The loop between inflammation and late systemic toxicity in head and neck cancer survivors

Curative treatment for head and neck cancers (HNC) typically involves a multidisciplinary approach, combining surgery, chemotherapy, and radiotherapy. Although a curative outcome is achieved in approximately 50 % of cases, long-term survivors frequently experience significant treatment-related sequelae, which substantially diminish both quality of life and overall life expectancy. These toxicities commonly manifest in clusters and encompass both local and systemic symptoms, the latter including asthenia, fatigue, sleep disturbances, thermoregulatory dysfunction, pain, gastrointestinal and neurocognitive impairments, and mood disorders. Emerging evidence over the past decades has increasingly implicated systemic inflammation as a central driver of these late effects. In this review, we summarize current evidence on late systemic toxicity in HNC survivors and examine the intricate relationship between systemic inflammation and said toxicity. Importantly, we highlight the need to recognize these symptoms not as isolated entities, but as components of an inflammatory symptom cluster, thus necessitating a therapeutic approach that targets underlying inflammation.