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.

Figure 1

A) Grade 2 hand-foot skin reaction showing early tender erythematous plaques at pressure points; B) Grade 2 hand-foot skin reaction demonstrating large sheets of desquamating skin overlying a tender erythematous plaque on the heel; C) Histology of an early HFSR lesion from Figure 1A shows epidermal thickening, reactive epithelial changes in the basal layer of the epidermis and in eccrine sweat ducts, mild perivascular infiltrate, and mild vascular dilatation (40X); D) Higher magnification of HFSR histology from Figure 1A (100X)

Figure 2

A) Kaplan-Meier curves for the development of HFSR toxicity with single agent sorafenib (°) versus combination therapy (*), p=0.0008. Median dose of sorafenib to noted HFSR toxicity for combination therapy was 21,117 mg versus not reached for single agent. B) Kaplan-Meier curves for the development of rash with single agent sorafenib (°) versus combination therapy (*), p=0.99. Median dose of sorafenib to noted rash for combination therapy was 26,870 mg versus 31000 mg for single agent.