Hand-Foot Skin Reaction Increases with Cumulative Sorafenib Dose and with Combination Anti-Vascular Endothelial Growth Factor Therapy

Abstract

Purpose: Sorafenib, a vascular endothelial growth factor (VEGF) receptor-2 and RAF kinase inhibitor, commonly causes skin toxicity. We retrospectively analyzed dermatologic toxicity in patients receiving combined antiangiogenic therapy involving sorafenib and bevacizumab. Experimental Design: Castration-resistant prostate cancer and metastatic non-small cell lung cancer patients were accrued to phase II studies, receiving sorafenib 400 mg twice daily. A phase I study explored sorafenib 200 to 400 mg twice daily with bevacizumab 5 to 10 mg/kg every 2 weeks in patients with advanced solid tumors. The probability of development of maximum grade of dermatologic toxicity as a function of the cumulative dose of sorafenib was determined. Additional analyses compared extent of toxicity, pharmacokinetics, and patient risk factors. Results: Ninety-six patients were enrolled: 54 received sorafenib and 42 received bevacizumab/ sorafenib. Hand-foot skin reaction (HFSR) was observed in 50 of 96 (52%) patients. Grade 2 to 3 HFSR developed in 16 of 54 (30%) sorafenib patients and 24 of 42 (57%) bevacizumab/ sorafenib patients (P = 0.012) and was associated with cumulative sorafenib exposure (P = 0.0008). Twenty-four of 42 phase I patients randomized to start with bevacizumab had increased risk of grade 2 to 3 HFSR than those starting with sorafenib (P = 0.013) after adjusting for association between HFSR risk and hypertension (P = 0.01), which was the only toxicity associated with HFSR. There was no association between HFSR and baseline history of neuropathy, prior taxane/platinum treatment, or systemic sorafenib levels. Conclusions: Sorafenib-related HFSR is associated with increasing cumulative sorafenib dose. HFSR is increased in patients treated with bevacizumab/sorafenib combination anti-VEGF therapy, and this finding is not explained by pharmacokinetic interaction between the two agents. Our results suggest that the pathophysiology of HFSR may be related to VEGF inhibition.

Phase I/II and Pharmacodynamic Study of Dovitinib (TKI258), an Inhibitor of Fibroblast Growth Factor Receptors and VEGF Receptors, in Patients with Advanced Melanoma

“…Dovitinib exposure correlates with a change in K trans in liver metastases at an early time point (day 2 of cycle 1) measured by DCE-MRI. (21,22); notably, no incidents of hand-foot syndrome were observed in this study with dovitinib treatment.…”

A Multicenter Phase II Study of Erlotinib and Sorafenib in Chemotherapy-Naïve Patients with Advanced Non–Small Cell Lung Cancer

“…However, the frequency and severity of diarrhea and hand-foot skin reaction were higher than in published reports (37,38). The phase I trial of sorafenib and erlotinib in solid tumors reported a cumulative effect of adverse events, with every patient receiving 150 mg/d erlotinib plus 800 mg/d sorafenib ultimately requiring dose reductions, mainly due to fatigue, gastrointestinal problems, and skin toxicity (9).…”

Differential Combined Effect of COX Inhibitors on Cell Survival Suppressed by Sorafenib in the HepG2 Cell Line

“…49) A recent study reported that sorafenib-induced HFSR was directly related to the cumulative sorafenib dose, the development of HT and HFSR was simultaneous, and HFSR was more prevalent in inpatients treated with sorafenib targeting the VEGF receptor and VEGF growth factor. 50) In addition, the overall incidence of all-grade and high-grade (i.e., grade 3 or 4) HT was 23.4%, 2) while that of all-grade and high-grade (i.e., grade 3 or 4) HFSR was 21% in patients treated with sorafenib.…”