title: Hand-foot skin reaction increases with cumulative sorafenib dose and with combination anti-vascular endothelial growth factor therapy.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Medical Oncology Branch, Biostatistics and Data Management Section, Center for Cancer Research, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Nilofer S
authors.initials: NS
authors.lastname: Azad
authors.forename: Jeanny B
authors.initials: JB
authors.lastname: Aragon-Ching
authors.forename: William L
authors.initials: WL
authors.lastname: Dahut
authors.forename: Martin
authors.initials: M
authors.lastname: Gutierrez
authors.forename: William D
authors.initials: WD
authors.lastname: Figg
authors.forename: Lokesh
authors.initials: L
authors.lastname: Jain
authors.forename: Seth M
authors.initials: SM
authors.lastname: Steinberg
authors.forename: Maria L
authors.initials: ML
authors.lastname: Turner
authors.forename: Elise C
authors.initials: EC
authors.lastname: Kohn
authors.forename: Heidi H
authors.initials: HH
authors.lastname: Kong
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors / Q000009:adverse effects*; D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects*; D019540:Area Under Curve; D001557:Benzenesulfonates / Q000009:adverse effects* / Q000493:pharmacokinetics; D000068258:Bevacizumab; D004305:Dose-Response Relationship, Drug; D005260:Female; D005533:Foot Dermatoses / Q000139:chemically induced*; D006229:Hand Dermatoses / Q000139:chemically induced*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000031:analogs & derivatives; D010671:Phenylurea Compounds; D011725:Pyridines / Q000009:adverse effects* / Q000493:pharmacokinetics; D012307:Risk Factors; D000077157:Sorafenib; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000502:physiology
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D000068258:Bevacizumab; D000077157:Sorafenib