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Evaluation of Optimal Threshold of Neutrophil-Lymphocyte Ratio and Its Association With Survival Outcomes Among Patients With Head and Neck Cancer

This cohort study investigates the optimal neutrophil-lymphocyte ratio (NLR) threshold as a potential prognostic biomarker for survival outcomes among US patients with head and neck cancer.


Introduction
Inflammation plays a major role in cancer progression. 1 Emerging biomarkers of systematic inflammation, such as elevated neutrophil-lymphocyte ratio (NLR), have been shown to be prognostic in many solid tumors. 2 Tumor cells were shown to release cytokines to stimulate the bone marrow to increase the number of neutrophils, [3][4][5] which in turn release cytokines promoting angiogenesis and metastasis. [6][7][8][9][10][11] Among patients with head and neck cancers, elevated NLR is an adverse prognostic marker for survival outcomes in multiple meta-analyses. [12][13][14][15][16][17] However, studies included in such meta-analyses were heterogeneous in patient demographics and treatment characteristics suggesting the mixed strength of association between NLR and survival outcomes. 17 For example, NLR has been shown to change after induction chemotherapy and head and neck surgery, 18,19 and NLR values may differ based on racial and ethnic backgrounds. 20 In addition, the clinical utility of NLR may be challenging, because its optimal threshold remains unclear based on prior studies using its median values or predefined thresholds to stratify high vs low NLR. 17 Furthermore, the majority of these studies were performed outside the United States. 17 Given geographic heterogeneity in the prevalence of human papillomavirus (HPV) 21 and that of other risk factors including smoking and alcohol intake, 22,23 NLR values may vary based on such lifestyle factors 24 and findings from such studies may not be generalizable to patients in the United States. 20,24 To address this knowledge gap and inform clinicians to identify such potentially high-risk patients, we performed a single-institution, observational cohort study of patients treated with chemoradiation in the United States to evaluate the association of NLR and survival outcomes.

Methods
This cohort study was approved by the Roswell Park Comprehensive Cancer Center institutional review board, and informed consent was waived because the research met the criteria for minimal risk to the study participants. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
Our retrospective database was built including all patients with primary head and neck cancer who underwent radiation therapy at the Roswell Park Comprehensive Cancer Center between January 2005 and April 2021. Patients were included for analysis if they were diagnosed with nonmetastatic head and neck cancer treated with curative-intent definitive chemoradiation receiving 70 Gy to gross disease and 56 Gy to elective neck lymph nodes. Intensity modulated radiation therapy (IMRT) was performed for all patients in this cohort as previously described. 25 NLR was obtained from routine complete blood counts (CBC) with differentiation, and patients with unknown NLR were excluded.
In addition to NLR prior to radiation therapy, other variables of interest included age, selfreported gender, self-reported race, smoking history, Karnofsky Performance Status (KPS), number of comorbidities, primary cancer site, cancer staging based on the American Joint Committee on Cancer (AJCC) 7th edition, HPV status, and chemotherapy agent. These variables were included for all of our multivariable analysis (MVA) models. All missing values were coded as unknown for analysis.
Among patients who self-reported other racial and ethnic backgrounds, they included African American, American Indian or Alaska Native, Asian, Hispanic, and those who were unknown or declined to answer. These racial and ethnic categories were combined as a single group prior to performing our analyses, because it would be difficult to show meaningful differences in outcomes owing to small subgroup sample sizes. The primary end point of this study was overall survival (OS) and cancer-specific survival (CSS), defined as the time intervals from diagnosis to any death or last follow up and head and neck cancer-related death or last follow up, respectively.

Statistical Analysis
A threshold for NLR was determined using an outcome-based method by maximizing the log-rank test statistic and the survival differences, 26 as previously shown in other disease sites. 27

Discussion
To our knowledge, this is the largest study of US head and neck cancer patients who underwent definitive chemoradiation to evaluate the association between NLR and survival outcomes. Elevated NLR was an independent, adverse prognostic factor for both OS and CSS. Furthermore, it was associated with performance status and tumor staging.
The association of high NLR with worse survival in our study was consistent with a growing body of literature. 17      Among patients with available HPV data, our study found that high NLR was not associated with survival. This finding is consistent with a prior report. 50 In contrast, other studies found that high NLR was an adverse prognostic factor for survival outcomes even in the HPV era. 18,[51][52][53][54] In addition, another study suggested HPV-associated head and neck cancers were also less likely to have high NLR, 53 which was not observed in our study. These discrepancies may be due to the heterogeneous nature of tumor biology among HPV-associated head and neck cancers based on smoking history. 30 Nearly 80% of patients in our study were either former or current smokers, and smoking has been shown to alter tumor gene expressions and tumor microenvironment, leading to changes in inflammation and immune-related pathways. 55,56

Limitations
This study has limitations, including those inherent in retrospective reviews. The neutrophils from our study were not isolated for further characterization of their phenotypes, and the heterogeneity of protumorigenic and antitumorigenic neutrophil phenotypes could not be evaluated in our study.
Although several studies showed a prognostic role of dynamic changes in NLR in various cancers, 57-60 our data on NLR after radiation therapy were missing in many patients and were not included for analysis in this study. In addition, the association between low NLR and survival would warrant further investigations, because febrile neutropenia may occur up to 15% with concurrent cisplatin. 61 Toxicity profiles including infection and febrile neutropenia were unavailable for analysis in our study. Furthermore, most patients in our study were White individuals treated with chemoradiation. Our findings may not be generalizable to other populations with different treatment modalities and racial backgrounds. [18][19][20]24

Conclusions
Our study's findings suggested that high NLR was an independent adverse prognostic factor for survival outcomes among patients with head and neck cancer undergoing chemoradiation. Patients with substantial disease burden and poor performance status were more likely to have high NLR.
Further studies would be warranted to tailor treatments based on the risk stratification by NLR.

ARTICLE INFORMATION
Accepted for Publication: February 17, 2022.