Pretreatment Cachexia Index Is Associated With Severe Treatment Toxicity and Overall Survival in HPV ‐Negative Head and Neck Squamous Cell Carcinoma

ABSTRACT Introduction Cancer cachexia is characterized by skeletal muscle loss, poor nutrition, and systemic inflammation and is common in head and neck cancer. We evaluated whether the Cachexia Index (CXI) predicts treatment toxicity and survival in HPV‐negative HNSCC. Methods This study included 353 patients undergoing curative‐intent surgery at two McGill University hospitals (2015–2025). Pretreatment CXI was calculated using skeletal muscle index, serum albumin, and neutrophil‐to‐lymphocyte ratio. Multivariable logistic and Cox regression assessed associations with severe treatment toxicity (CTCAE grade ≥ 3), overall survival (OS), and disease‐free survival. Results The lowest CXI quintile was independently associated with severe treatment toxicity (OR 2.04, 95% CI 1.07–3.87). The two lowest CXI quintiles were associated with worse OS (HR 3.00 and 2.83), while each 100‐unit CXI increase reduced mortality risk by 8.9% (HR 0.91, 95% CI 0.86–0.97). Conclusions Low pretreatment CXI was independently associated with severe treatment toxicity and poorer overall survival. However, CXI was not independently associated with treatment intolerance or disease‐free survival after multivariable adjustment. These findings support further evaluation of CXI as a pretreatment risk stratification tool.