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Prognostic role of baseline neutrophil ‐ to ‐ lymphocyte ratio in metastatic solid tumors

High baseline neutrophil‐to‐lymphocyte ratio (NLR) has been associated with poor survival in a number of solid tumors, but has not been extensively investigated in the context of radiation oncology. Developing more robust models to predict survival would inform patient care for patients with metastatic solid tumors. The present study was undertaken to evaluate the effect of baseline NLR (using 4 as a cutoff) on survival in 320 consecutive patients with metastatic cancer who were referred to a single radiation oncologist between 2012 and 2015, with a median follow‐up of 20.6 months. The median NLR was 4.4 (interquartile range, 2.8‐7.2). Patients with a baseline NLR ≤4 had a median survival of 9.3 months compared to 4.1 months for NLR >4 (P<0.001). The number of active tumors, Eastern Cooperative Oncology Group perfor‐ mance status score, baseline albumin, primary tumor site, liver metastases and baseline NLR predicted overall survival on both univariate and multivariate analysis (P<0.05 for all). After adjusting for known prognostic factors for advanced solid tumors, baseline NLR >4 independently predicted adverse survival in this cohort.


Introduction
Tumor-promoting inflammation by innate immune cells fosters multiple hallmarks of cancer (1). The neutrophil-to-lymphocyte ratio (NLR) is a widely utilized marker of host inflammation (2). High baseline NLR (>4) has been demonstrated to have prognostic significance for overall survival in solid tumors, with a hazard ratio of 1.8 (3). Our group has previously validated the NEAT model, including the number of active tumors ('N'), Eastern Cooperative Oncology Group (ECOG) performance status ('E'), albumin ('A'), and primary tumor site ('T') as important prognostic factors for patients with metastatic cancer referred to radiation oncology (4,5). Other validated models identified age, extent of prior chemotherapy, recent hospitalization, liver metastases and bone-only metastases as prognostic factors for radiation oncology patients with metastatic cancer (6,7). However, despite extensive research, these validated models only accounted for 30-50% of observed survival (5).
The prognostic role of baseline NLR has been demonstrated in 100 studies for several types of solid tumors (3). To date, limited data has been provided for NLR in patients treated with radiation, particularly in those with metastatic solid tumors (8,9). Previous studies have demonstrated that patients with metastatic disease treated with radiation tend to have a baseline NLR of 4-5 (8,9). By contrast, the baseline NLR for the general population is 1.65-2.15 (10,11). Since NLR is a widely available and cost-effective measure of systemic inflammation, the current study hypothesized that elevated NLR may add further prognostic value, thereby improving predictive accuracy.

Materials and methods
Inclusion criteria. The present retrospective study included 320 consecutive patients (age range, 23-97 years), with metastatic stage IV solid tumor who were referred to a single physician in a large community hospital-based radiation Οncology Department between May 2012 and October 2015. This minimal risk study was approved by the Good Samaritan Hospital Medical Center Institutional Review Board. Statistical analysis. Statistical analysis was performed with Stata 13.1 (StataCorp LP). The primary outcome was overall survival, defined as the time from the initial radiation oncology consultation to the date of death from any cause. Patients were included regardless of treatment received, and patients who were lost to follow-up were censored at the date of the last follow-up. Survival data were analyzed using the Kaplan-Meier method and summarized by median and 6-month survival. Differences in survival were assessed through the log-rank method. The association of individual variables with survival was assessed using the Cox proportional hazards model that was verified by tests of correlations over time with examination of residual plots. The Pearson χ 2 test was performed to determine whether there were baseline differences in variables that were associated with high or low NLR. Statistical tests were two-sided, and P<0.05 was considered to indicate a statistically significant difference.
Patient characteristics. The study population included 320 patients with distant metastases who were referred for radiation oncology evaluation, with 55% inpatient and 45% outpatient consultations. The median age was 68 years (interquartile range, 60-78 years), the median NLR was 4.4 (interquartile range, 2.8-7.2) and the median albumin was 3.4 g/dl (interquartile range, 2.8-3.8 g/dl). In terms of performance status, 39% of the patients were ECOG 0-1, 29% were Radiation therapy and systemic therapy. Among the 320 patients evaluated, 81% were treated with radiation therapy. Treatment was personalized to account for disease site and clinical status and goals of treatment. To summarize, the majority of the patients were treated with standard palliative regimens, most commonly 30 Gy in 10 fractions. Patients with a poor prognosis were either not treated or treated with short-course radiation (8-20 Gy in 1-5 fractions). Patients with limited brain metastatic disease (typically 1 to 4 brain metastases) were often treated with fractionated stereotactic radiotherapy (27 Gy in 3 fractions) or single-fraction stereotactic radiosurgery (21-24 Gy in 1 fraction). Patients with good performance status and oligometastatic disease (defined as ≤5 metastases) were treated with curative intent dose-intensive treatment regimens (12,13). Systemic therapy was administered at the discretion of the treating medical oncologist and, depending on the diagnosis, consisted of chemotherapy, hormonal therapy, biologically targeted therapy, immunotherapy and/or supportive care.

Results
Predictors of survival on univariate analysis. The median survival for all patients was 6.7 months, with a median follow-up for surviving patients of 20.6 months. On univariate analysis, baseline NLR, number of tumors, ECOG performance status, serum albumin, primary tumor site, prior hospitalization within the last 3 months, liver metastases, bone-only and liver metastases, were found to be significant predictors of survival (Table I). The median survival for patients with an NLR of ≤4 was 9.3 months vs. 4.1 months for those with an NLR of >4 (Fig. 1). Age and number of prior palliative chemotherapy cycles were not found to be statistically significant in predicting survival.

Discussion
The present study demonstrated that baseline NLR is an independent predictor of survival in patients with metastatic cancer, even when accounting for potential confounding    (5). In terms of a predictive model, adding NLR did not significantly improve the performance of the NEAT model, having little effect on the C-index or modified r2 coefficient of determination (unpublished data). The mechanism underlying the association of high baseline NLR with poor survival remains elusive. The impact of host antitumor immunity on patient clinical outcome with advanced solid tumors is of great interest to practicing oncologists. Tumors accompanied by significant systemic inflammation behave more aggressively, which likely reflects the contribution of the microenvironment to disease progression (14). Neutrophils are not only antagonists of microbial infection and facilitators of wound healing, but also promoters of cancer initiation, progression and metastasis (15). In tumors, neutrophils suppress T cell function, leading to tumor progression (16). Tumor-infiltrating lymphocytes, particularly those with Th1 polarization, are associated with improved prognosis (17).
Although neutrophils and lymphocytes are non-specific parameters that are affected by concurrent infection, inflammation, corticosteroids, chemotherapy and radiation therapy, baseline NLR is a promising, readily available and cost-effective biomarker that adds prognostic value to known clinical and laboratory prognostic factors (3,8,18). In the present study, patients with an NLR >4 with metastatic disease that were referred to radiation oncology had a median survival of 4.1 months. Further investigation of NLR in specific subsets of patients, including those with specific tumor types, oligometastatic and widespread metastatic disease treated with radiation therapy, is warranted.