Current challenges in standardising classification and management of locally advanced cutaneous squamous cell carcinoma

PD-1 inhibition is the standard of care for advanced cutaneous squamous cell carcinoma (CSCC) achieving clinically meaningful and durable responses. According to current guidelines, its use is restricted to disease that is considered unsuitable for curative intent with surgery or radiotherapy. Neoadjuvant concepts have demonstrated major pathologic response rates between 50% and 70% after only 2-4 cycles with high event-free and disease-free survival rates. Decisions between neoadjuvant approaches, surgery with adjuvant therapy, definite radiotherapy or cemiplimab are made within a multidisciplinary team and are further influenced by regulatory approvals by FDA and EMA. Comparative data on definitive radiotherapy and PD-1 inhibition is missing and resectability currently guides the choice between neoadjuvant and definite approaches. However, the rationale for surgery can change with treatment response, allowing for response-adapted de-escalation and, in some cases, omission of surgery. In trials of neoadjuvant immune checkpoint inhibitors for resectable CSCC, patient withdrawal has increased because of deep clinical responses. Given the clinical heterogeneity of CSCC, lack of a treatment focused staging system, and variability in management, harmonisation of treatment algorithm remains challenging. Evidence on when to pursue neoadjuvant approaches to improve patient selection as well as tailoring treatment plans based on outcomes are needed. Here, we discuss current challenges of standardising management and potential for the implementation of response-adapted treatment strategies in CSCC.