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.

The effects of local irradiation on circulating lymphocytes in dogs receiving fractionated radiotherapy

“…Furthermore, findings from a subset of dogs with additional CBCs available beyond the pre‐treatment and mid‐treatment timepoints revealed significant and prolonged decreases in the ALC. These results are similar to those of other human studies and suggest a protracted effect of irradiation on lymphocyte counts …”

“…Other studies looking at changes in the NLR found that post‐treatment NLR was more indicative of a poor clinical outcome as opposed to the pre‐treatment NLR, often because of the decrease in ALC . While we did find an increased NLR based on mid‐treatment CBCs, assessment of clinical outcome was beyond the scope of this paper.…”

“…Definitive‐intent fractionation involves smaller doses per treatment, while hypofractionated radiation involves larger doses delivered over only a few treatments . Several studies in human medicine reported decreases in the absolute lymphocyte count (ALC) and increases in the neutrophil:lymphocyte ratio (NLR) in patients undergoing both definitive intent and hypofractionated courses of localized radiotherapy . The most common theory proposed for these changes relates to the irradiation of circulating lymphocytes and their subsequent apoptotic death over the course of radiotherapy.…”

“…The most common theory proposed for these changes relates to the irradiation of circulating lymphocytes and their subsequent apoptotic death over the course of radiotherapy. These changes can persist beyond the time a patient is irradiated and can persist for up to 12 months or longer after completion of a course of radiotherapy in humans . Also of note, NLR has been used as a biomarker for subclinical inflammation.…”

Peripheral blood cell count ratios are predictive biomarkers of clinical response and prognosis for non‐surgical esophageal squamous cell carcinoma patients treated with radiotherapy

“…The NLR represents the balance between inflammatory and immune responses in peripheral blood. Previous studies have shown that a high pretreatment NLR is associated with a poor outcome in many solid tumors, 23‐25 while a low post‐treatment NLR can indicate a favorable prognosis 26 . Radiotherapy can kill tumor cells directly or indirectly and stimulate inflammatory responses at the same time.…”