Management Of Tyrosine Kinase Inhibitor–Induced Hand–Foot Skin Reaction: Viewpoints from the Medical Oncologist, Dermatologist, and Oncology Nurse

Recommendations for the treatment of grade 1 HFSR include early and appropriate dermatologic management and active collaboration among HCPs.⁴⁰

The Dermatologist's Viewpoint

Although the exact pathogenesis of HFSR has not been fully elucidated, research into its cause(s) is ongoing. Theoretically, traditional HFS is thought to be due to the direct toxic effects of drugs or their ability to invoke a “host-vs-host” response. In contrast, a unique mechanism has been proposed for TKI-associated HFSR: simultaneous blockage of VEGFRs and PDGFRs.²

Three histopathologic features have been found to predominate in HFSR: dyskeratotic keratinocytes at various states of necrosis (Figure 4⁴¹), basal layer vacuolar degeneration, and mild perivascular or lichenoid lymphocyte-predominant infiltrate.² Immunohistochemistry with a variety of skin-cell markers has shown a significant modification of normal maturation of keratinocytes, which are often apoptotic. Minor modifications of blood vessels are also seen, but no signs of intense vasculitis are evident. This is important because HFSR is suspected of being a “class effect” of TKIs that target VEGFRs. HFSR is not seen in patients treated with single-agent bevacizumab, and the lack of histologic evidence of significant damage to blood vessels suggests that HFSR does not result from the general inhibition of angiogenesis. A retrospective analysis found that HFSR rates were higher when patients were treated with sorafenib and bevacizumab in combination, supporting the hypothesis that HSFR is due to the anti-VEGF properties of sorafenib.⁴² Other possible causes of HFSR include activation by a ligand other than VEGF and/or inhibition of one of the other protein targets inhibited by both sorafenib and sunitinib.^{[3] and [35]}

Incidence and Severity of HFSR With TKI

To determine the incidence and severity of HFSR specific to sorafenib, a double-blind, prospective, dermatologic substudy was performed in patients enrolled in the phase III TARGET trial.³⁵ Eighty-five patients with RCC were randomized to receive either sorafenib (n = 43) or placebo (n = 42). Dermatologic examinations were performed before and during treatment. Ninety-one percent of sorafenib-treated patients experienced at least one cutaneous reaction compared with 7% of those in the placebo group. A variant of HFSR clinically distinct from chemotherapy-induced HFS was observed in 60% of sorafenib-treated patients. Reversible grade 3 HFSR leading to dose reduction occurred in two sorafenib-treated patients. Additional cutaneous reactions were facial erythema, scalp dysesthesia, alopecia, and subungual splinter hemorrhages.

HFSR (of any grade) has been shown to occur in approximately 30% of patients treated with sorafenib and 20% of those who received sunitinib in clinical studies.⁴³ Grade 3/4 HFSR has been observed in approximately 6% of sorafenib-treated and 5% of sunitinib-treated patients. HFSR was not reported in a phase II study of 142 patients with relapsed or refractory soft-tissue sarcoma treated with pazopanib.⁴⁴ In a phase III randomized, double-blind, placebo-controlled trial of pazopanib in patients with advanced RCC, the incidence of HFSR was <10%, while the incidence of grade 3/4 HFSR was <1%. Potential differences may be explained by variations in the potency and selectivity of the TKIs.²⁷

Management Strategies

Our work at the Dermatology Center at the Gustave-Roussy Institute has shown that early intervention against the dermatologic adverse effects of these TKIs can inhibit patient progression to a more serious form of HFSR.^{[34] and [38]}

Effective management of HFSR can begin prior to initiation of treatment with sorafenib or sunitinib. Patients should be advised to remove any preexisting hyperkeratotic areas or calluses, keep skin well-moisturized with appropriate creams, and cushion pressure points with cotton socks, soft shoes, and/or insoles. Dose modification is typically not required for grade 1 HFSR; symptomatic treatments should be employed instead.

If HFSR symptoms progress to grade 2 or 3, with pain and a decrease in quality of life, the dose of sorafenib or sunitinib can be modified until symptoms recede, after which the patient can be brought back to the full dose. Very often, the patient can tolerate the full-dose treatment simply by decreasing the dose briefly.³ A recommended dose-modification scheme is shown in Figure 5.³