Treatment de-escalation strategies in HPV-positive head and neck squamous cell carcinoma: a comprehensive review

Head and neck squamous cell carcinoma (HNSCC) represents a diverse group of malignancies arising from epithelial tissues in the oral cavity, pharynx, larynx, and paranasal sinuses. Recent decades have seen a shift in aetiology, with human papillomavirus (HPV)-associated HNSCC, particularly oropharyngeal squamous cell carcinoma (OPSCC), increasing in prevalence and now accounting for nearly 50% of cases in Europe. HPV-positive tumours exhibit distinct biological features, including younger patient age, a lower comorbidity burden, more frequent nodal involvement, and increased sensitivity to radiotherapy and cisplatin-based CRT, translating into superior clinical outcomes compared with HPV-negative counterparts. These favourable characteristics have prompted extensive investigation into treatment de-escalation strategies aimed at minimising toxicity while maintaining oncological efficacy. Approaches include reduced-intensity radiotherapy, modified cisplatin dosing, substitution with alternative systemic agents, incorporation of immunotherapy, and minimally invasive surgical techniques such as transoral robotic surgery with risk-adapted adjuvant therapy. Phase II and III trials have demonstrated promising results in selected patient populations, particularly regarding reduced radiotherapy doses and adjuvant therapy following surgery, while substitution of cisplatin with cetuximab or hypoxia-modifying agents has generally been less effective. Emerging evidence suggests that HPV-positive tumours may exhibit intrinsic cisplatin sensitivity, highlighting the potential for biomarker-guided therapy. Nevertheless, patient heterogeneity nucleotyde driven by smoking history or tumour hypoxia — necessitates careful risk stratification. Currently, treatment de-escalation remains investigational, and integration of molecular, imaging, and histopathological markers is essential to safely implement personalised therapy. Future research should focus on identifying predictive biomarkers and refining individualised strategies to balance efficacy and toxicity in HPV-driven HNSCC.