Association of Posttreatment Lymphopenia and Elevated Neutrophil-to-Lymphocyte Ratio With Poor Clinical Outcomes in Patients With Human Papillomavirus-Negative Oropharyngeal Cancers

Abstract

Importance: Better biomarkers are needed for human papillomavirus (HPV)-negative oropharyngeal cancer (OPC) to identify patients at risk of recurrence. Lymphopenia and an elevated ratio of neutrophils to lymphocytes (NLR) have been associated with poor disease outcomes in a number of solid tumors.

Objective: To test the hypothesis that postradiotherapy lymphopenia and elevated NLR are associated with poor clinical outcomes.

Design, setting, and participants: This single-institution retrospective analysis included patients with HPV-negative OPC treated from January 1, 1997, through January 4, 2017. Median follow-up was 37 months (range, 2-197 months). A total of 108 patients with HPV-negative OPC and at least 1 complete blood cell count 2 to 12 months after the start of radiotherapy were included. Data were analyzed from August 26 to September 7, 2017.

Interventions: Surgery followed by radiotherapy vs definitive radiotherapy, with or without chemotherapy.

Main outcomes and measures: Absolute lymphocyte (ALC) and absolute neutrophil (ANC) counts were tested as variables affecting locoregional control, recurrence-free survival, and overall survival.

Results: Of a total of 108 patients included in the analysis (87.0% male; mean age, 56 years [range, 35-84 years]), 57 received surgery followed by postoperative radiotherapy and 51 received definitive radiotherapy. During treatment, 67 of 79 patients (84.8%) had grades 3 to 4 lymphopenia and 17 of 79 (21.5%) had grade 4 lymphopenia. The ANC recovered by 6 months after radiotherapy, but ALC remained depressed to 1 year after radiotherapy. Posttreatment lymphopenia and elevated NLR were associated with worse recurrence-free and overall survival. The estimated 3-year LRC in patients with and without grades 3 to 4 lymphopenia at 3 months after radiotherapy start was 73% vs 82% (hazard ratio [HR], 0.58; 95% CI, 0.19-1.8); estimated 3-year recurrence-free survival, 36% vs 63% (HR, 0.45; 95% CI, 0.23-0.87); and estimated 3-year overall survival, 34% vs 64% (HR, 0.45; 95% CI, 0.23-0.88). In multivariable analysis, an association with worse overall survival was found for definitive radiotherapy (HR, 3.3; 95% CI, 1.6-7.1) and grades 3 to 4 lymphopenia (HR, 2.6; 95% CI, 1.3-5.5) at 3 months after radiotherapy.

Conclusions and relevance: Lymphopenia and NLR as early as 3 months after treatment start may serve as biomarkers of clinical outcomes in patients with HPV-negative OPC. These patients may benefit from adjuvant treatment intensification or closer surveillance.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Oppelt reported serving on the speaker bureau for Bristol Myers Squibb outside the submitted work. Dr Adkins reported grants from Eli Lilly, Pfizer, Novartis, Merck, Gliknik, Celgene, Enzychem, Celldex, and Medimmune outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Box and Whisker Plots of Outcomes

Box and whisker plots of absolute neutrophil count (ANC), absolute lymphocyte count (ALC), and ratio of neutrophils to lymphocytes (NLR) at pretreatment, the ALC nadir during treatment and 3, 6, and 12 months after radiotherapy (RT) start. Median is denoted by the line inside the box; interquartile range, box. The whiskers include 95% of a normally distributed range around the median. Open circles indicate outliers (to convert ALC and ANC to ×109 per liter, multiply by 0.001).

Figure 2.. Kaplan-Meier Curves for Outcomes by Absolute Lymphocyte Count (ALC)

Kaplan-Meier curves of locoregional control, recurrence-free survival, and overall survival for patients stratified by designated points for measurement of ALC after radiotherapy (RT) start. Grades 3 to 4 lymphopenia was used for the 3-month RT cutpoint. The median ALC was used for the 6- and 12-month RT cutpoints (to convert ALC to ×109 per liter, multiply by 0.001). HR indicates hazard ratio.

Figure 3.. Kaplan-Meier Curves for Outcomes by Ratio of Neutrophils to Lymphocytes (NLR)

Kaplan-Meier curves of locoregional control, recurrence-free survival, and overall survival for patients stratified by designated points for measurement of NLR after radiotherapy (RT) start. The median NLR was used for the 3- and 12-month RT cutpoints. HR indicates hazard ratio.