| Sumario: | Background & Significance: Inflammation is increasingly recognized as a key biological mechanism underlying cancer-related depressive symptoms, particularly in patients with head and neck cancer (HNC), who are especially vulnerable due to treatment intensity and functional impairments. Although prior studies have reported associations between inflammation and depression, much of the evidence remains fragmented, often relying on cross-sectional or short- term designs. Consequently, our understanding of how these relationships change during cancer treatment, including IMRT, is limited. The present study addresses this gap by employing repeated measures and multivariable modeling to evaluate the longitudinal associations between specific inflammatory markers and depressive symptom severity throughout the treatment. Purpose: This study examined the longitudinal association between inflammatory markers and depressive symptoms in head and neck cancer (HNC) patients undergoing intensity-modulated radiation therapy (IMRT). Methods: A secondary analysis was conducted using data from a longitudinal observational study of 148 HNC patients (mean age 59.3 ± 10.1 years; 72.3% male; 80.4% White). Data were collected at four time points: before IMRT, immediately after IMRT, 3 months post-IMRT, and 1-year post-IMRT. Depressive symptoms were assessed using the Patient Health Questionnaire-8 (PHQ-8). C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor-alpha (TNF- ), IL-1, IL-10, IL-1 receptor antagonist (IL-1ra), and soluble TNF receptor 2 (sTNFR2) were log10-transformed for analysis. Generalized estimating equations (GEE) were used to examine longitudinal associations between depressive symptoms and inflammatory markers, adjusting for demographic and clinical covariates. Findings and Interpretations: Depressive symptoms peaked immediately post-RT (mean PHQ-8 = 8.9) and declined over the following year. Increased CRP (Exp(B) = 1.38, p < .001), IL-1ra (Exp(B) = 1.70, p = .005), and TNFR2 (Exp(B) = 1.86, p = .046) were significantly associated with higher PHQ-8 scores. IL-6 and TNF- were not significant predictors. Protective factors included being married, non-smoking status, and better ECOG performance status. In addition, not having undergone surgery or chemotherapy was associated with higher depressive symptoms. Discussion: CRP, IL-1ra, and TNFR2 were significantly associated with greater depressive symptoms in HNC patients undergoing IMRT, highlighting the role of systemic inflammation in psychological distress. Symptoms peaked immediately post-RT and declined over time, indicating phase-specific vulnerability. These findings support inflammation-targeted screening and interventions and emphasize the need for integrated biological and psychosocial approaches to managing depression during cancer treatment.
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