Multikinase inhibitors (MKIs) are a class of oncologic drugs that inhibit several types of protein kinases, which play a role in oncogenesis (KIT, RET, RAF-1, and BRAF), tumor angiogenesis (VEGF receptors 1, 2, and 3 and TIE-2), and tumor microenvironment (PDGFR and fibroblast growth factor receptor).

MKIs are effective in the treatment of a broad array of solid tumors and include regorafenib, sorafenib, vandetanib, sunitinib, lenvatinib, cabozantinib, and pazopanib. Numerous mucocutaneous side effects have been observed with these agents:

Hand-foot skin reaction (HFSR) has been reported in both children and adults. It can affect up to 60%-70% of patients being treated with MKIs, particularly those treated with regorafenib, sorafenib, sunitinib, and cabozantinib. HFSR is less likely to occur in later cycles of therapy than it would be in earlier cycles. Pathogenetically, it is thought that inhibition of VEGF leads to diminished capacity to repair trauma-induced changes in these locations. Severity of HFSR has been inversely correlated to serum zinc level in one study.

As per the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE v5), HFSR severity has been described in 3 grades:

• Grade 1: Minimal skin changes or dermatitis (eg, erythema, edema, or hyperkeratosis) without pain
• Grade 2: Skin changes (eg, peeling, blisters, bleeding, fissures, edema, or hyperkeratosis) with pain; limiting instrumental activities of daily living
• Grade 3: Severe skin changes (eg, peeling, blisters, bleeding, fissures, edema, or hyperkeratosis) with pain; limiting self-care activities of daily living

A papulopustular eruption is seen with erlotinib, cetuximab, panitumumab, and sorafenib. It has been reported to occur in greater than 75% of patients and occurs as early as 1 to 2 weeks after starting treatment. In addition to the head and neck, this eruption most commonly involves the trunk and proximal upper extremities.

A pruritic exanthematous eruption is not uncommon with MKI therapy. It has been reported to occur in up to 10% of patients. Onset is typically within 1 to 3 weeks of drug initiation, and incidence decreases with subsequent drug cycles. Xerosis occurs in about 33% of patients over the course of weeks after initiating MKI therapy. Xerosis peaks at 1-3 months and most commonly involves the extremities.

Ultraviolet A (UVA)-induced photosensitivity has been reported from vandetanib, including phototoxic and photoallergic reactions. Additionally, photodistributed pigmentation occurs in up to one-fifth of patients, seen at the same time as the photosensitivity or following its resolution.

Stomatitis, nail, and hair changes are also seen. Eruptive nevi as well as multiple and eruptive keratoacanthomas (KAs) have been reported in patients on sorafenib and sunitinib. A yellow discoloration of the skin is reported with sunitinib use. This is thought to be secondary to the dye contained in the drug and is reversible on drug discontinuation. Dasatinib has been reported to cause seborrheic dermatitis-like eruption.