suppression of the immune response [7, 54]. Additionally, reduction of the number of lymphocytes results in decreased release of cytokines, such as interferon and tumor necrosis factor-α by tumor macrophages. These cytokines promote apoptosis of tumor cells, which is a key host defense against tumor cell invasion. The collective effect of these changes is attenuation of the antitumor-specific immune system [55, 56]. There is also a link between the immune system and systemic inflammation. Wong et al. [25] proposed that chronic inflammation is associated with increased myeloid-derived suppressor cells (MDSCs), which suppress the immune response. They also found that MDSC-mediated immune suppression resulted in dysfunction of the acquired (T cells) and innate (NK cells) immune systems; both of which play a major role in scavenging pathogens and mutant cells under normal conditions.

This study demonstrated that pretreatment NLR can be used to evaluate prognosis in HNC patients, but the optimum NLR cutoff value remains unclear. In the studies we analyzed, the NLR cutoff values ranged from 2.1 to 4.39 and were selected from the means of all patients in each study, or on the basis of previous research. Different studies used different cutoff values, making it difficult to perform the meta-analysis using a single, defined cutoff value. In order to obtain the optimal range of cutoff values, we divided the range into three equal groups for subgroup analysis using NLR cutoff values of 3.0 and 4.0, and a performed a meta-analysis of each subgroup. It is noteworthy that the increase in NLR resulted in similar mortality risks in subgroups 1 and 2, whereas the risk was significantly greater in subgroup 3 than in the other two subgroups. We infer that the prognostic value of NLR in HNC patients is influenced by a range of cutoff values. Optimally, we recommend using a continuous range of NLR values, rather than point values when selecting and comparing NLR cutoff values in future studies.

This meta-analysis had several limitations. First, all included studies were retrospective observational studies, and although multivariate analysis can control for confounding factors to a certain degree, selection bias was inevitable. Second, the NLR values could easily have been affected by infectious diseases, chronic infections, and use of glucocorticoid hormones that might have been present in the same period. Inflammation and NLR elevation are also believed to be associated with coronary heart diseases including acute coronary syndrome [57]. Interference of the NLR values by potential confounding factors associated with other diseases was thus inevitable. Third, NLR is closely associated with other variables associated with systemic inflammation, such as C-reactive protein and platelet-to-lymphocyte ratio. Interactions among these factors might have resulted in high collinearity in multivariate analysis by the Cox regression model, thereby influencing the evaluation of prognosis by NLR alone. Finally, there was a risk of reporting bias related to the method of retrieving full-text studies. Some studies did not report clinically significant results, and thus did not contribute to the calculated HR values, and some studies only included positive results in the data analysis.

This meta-analysis showed that HNC patients with elevated pretreatment NLR had poor prognosis and were prone to local invasion and distant metastasis. NLR, which is easily obtained from peripheral blood samples, can help clinicians to determine the prognosis of HNC patients. Preoperative and postoperative interventions to regulate inflammatory and immune responses have a place in the long-term treatment of HNC, but future studies are required to validate the clinical use of NLR.