Optimizing the therapeutic ratio: a narrative review of de-escalation and response-adapted strategies in series including human papillomavirus negative head and neck cancer

Background and Objective: Head and neck cancer (HNC) treatments, primarily involving radiotherapy (RT) and chemoradiotherapy (CRT), often result in significant acute and late toxicities that profoundly impact patients' quality of life. Although there are data supporting treatment de-escalation for human papillomavirus (HPV)-positive HNC patients, there is growing interest in applying similar principles to HPV-negative disease in order to maintain oncologic efficacy while reducing treatment-related morbidity. This review aims to synthesize and critically appraise the current evidence regarding dose and/or volume de escalation strategies specifically implemented in the treatment of HPV-negative HNC. Methods: , 2025, using the following search criteria: (radiotherapy) AND ("head neck cancer" OR "head and neck cancer") AND (HPV-negative) AND ("de-escalation" OR "deescalation" OR "deintensification" OR "de-intensification" OR "reduced dose" OR "reduced volume"). All studies were screened for inclusion based on title and abstract, and the full texts were read and discussed by the research group in cases of uncertainty. Key Content and Findings: Six studies were included in this review. For HPV-negative head and neck squamous cell carcinoma (HNSCC), neoadjuvant nivolumab combined with chemotherapy enabled response-stratified de-escalated CRT, achieving favorable survival outcomes with reduced acute toxicities. In nasopharyngeal carcinoma (NPC), reduced intensity modulated radiotherapy (IMRT) target volumes following induction chemotherapy (IC) demonstrated non-inferior locoregional control (LRC) and significantly improved long-term quality of life, mitigating late toxicities such as xerostomia and hearing loss. Regarding elective nodal irradiation (ENI), studies confirmed that lower radiation doses maintained LRC while leading to clinically meaningful reductions in toxicity without increasing isolated regional recurrences (RRs). Conclusions: Dose and volume de-escalation appear feasible and beneficial in series that included HPV-negative HNSCC and NPC patients, maintaining oncologic efficacy while significantly reducing treatment-related toxicities. These findings expand the de-escalation paradigm beyond HPV-positive disease, offering a more tolerable therapeutic landscape.