Current status and future perspectives of treatment de-escalation in localized head and neck cancer

Head and neck squamous cell carcinoma (HNSCC) often requires invasive multimodal therapy, including surgery, radiotherapy, and chemotherapy. Although these interventions have improved treatment outcomes, patients frequently experience long-term functional impairment and treatment-related morbidity. Consequently, clinical research has shifted toward treatment de-escalation, a paradigm aimed at preserving quality of life while maintaining oncologic control. This review summarizes the current evidence from prospective clinical trials on de-escalation strategies for HNSCC of the oropharynx, hypopharynx, larynx, and oral cavity, with a focus on radiotherapy-based approaches. Investigators have evaluated several de-escalation strategies, including total radiation dose reduction in definitive chemoradiotherapy, modification or omission of concurrent systemic therapy, de-intensification of prophylactic nodal irradiation, response-adapted treatment de-intensification, and minimally invasive approaches such as transoral surgery with risk-adapted postoperative therapy. These strategies target favorable-risk populations, particularly patients with human papillomavirus-associated oropharyngeal cancer. Although numerous phase II studies have reported encouraging clinical outcomes and acceptable toxicity profiles, definitive evidence supporting the safety and efficacy of de-escalation strategies remains unestablished in large-scale phase III trials. Unwarranted de-escalation for HNSCC should be avoided, particularly for medically fit patients, and promising strategies require validation in phase III trials before routine clinical adoption. Future challenges include prospective validation through clinical trials and the integration of predictive biomarkers to balance the delicate trade-off between toxicity reduction and oncologic safety.