Hand-Foot Skin Reaction
HFSR occurs in 30%−60% of patients receiving sorafenib and 15%−20% of patients treated with sunitinib,1 often appearing after 2 to 4 weeks of treatment. It seems to be dose dependent and rapidly disappears after treatment discontinuation.
HFSR usually presents as painful symmetric erythematous and edematous areas on the palms and soles, often preceded or accompanied by paresthesia (tingling sensations and intolerance to contact with hot objects); these sensations seem to be aggravated by a warm environment. HFSR can also affect the lateral sides of fingers or the periungual zones. Hyperkeratosis and desquamation are often associated. Painful hyperkeratotic areas on pressure points, surrounded by rings of erythematous and edematous lesions, are classically observed (Figure 1), and painful bullous lesions may be seen (Figure 2). Sole involvement can result in walking impairment. Preexistent sole hyperkeratosis seems to confer a predisposition to painful sole involvement and functional consequences. Although this syndrome can sometimes clinically resemble the more classic chemotherapy-induced acral erythema (AE), kinase inhibitor-induced HFSR has more localized and hyperkeratotic lesions, distinct from classic AE.
Histologic examination of HFSR shows epidermal changes suggestive of keratinocyte differentiation modifications. The granular layer is thinner or absent in several specimens, and some areas of parakeratosis are seen. Epidermal cells are swollen in the superficial stratum spinosum. Numerous mitoses are seen in the basal layers and also above the basal and suprabasal layers, where normally they should not be found physiologically. Dyskeratotic keratinocytes suggestive of apoptotic cells are observed.
As a preventive measure, patients with plantar hyperkeratosis are advised to have a pedicure prior to treatment. During treatment, however, shock absorbers can be used to relieve painful pressure points, and sandals seem to be helpful in some cases. Symptomatic treatment with over-the-counter emollient and keratolytic ointments (containing salicylic acid or urea) can be used. When grade 3 HFSR occurs (pain interfering with function), a dose reduction (to 50% of the dose) or treatment interruption for 1−2 weeks is recommended until symptoms return to grade 1. When treatment is resumed, the dose should be decreased by one level; the full dose should be returned after 3−4 weeks. As is the case with most of the other side effects occurring with kinase inhibitors, resuming treatment is not always associated with similar side effects, in our experience.
