Cutaneous squamous cell carcinoma (cSCC) is one of the most frequently diagnosed non-melanoma skin cancers, with a rising global incidence. Early-stage and low-risk cSCC are typically managed through surgery and, in some cases, localized therapeutic modalities. However, locally advanced or metastatic cSCC presents significant morbidity and mortality, necessitating a different therapeutic approach.1 Therapeutic recommendations are based on the extent of the disease and primarily consist of surgical resection, possible lymph node dissection, and consideration of adjuvant radiation therapy with or without concurrent systemic therapy.2
Before modern therapies, cytotoxic chemotherapy and platinum-based agents were the mainstays of treatment for advanced cSCC. These agents included cisplatin, bleomycin, interferon, 5-fluorouracil, and doxorubicin, with varied response rates and significant side effects such as nausea, emesis, and hematological toxicities. Combination with other modalities often confounded long-term efficacy data.1 The current guidelines recommend radiotherapy (RT) if surgery is not feasible, and multidisciplinary teams can consider concurrent systemic therapy in select cases (Table 1).2
Epidermal growth factor receptor (EGFR) Inhibitors
EGFR-targeted therapies are generally more tolerable than cytotoxic agents but come with side effects such as cutaneous adverse events and diarrhea. Resistance to EGFR inhibitors is a known issue, with combination therapies being explored to combat this.1
Cemiplimab
Pembrolizumab
Given the published trial data supporting the efficacy and safety of these agents, the current guidelines recommend their use if curative surgery and curative RT are not feasible (Table 2).2 See the immunotherapy in cSCC section of the portal for additional details about approved and emerging treatments as well as advancements in neoadjuvant and intralesional approaches.
Advanced cSCC requires a comprehensive, multidisciplinary approach for effective management. While traditional cytotoxic chemotherapy played a significant role in the past, modern therapies, including targeted therapies and systemic immunotherapies, have shown promise in improving outcomes and quality of life for patients with advanced cSCC. Ongoing research and clinical trials continue to refine these therapeutic strategies, offering hope for better management of this challenging condition.2 As such, clinicians must remain current on the latest evidence-based guideline recommendations and how to apply them to patient preferences for treatment.
