Perioperative Systemic Therapy for High-Risk Cutaneous Squamous Cell Carcinoma

The incidence of cutaneous squamous cell carcinoma (CSCC) is on the rise. While the majority of cases are curable with surgery alone, the burden of high-risk tumors that require additional therapies is increasing. While systemic therapy has long been used to treat locally advanced and metastatic CSCC, immunotherapy is a more recent advancement, and use of neoadjuvant and adjuvant systemic therapy in the perioperative setting is an area of ongoing study. While chemotherapy, epidermal growth factor inhibitors, and chemoradiation have all been studied in the perioperative setting, the response is highly variable, and side effects are common. Immunotherapy, in particular programmed cell death protein/ligand-1 inhibitors, have revolutionized treatment of advanced CSCC. Cemiplimab and pembrolizumab have been studied for neoadjuvant and adjuvant use, and atezolizumab for neoadjuvant use. Cemiplimab has shown the most promise, with a 64-75% major or complete pathologic response rate in the neoadjuvant setting, and significantly improved recurrence, metastasis, and disease-free survival rates over placebo in the adjuvant setting. While neoadjuvant and adjuvant immunotherapy has evolved as a promising treatment option for high-risk CSCC, several questions remain unanswered and are subject to ongoing research. This includes investigating optimal treatment regimens, duration, and timing; developing methods to better predict and identify responders; establishing long-term outcomes and safety data; and carrying out further studies in special populations such as organ transplant recipients.