Multikinase inhibitors (MKIs) represent a diverse array of targeted chemotherapies (Table 33.1) that are used in the treatment of both solid and hematologic malignancies. MKIs target surface receptor tyrosine kinases and intracellular protein kinases in signaling pathways. They bind the adenosine triphosphate (ATP)-pocket of the enzyme, either reversibly or irreversibly, and prevent kinase activity. MKIs have a large range of selectivity, which usually includes inhibition of angiogenesis by targeting vascular endothelial growth factor receptor (VEGFR).¹

While MKIs can cause a specific set of toxicities (Table 33.2), hand-foot skin reaction (HFSR) represents the prototypical dermatologic adverse effect associated with these agents, is common, can be debilitating and is often dose limiting. Other dermatologic adverse events (dAEs) associated with MKIs include inflamed keratoses, keratosis pilaris-like eruptions (Figure 33.1), facial erythema or a seborrheic dermatitis-like eruption, atypical squamous proliferations (including keratoacanthomas [KAs] and squamous cell carcinomas [SCCs]), hair thinning and texture or color change (including depigmentation), subungual splinter hemorrhages of the nails (25%-70% of patients depending on agent), and follicular cyst-like lesions. Inhibition of VEGF is associated with impaired wound healing.

HFSR is most commonly seen 2 to 4 weeks after starting the offending agent. Patients present with hyperkeratotic, callus-like lesions, usually with surrounding or underlying erythema or bullae (Figures 33.2 and 33.3). It preferentially affects skin that is under pressure or experiences friction and presents with pain, tingling, and burning that are usually present. Although it is classically a disorder of the hands and feet, it can occur in other sites that experience friction, including the scrotum and gluteal crease when activity levels are high. This toxicity can dramatically impact patient quality of life.