Post-Radiation Immunosuppression is Associated with Poor Clinical Outcomes in HPV-negative Oropharyngeal Cancers

Abstract

An elevated neutrophil to lymphocyte ratio (NLR) in the peripheral blood has been associated with poor disease outcomes in a number of solid tumors sites. However, the prognostic value of NLR in human papilloma virus (HPV)-negative oropharyngeal cancers (OPCs) remains controversial. We hypothesized that post-radiation lymphopenia and NLR would be associated with patient outcomes. HPV-negative oropharyngeal cancer patients treated with radiation therapy at an academic center from 1997-2013 were queried from a prospectively maintained database. Absolute lymphocyte counts (ALC) and absolute neutrophil counts (ANC) were evaluated before treatment, at the lymphocyte count nadir during treatment, 3 months, 6 months, and 12 months after radiation (RT) start. Logistic regression was used to determine clinical and treatment-related predictors of lymphopenia. Kaplan-Meier and Cox analyses were done for loco-regional control (LRC), progression free survival (PFS), and overall survival (OS). We identified 108 patients with HPV-negative oropharyngeal cancers, of whom 57 received surgery followed by post-operative radiation (PORT) and 51 received definitive RT. Median radiation dose was 70Gy for definitive RT and 66Gy for PORT. Median follow up was 37 months (range 2-197). During treatment, 85% of patients developed grade ≥ 3 lymphopenia and 22% with grade 4 lymphopenia, with no difference in lymphopenia rates between patients receiving PORT and those receiving definitive RT. Stage T3-4 tumor vs. T1-2 (OR = 5.3, 95% CI 1.4-20, p = 0.015) was the only clinical factor associated with developing grade 4 lymphopenia. Chemotherapy and surgery did not significantly associate with grade ≥ 3 lymphopenia at any timepoint. Pre-treatment and treatment nadir blood counts were not associated with OS. Three months after RT start, 19 (29%) out of 65 patients with blood counts had grade ≥ 3 lymphopenia. The estimated 3-year LRC, PFS, and OS in patients with and without grade ≥ 3 lymphopenia at 3 months after RT was 73% vs. 82% (p = 0.334), 36% vs. 63% (p = 0.014), and 34% vs. 64% (p = 0.016), respectively. In multivariable analysis, definitive radiation (HR = 3.2, 95% CI 1.5-6.7) and grade ≥ 3 lymphopenia (HR =2.5, 95% CI 1.3-5.0) at 3 months after RT were associated with worse OS. Lymphopenia and NLR as early as 3 months post-radiation associate with poor clinical outcomes in HPV-negative oropharyngeal cancer patients. Validation in a prospective clinical trial is warranted.