Developments in the treatment of locally advanced and metastatic squamous cell carcinoma of the skin: a rising unmet need

Abstract

Squamous cell carcinoma of the skin (SCCS) is a common malignancy with potentially devastating consequences in patients with locally advanced or metastatic disease. Its rising incidence, primarily a result of an aging population and increased ultraviolet (UV) radiation exposure, characterize an emerging unmet need. A firm understanding of the biology of this disease, likely distinct from that of other squamous malignancies because of the influence of UV radiation, is necessary in the evaluation of treatment paradigms. Careful recognition of high-risk features pertaining to tumor and host characteristics is paramount to proper management. However, a lack of standardization in guidelines in this regard creates a challenge for physicians. Questions persist regarding additional evaluation and treatment for advanced disease such as the roles for sentinel lymph node biopsy and the adjuvant use of radiation and chemotherapy. With respect to advanced disease, multiple combinations of chemotherapy have been tested with variable success, but no rigorous randomized studies have been conducted. In addition, EGFR inhibitors such as cetuximab and erlotinib have displayed antitumor activity and as such, warrant further investigation. In sum, the treatment of locally advanced and metastatic SCCS is a ripe area for clinical investigation. This article summarizes the current understanding of disease biology and emerging questions in the management of this disease.

Fig. 1

Disease biology of SCCS. The disease biology of SCCS has yet to be fully elucidated. Immunosuppression of the host is a strong risk factor for the development of SCCS, e.g., lymphoma, organ transplant. Ultraviolet (UV) radiation has an established role in the development of precancerous lesions, i.e., actinic keratosis (AK). TP53 mutation or inactivation whether de novo or induced by UVB may aid in malignant transformation. RAS mutations and CDK2NA mutations/inactivation may also play a role. HPV may play a role in the early stages of carcinogenesis, but its link to disease maintenance or progression has not been proven.