High-risk cutaneous squamous cell carcinoma: a review of current evidence and emerging standards

OBJECTIVE: High-risk cutaneous squamous cell carcinoma represents 3-5 per cent of all cutaneous squamous cell carcinomas but causes most disease-specific deaths. Head and neck tumours are often high risk. Recent phase-3 trials have challenged surgery plus or minus radiotherapy as standards of care. This review updates definitions and evidence on emerging treatments. METHODS: Narrative review. RESULTS: High-risk cutaneous squamous cell carcinoma is defined by size greater than 2 cm, deep invasion, poor differentiation, perineural/lymphovascular invasion, nodal spread or immunosuppression. Surgery remains central, with adjuvant radiotherapy improving locoregional control. The KEYNOTE-630 trial of adjuvant pembrolizumab showed a non-significant recurrence-free survival gain (hazard ratio 0.76), with benefit in elderly and extracapsular extension subgroups. The C-POST trial established adjuvant cemiplimab as the first systemic therapy significantly improving disease-free survival (hazard ratio 0.32; 24-month disease-free survival 87 per cent vs 64 per cent). Emerging strategies include neoadjuvant programmed cell-death protein 1 blockade, circulating tumour DNA-guided monitoring and combinations. CONCLUSIONS: Cemiplimab redefines the post-operative standard; pembrolizumab awaits confirmation. Future directions include earlier immunotherapy, biomarker validation and access expansion.