Among tyrosine kinase inhibitors used in targeted cancer therapy, which is the most common cause of hand-foot skin reaction (HFSR) as a dose-limiting toxicity?

Explanation

## Hand-Foot Skin Reaction (HFSR) in Targeted Therapy **Key Point:** Sorafenib is the most notorious TKI for causing hand-foot skin reaction, occurring in 15–30% of patients and frequently requiring dose reduction or discontinuation. ### Mechanism of HFSR HFSR is a chemotoxicity syndrome characterized by: - Symmetrical erythema, edema, and hyperkeratosis of palms and soles - Occurs 2–6 weeks after initiation - Caused by TKI inhibition of VEGFR and PDGFR in dermal vasculature and keratinocytes - Sorafenib's dual inhibition of RAF and VEGFR makes it particularly prone to this effect ### Comparative TKI Toxicity Profile | TKI | HFSR Incidence | Other Dose-Limiting Toxicity | Clinical Context | |-----|----------------|------------------------------|------------------| | **Sorafenib** | 15–30% (most common) | Diarrhea, hypertension | Renal cell carcinoma, hepatocellular carcinoma | | Sunitinib | 5–10% | Fatigue, thrombocytopenia | GIST, renal cell carcinoma | | Erlotinib | <5% | Rash, diarrhea | NSCLC with EGFR mutation | | Imatinib | <2% | Fluid retention, GI upset | CML, GIST | | Gefitinib | <2% | Rash, diarrhea | NSCLC with EGFR mutation | **High-Yield:** Sorafenib is the multikinase inhibitor with the highest propensity for HFSR; this is a classic NEET PG board question. ### Management of HFSR 1. Dose reduction (most effective) 2. Topical keratolytics (urea 20–40%, salicylic acid) 3. Emollients and protective footwear 4. Temporary discontinuation if severe **Clinical Pearl:** HFSR is not a sign of toxicity requiring immediate cessation—it is predictable and manageable with dose adjustment, and often correlates with better response in renal cell carcinoma. [cite:Harrison 21e Ch 100]