TABLE 1.

Overview of adjuvant therapy options for treatment of high‐risk cSCC

Adjuvant therapy	Description	References
Radiation therapy	Radiation (often EBRT with 3D‐CRT or IMRT, orthovoltage or electron beam RT, or PBRT) to sites of high‐risk tumors following surgical excision with clear margins to reduce risk of recurrence and metastasis, or following incomplete surgical resection as salvage therapy, and/or as elective therapy to sentinel LN and regional LNs. Adjuvant RT (ART) may be used to treat positive LNs and/or patients with PNI or other high‐risk factors	7, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53
Chemotherapy	Systemic therapy via oral or intravenous routes using one or more anticancer drugs (e.g., cisplatin, carboplatin, oxaliplatin, 5‐FU, and vinca alkaloids) to kill or slow growth of any rapidly growing and dividing cancer cells that may remain after surgery and/or RT. Chemotherapy may be combined with ART (ACRT)	7, 43, 51, 83
Immunotherapy and targeted therapy	Systemic therapy via small molecules (e.g., mAbs, cytokines, or other proteins or chemicals) that target certain cells, parts of cells, or immune system mechanisms (e.g., receptors or ligands) to help stimulate or suppress the immune system to fight cancer. Immunotherapy and targeted therapy are usually delivered intravenously; however, some therapeutics targeting specific cancer cells may be given orally. Immune checkpoint inhibitors and EGFR inhibitors are commonly used. Immunotherapy and/or targeted therapy may be used in the adjuvant setting, and have predominantly been used within the context of clinical trials. Local immunotherapies (e.g., oncolytic viruses) are also under investigation, as are first‐line and neoadjuvant immunotherapies	7, 43, 45, 92, 93, 94, 95, 96, 97, 98
Clinical trials	Recent clinical phases I, II, or III trials have tested or are testing concurrent ART and chemotherapy (ACRT) versus ART in high‐risk cSCC, as well as systemic therapy using immune checkpoint inhibitors and/or EGFR inhibitors or other immune modulators in adjuvant and neoadjuvant settings	7, 43, 82, 85, 94, 95, 96, 97, 98, 104, 105, 113, 114, 115, 116, 117

Note: Adjuvant treatment options following current standard‐of‐care surgical treatment for high‐risk cSCC.

Abbreviations: ACRT, adjuvant chemotherapy plus adjuvant radiation therapy (adjuvant chemoradiotherapy); ART, adjuvant radiation therapy; cSCC, cutaneous squamous cell carcinoma; 3D‐CRT, three‐dimensional conformal radiotherapy; EBRT, external beam radiation therapy; EGFR, epidermal growth factor receptor; 5‐FU, 5‐fluorouracil (antimetabolite); IMRT, intensity‐modulated radiation therapy; LN, lymph node; LNs, lymph nodes; mAbs, monoclonal antibodies; PBRT, proton beam radiation therapy; PNI, perineural invasion; RT, radiation therapy.