title: Risk of hand-foot skin reaction with the novel multikinase inhibitor regorafenib: a meta-analysis.
abstract: BACKGROUND
  Regorafenib is a novel receptor tyrosine kinase inhibitor approved for use in metastatic colorectal cancer (mCRC) and locally advanced gastrointestinal stromal tumors (GISTs). The drug targets multiple receptors, including VEGF-R1/-R2/-R3, TIE-2, FGFR-1, PDGFR-α/β, KIT, RET, RAF, p38 MAPK. Adverse events include asthenia, hypertension, diarrhea, and hand-foot skin reaction (HFSR), with the latter representing one of the most clinically significant untoward events. The incidence and risk of HFSR with regorafenib have not been systematically investigated.
  
  
  METHODS
  We conducted a meta-analysis to ascertain the incidence and risk of developing HFSR in cancer patients treated with regorafenib. Electronic databases (PubMed, Scopus, Web of Science) and the ASCO website were searched for publications from January 1998-January 2013. Eligible studies were limited to Phase II/III clinical trials employing regorafenib (160 mg/day). The incidence, relative risk (RR), and 95 % CIs were calculated using random- or fixed-effects models based on the heterogeneity of included studies.
  
  
  RESULTS
  A total of 1,078 patients treated with regorafenib for mCRC, GIST, renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) were included. The overall incidence of all-grade and high-grade HFSR were 60.5 % (95 % CI: 48.3-71.6 %) and 20.4 % (95 % CI: 15.4-26.6 %), respectively. The RRs of all-grade and high-grade HFSR with regorafenib in comparison to controls were increased for all-grade (RR = 5.4, 95 % CI: 3.76-7.76, p < 0.001) and high-grade (RR = 41.99, 95 % CI: 5.88-299.93, p < 0.001) HFSR. The incidence of HFSR varied significantly with tumor type (p = 0.007), and was 71.4 % (95 % CI: 57.4-82.3 %) for RCC, 60.2 % (95 % CI: 52.3-67.6 %) for GIST, 50.0 % (95 % CI: 34.2-65.8 %) for HCC, and 46.6 % (95 % CI: 42.3-51.0 %) for mCRC.
  
  
  CONCLUSIONS
  The incidence and risk of development of HFSR with regorafenib is high, and may vary significantly with tumor type. Knowledge of this is important for patient counseling and clinical trial development, to ensure adherence and maximize clinical outcomes.
authors.affiliation: Dermatology Service, Memorial Sloan-Kettering Cancer Center, Rockefeller Outpatient Pavilion, Suite 228, 160 E 53rd St, New York, NY 10022, USA.
authors.forename: Viswanath Reddy
authors.initials: VR
authors.lastname: Belum
authors.forename: Shenhong
authors.initials: S
authors.lastname: Wu
authors.forename: Mario E
authors.initials: ME
authors.lastname: Lacouture
mesh_terms: D002986:Clinical Trials as Topic; D060831:Hand-Foot Syndrome / Q000453:epidemiology / Q000473:pathology*; D006801:Humans; D015994:Incidence; D009369:Neoplasms / Q000188:drug therapy; D010671:Phenylurea Compounds / Q000009:adverse effects* / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D011725:Pyridines / Q000009:adverse effects* / Q000627:therapeutic use; D012307:Risk Factors; D012867:Skin / Q000187:drug effects / Q000473:pathology*
chemical_list: D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C559147:regorafenib