Weight loss during chemoradiotherapy remains a major clinical challenge in locally advanced head and neck squamous cell carcinoma (HNSCC), contributing to increased toxicity and poorer outcomes. Mechanical barriers to oral intake, systemic inflammatory activation, and individual genetic susceptibility could contribute to nutritional decline. Interleukin-1ß and interleukin-6 plays are key mediators of cancer-related inflammation and metabolic dysregulation, and functional genetic variants may modulate inflammatory responses and weight loss susceptibility.

To evaluate the associations of feeding route, systemic inflammatory changes, and IL1B rs16944 and IL6 rs1800795 genetic variants with percentage weight loss in patients with locally advanced HNSCC undergoing chemoradiotherapy.

A retrospective cohort of 46 patients (mean age 60 years, 32 men and 11 women, 35 smokers and 30 alcohol users) with locally advanced HNSCC (TNM stage III or IV) treated with chemoradiotherapy was analyzed. Percentage weight loss was calculated between treatment initiation and completion. The feeding route was categorized as oral intake versus tube feeding. Systemic inflammatory indices, neutrophile-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic immune-inflammation index (SII), and systemic inflammatory response index (SIRI) were calculated as log-transformed differences between post- and pre-treatment values. Data were collected from medical records. Genotyping of IL1B rs16944 (T>C) and IL6 rs1800795 (G>C) variants was performed using real-time PCR with TaqMan assays. Multivariable linear regression models were used to assess independent associations between clinical, inflammatory, and genetic variables and percentage weight loss. Variables with p< 0.05 were considered statistically significant.

Tube feeding was independently associated with reduced weight loss, with patients receiving tube feeding exhibiting approximately 6% less treatment-related weight loss compared to oral intake alone (p = 0.009). Significant associations were observed between inflammatory changes and weight loss, including PLR (ß = -582.8, p = 0.003), LMR (ß = -591.2, p = 0.002), SII (ß = 583.6, p = 0.002), and SIRI (ß = -588.5, p = 0.002), indicating that greater systemic inflammatory shifts during treatment correlated with increased weight loss. Carriers of the IL6 rs1800795 GC or CC genotypes experienced approximately 5% higher weight loss compared to the wild-type GG genotype (p = 0.02).

Treatment-related weight loss in locally advanced HNSCC could be influenced by clinical nutritional support, systemic inflammatory dynamics, and IL6 genetic variant. Tube feeding appears protective, while inflammatory escalation and the IL6 rs1800795 variant increase nutritional risk. These findings support integrated nutritional and biological risk stratification to personalize supportive care during chemoradiotherapy of HNSCC patients, although larger prospective studies are needed to confirm these associations.