Regorafenib-associated hand-foot skin reaction: practical advice on diagnosis, prevention, and management

Ann Oncol. 2015 Oct;26(10):2017-26. doi: 10.1093/annonc/mdv244. Epub 2015 Jun 1.


Background: Regorafenib is an orally available, small-molecule multikinase inhibitor with international marketing authorizations for use in colorectal cancer and gastrointestinal stromal tumors. In clinical trials, regorafenib showed a consistent and predictable adverse-event profile, with hand-foot skin reaction (HFSR) among the most clinically significant toxicities. This review summarizes the clinical characteristics of regorafenib-related HFSR and provides practical advice on HFSR management to enable health care professionals to recognize, pre-empt, and effectively manage the symptoms, thereby allowing patients to remain on active therapy for as long as possible.

Design: This review is based on a systematic literature search of the PubMed database (using synonyms of HFSR, regorafenib, and skin toxicities associated with targeted therapies or cytotoxic chemotherapy). However, as this search identified very few articles, the authors also use their clinical experience as oncologists and dermatologists managing patients with treatment-related HFSR to provide recommendations on recognition and management of HFSR in regorafenib-treated patients.

Results: Regorafenib-related HFSR is similar to that seen with other multikinase inhibitors (e.g. sorafenib, sunitinib, cabozantinib, axitinib, and pazopanib) but differs from the hand-foot syndrome seen with cytotoxic chemotherapies (e.g. fluoropyrimidines, anthracyclines, and taxanes). There have been no controlled trials of symptomatic management of regorafenib-related HFSR, and limited good-quality evidence from randomized clinical trials of effective interventions for HFSR associated with other targeted therapies. Recommendations on prevention and management of regorafenib-related HFSR in this review are therefore based on the expert opinion of the authors (dermatologists and oncologists with expertise in the management of treatment-related skin toxicities and oncologists involved in clinical trials of regorafenib) and tried-and-tested empirical experience with other multikinase inhibitors and cytotoxic chemotherapies.

Conclusions: As recommended in this review, treatment modifications and supportive measures to prevent, reduce, and manage HFSR can allow patients to continue regorafenib at the optimal dose to derive benefit from treatment.

Keywords: hand–foot skin reaction; hand–foot syndrome; palmar–plantar erythrodysesthesia; regorafenib; symptom management; treatment modifications.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Clinical Trials as Topic
  • Disease Management
  • Gastrointestinal Neoplasms / drug therapy*
  • Hand-Foot Syndrome / diagnosis
  • Hand-Foot Syndrome / etiology
  • Hand-Foot Syndrome / prevention & control*
  • Humans
  • Phenylurea Compounds / adverse effects*
  • Prognosis
  • Protein Kinase Inhibitors / adverse effects*
  • Pyridines / adverse effects*
  • Risk Factors


  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Pyridines
  • regorafenib