Relation of baseline neutrophil-to-lymphocyte ratio to survival and toxicity in head and neck cancer patients treated with (chemo-) radiation

Medical records of HNSCC patients consecutively treated with primary or adjuvant curative-intent intensity-modulated radiation therapy with or without concomitant systemic therapy between January 2007 and December 2010 at the Department of Radiation Oncology, Inselspital, Bern University Hospital were retrospectively analyzed. Patients diagnosed with oral cavity (OCC), oropharynx (OC), hypopharynx (HC) and laryngeal cancers (LC) were included in the analysis. History of another malignancy within 5 years of diagnosis, prior radiation to the head and neck, non-squamous cell carcinoma histology, distant metastases, lack of differentiated CBC within 10 days before oncologic surgery or RT start, and early abortion of RT were defined as exclusion criteria. This study was approved by the local ethics committee (289/2014).

The standard treatment was based on institutional policies following the multidisciplinary tumor board decision as previously published [32, 33]. All cases were presented at the weekly institutional interdisciplinary head-and-neck tumor board. After completion of staging examinations and final TNM staging (AJCC), selection of treatment modalities and treatment sequencing were defined. The standard treatment in OCC was to perform surgery followed by adjuvant radiotherapy (RT) [30, 32], while in OC, HC and LC the joint recommendations of the multidisciplinary meeting was primary RT [31, 33]. Case-based decisions were made concerning the use of concomitant systemic therapy and up-front neck dissection. The delivery of radiotherapy, the definition of clinical target volume (CTV) and planned target volume (PTV) followed departmental guidelines [32, 33] based on international recommendations [34‐36]. All treatment plans were contoured and calculated using Eclipse treatment planning system (Varian Medical Systems, Palo Alto, CA). The standard concomitant therapy consisted of cisplatin 100 mg/m2 day 1 in three-week intervals for all patients. In few cases of induction chemotherapy, cisplatin, docetaxel, and 5-fluorouracil were used. Patients not deemed medically fit for cisplatin chemotherapy because of pre-existing co-morbidities were evaluated for weekly treatment with monoclonal antibody cetuximab [37] or carboplatin three weekly. Pre-treatment CBC with differential values was used to calculate NLR and PLR.

Potential causes of changes in the CBC (e.g. infection, steroid use) were identified, and patients were excluded from the analysis. Patients were regularly followed, and toxicities were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 (https://​evs.​nci.​nih.​gov/​ftp1/​CTCAE/​CTCAE_​4.​03/​CTCAE_​4.​03_​2010-06-14_​QuickReference_​5x7.​pdf).

NLR was calculated by dividing absolute neutrophil count by absolute lymphocyte count measured in peripheral blood. PLR was calculated by dividing absolute thrombocyte count by absolute lymphocyte count. Due to its non-normal distribution, NLR and PLR were log_e-transformed to obtain symmetric distributions and then analyzed as continuous variables. Frequencies and percentages are reported for categorical variables, medians with range or interquartile range for continuous variables. The primary endpoint of the study was overall survival (OS), and the secondary endpoints were locoregional relapse-free survival (LRFS) and distant recurrence-free survival (DRFS). Time-to-event was calculated for OS, LRFS, and DRFS from the start of RT to death (OS), locoregional relapse (LRFS), and distant recurrence (DRFS), respectively, with censoring of patients without such events at last follow up. Median times to event were estimated using the Kaplan Meier method. The prognostic value of NLR and PLR, and other variables (i.e. age, gender, smoking status, Karnofsky Performance Status (KPS), UICC stage, tumor grade, hemoglobin level) were assessed by univariable Cox regression analysis. Subsequently, multivariable analysis with forward elimination was planned with inclusion of all variables with a p-value < 0.05 in the univariable analysis. The association of NLR and PLR with acute and late toxicities (i.e. pain, dermatitis, mucositis, dysphagia, xerostomia) was examined using logistic regression. Analyses were carried out using SPSS version 23 (IBM Corp., Chicago, IL). The threshold for statistical significance was set at p < 0.05, and no correction for multiple testing was performed.

One hundred and eighty-six patients were included in the study. Patients’ and disease characteristics are presented in Table 1. The majority of patients were male and in good performance status (KPS ≥ 70). The primary tumor was located in the oral cavity or oropharynx in approximately 75% of the cases, and more than half of all patients had UICC stage IVA or IVB disease. Median NLR and PLR were 3.28 and 189, respectively. There was a statistically significant correlation between NLR and PLR (Spearman’s rho = 0.65, p < 0.001). Baseline NLR and PLR were not associated with gender, smoking status, site of the primary tumor, stage of disease or tumor grade.

At a median follow-up time of 40 months, 60 patients (32%) died; median OS was not reached. Higher NLR was associated with lower OS (Table 2). When dividing the population into two groups according to the median NLR, there was a significant OS difference between the groups (Fig. 1). For PLR there was a non-significant association between higher PLR and lower OS (Fig. 2). On univariable analysis log_e NLR was associated with OS. Also, older age, worse Karnofsky Performance Status (KPS ≤ 70), and UICC stage IV were associated with lower OS. Performance status, UICC stage IV and log_e NLR remained of prognostic value in multivariable analysis (Table 2).

Of the variables tested, only UICC stage IV was associated with increased loco-regional, distant, and any recurrence rate, whereas no association was found for all other variables tested (Table 3). Consequently, no multivariable analyses were conducted. In patients with high NLR, recurrences occurred earlier, but the correlation was not statistically significant (Fig. 3).

Rates and grades of the most common acute toxicities are summarized in Table 4. There was no correlation between baseline NLR or PLR and the grade of toxicity (data not shown).