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Acral and nail unit melanomas are rare subtypes of melanoma, which have poor prognoses. Current guidelines for optimal treatment are lacking. Recent clinical trials have evaluated new pharmacotherapeutic agents for melanoma treatment, with dramatically improved survival rates; however, studies on acral and nail unit melanomas are limited in comparison to trials on cutaneous melanoma. This is a comprehensive review of the literature regarding the available treatment options for acral and nail unit melanomas, with consideration of safety and tolerability. Programmed cell death protein 1 inhibitors are more efficacious than cytotoxic T lymphocyte-associated antigen-4 blockers in acral and nail unit melanomas, although both are well-tolerated. Tyrosine kinase inhibitors have good clinical activity, however, data on safety is relatively limited. There is minimal data on high dose interferon α-2b and cyclin-dependent kinase 4 and 6 inhibitors, and efficacy and safety must be evaluated in future trials before they can be recommended for use in this patient population. Prospective clinical trials on acral and nail unit melanomas are lacking, and must be performed in large patient populations, with international collaboration likely necessary in order to enroll adequate participants.

The pharmacotherapeutic management of nail unit and acral melanomas