Background and Objectives: Alcohol misuse, depressive symptoms, maladaptive coping, and impaired health-related quality of life (HRQoL) are clinically relevant in head-and-neck cancer, but their interrelationships are not fully captured by clinical stage alone. This multicenter study examined these domains at first admission and explored whether data-driven psychosocial phenotypes could complement stage-based stratification. Materials and Methods: In this multicenter cross-sectional study conducted at participating ENT/oncology centers in Timișoara and Oradea, Romania, during May 2024–October 2026, 64 adults with head-and-neck cancer completed the Alcohol Use Disorders Identification Test (AUDIT), Patient Health Questionnaire-9 (PHQ-9), EuroQol five-dimension questionnaire (EQ-5D), and Coping Orientation to Problems Experienced (COPE). Patients were compared by stage (I–III vs. IV). We also examined correlations, modeled poor HRQoL (EQ-5D health sum ≤ 9), derived COPE factor scores, identified psychosocial profiles by unsupervised clustering, and explored an indirect-association framework linking AUDIT, PHQ-9, and EQ-5D problem severity. Results: Stage IV disease was associated with greater tumor burden but not with worse psychosocial scores. Overall, 18.8% met criteria for possible alcohol dependence (AUDIT ≥ 20), and PHQ-9 scores correlated with poorer EQ-5D health status (ρ = −0.275; p = 0.028). Three psychosocial profiles showed significant differences in alcohol-risk burden, depressive symptoms, and coping signatures. The exploratory indirect-effect analysis did not support a statistically significant PHQ-9-mediated association between AUDIT and EQ-5D problem severity (indirect effect 0.002; 95% CI −0.018 to 0.022). Conclusions: Alcohol-related risk and depression-associated HRQoL burden were common and were not meaningfully explained by stage alone. Exploratory phenotype-based stratification may help identify patients who could benefit from earlier supportive-care triage.
Hut et al. (Wed,) studied this question.