Tyrosine kinase inhibitors (TKIs) -Induced Hand–Foot Skin Reaction vs Hand–Foot Syndrome: Literature Review

Review Article

Abstract

Background: Cutaneous toxicities represent significant dose-limiting factors in systemic anticancer therapy. Among these, Hand–Foot Syndrome (HFS) and Hand–Foot Skin Reaction (HFSR) are frequently conflated despite distinct etiopathogenic and clinical profiles. Our review delineates the divergent characteristics of HFS, associated with conventional cytotoxic chemotherapy, and HFSR, predominantly induced by Tyrosine Kinase Inhibitors (TKIs).

Methods: A comprehensive literature review was conducted across PUBMED, MEDLINE, and other major databases including published articles from 2000 until June 2025 evaluating clinical trials, case reports, observational studies, and literature reviews with meta-analyses concerning TKI-induced HFSR and chemotherapy-associated HFS.

Results: HFSR incidence is particularly high with multi-target TKIs such as regorafenib (45–50%) and sorafenib (30–40%). Pathophysiologically, HFSR stems from VEGFR and PDGFR inhibition, impairing microvascular repair and promoting hyperkeratosis at mechanical pressure points. Clinically, it manifests as well-demarcated, hyperkeratotic plaques appearing within 1–2 weeks of treatment. Conversely, HFS—driven by agents like capecitabine—presents as diffuse, symmetric erythema and edema, typically emerging 2–4 weeks post-initiation. The mechanism involves drug accumulation in eccrine glands and direct keratinocyte apoptosis. While HFS often necessitates dose intensity modifications, HFSR management emphasizes proactive topical keratolytic and pressure-point cushioning. Emerging evidence further suggests that HFSR development may serve as a surrogate biomarker for TKI efficacy.

Conclusion: Precise differentiation between HFS and HFSR is imperative for oncological practice While HFS requires systemic adjustments to mitigate toxicity, HFSR demands a localized, proactive dermatological approach to maintain therapeutic continuity. Recognizing these nuances allows clinicians to preserve dose intensity while addressing the functional and prognostic implications of these reactions. Crucially, prophylactic management of both conditions include aggressive lipid-replenishing hydration, the use of ergonomic, shock-absorbing footwear, and the proactive mitigation of mechanical pressure points to prevent debilitating hyperkeratotic or erythematous lesions.