Beyond Prognosis: Longitudinal Dynamics of the Neutrophil-to-lymphocyte Ratio Driven by Radiation-induced Lymphopenia During Radiotherapy for Head and Neck Cancer
Year: 2026
Type: article
Study design: Observational Study
Abstract: Introduction Head and neck squamous cell carcinoma (HNSCC) is commonly treated with intensity-modulated radiotherapy (IMRT). IMRT frequently induces treatment-related lymphopenia, potentially disrupting systemic immune homeostasis. The neutrophil-to-lymphocyte ratio (NLR), a widely used prognostic biomarker in oncology, may therefore reflect radiation-induced immune imbalance rather than systemic inflammation alone. However, the longitudinal behavior of neutrophils, lymphocytes, and NLR during IMRT remains poorly characterized. Objective To prospectively evaluate longitudinal shifts in neutrophil and lymphocyte dynamics via NLR during IMRT for HNSCC and explore their association with clinical outcomes. Methods A prospective observational study included patients with HNSCC treated with IMRT (≥50 Gy involving the oral cavity). Patients who did not complete radiotherapy failed to adhere to institutional oral supportive care, or discontinued treatment were excluded. Before IMRT, all patients underwent comprehensive dental management, including elimination of oral infectious foci, extraction of hopeless teeth, periodontal therapy, and oral hygiene instruction. During IMRT, patients underwent oral evaluations 3-times weekly and received preventive photobiomodulation therapy for oral mucositis (660-nm red laser, 100 mW, beam area 0.098 cm 2 , power density 1.02 W/cm 2 , 10.20 J/cm 2 , 10s/point). Peripheral blood samples were collected immediately before IMRT (T0), during the fourth treatment week (T1), and one week after treatment completion (T2). Longitudinal changes were analyzed using Friedman and paired Wilcoxon tests. Associations with overall survival were explored using Cox regression adjusted for age and tumor stage. The study was approved by the institutional Research Ethics Committee (CAAE: 65662422.9.0000.5440). Results Thirty patients were included (median age, 57-years [IQR, 53.3–65.3]); 83.3% were male, 76.7% had stage III/IV disease, and 60.0% received concurrent cisplatin-based chemoradiotherapy. After a median follow-up of 17.5-months, 40.0% died and 43.3% developed recurrence. NLR significantly increased during treatment (p<0.001), from median of 1.94 at T0 to 6.12 at T1 and remaining elevated at T2 (5.59). This increase was predominantly driven by a marked decline in lymphocyte counts (median 2.10, 0.60, and 0.65 × 10⁹/L at T0, T1, and T2, respectively; p<0.001), whereas neutrophil counts remained relatively stable (p=0.196). Neither NLR nor absolute neutrophil counts were independently associated with overall survival after adjustment for age and tumor stage. Discussion The marked and sustained elevation of NLR during and shortly after IMRT reflects an acute homeostatic imbalance between systemic innate response and adaptive immunity. Rather than isolated neutrophilia, this shift is predominantly propelled by treatment-related lymphocyte consumption ‒ a hallmark of radiation-induced lymphopenia. This proportional loss of lymphocytes over neutrophils impairs host immunosurveillance during active treatment. Although not powered to establish survival associations, these findings characterize the kinetic window of therapy-induced immune dysregulation. Conclusion These findings suggest that longitudinal NLR changes during IMRT are predominantly lymphopenia-driven and provide a rationale for future studies investigating radiation-induced immune alterations and their clinical implications.
Institutions: Universidade de São Paulo, Clinics Hospital of Ribeirão Preto
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7223087040