First AD

Second AD

A 60-year-old man presents with localized tender plaques of hyperkeratosis and a surrounding erythematous halo on the weight-bearing plantar aspect of his feet after beginning cancer treatment.

A. Capecitabine, hand-foot skin reaction 

Regorafenib (Stivarga) is an oral multikinase (serine-threonine and tyrosine-kinase) inhibitor which targets factors involved in angiogenesis (vascular endothelial growth factor (VEGFR) 1-3 and TIE2), oncogenesis (KIT, RET, RAF-1, BRAF), and regulation of the tumor microenvironment (platelet-derived growth factor receptor-beta (PDGFR-B), and fibroblast growth factor receptors).

Regorafenib has been shown to be an effective treatment option for patients with metastatic colorectal cancer (CRC) or advanced gastrointestinal stromal tumors (GIST) unresponsive to other standard therapies, based on findings from two phase III trials: the 

The most common mucocutaneous adverse events seen with regorafenib include: hand-foot skin reaction (HFSR), rash, and oral mucositis. Both hand-foot skin reaction and rash tend to occur early in the first cycle of therapy (after a median of approximately 2 weeks of therapy); although it has been reported to occur as early as 5 days after starting treatment.

Initial symptoms of HFSR may start with tingling within the first week of therapy, and then may progress to pain, tenderness, formation of hyperkeratosis, erythema, and edema in the soles and palms--especially in areas of flexion and weight-bearing locations. These areas that undergo pressure develop the most severe symptoms, and blisters can form that significantly affect mobility. Importantly, HFSR differs from the classic hand-foot syndrome (HFS) seen with more traditional cytotoxic agents such as 5-fluorouracil, capecitabine, doxorubicin, or liposomal doxorubicin. In HFS, clinical presentation includes symmetrical erythema and edema of the palms and soles, which may evolve into necrosis, blistering, desquamation, followed by ulceration and crusting. Most notably, hyperkeratosis at sites of pressure and friction is absent in HFS, while it is a hallmark of HFSR.

Hand-foot skin reaction has also been observed with other oral multikinase therapies including sorafenib (34%) and sunitinib (19%). The mechanism of action is believed to be inhibition of mulitiple molecular pathways targeted by these agents including VEGFRs, PDGFRs, and c-KIT.

Patients who develop HFSR can be managed conservatively, and typically will not require a treatment dose reduction or discontinuation. Unlike cutaneous reactions seen with other chemotherapy, there is no relationship between the presence of HFSR and chemotherapeutic efficacy.  Symptoms of HFSR can be managed with topical steroids, emollients, and keratolytic agents (i.e., urea cream or a salicylic acid containing agent). Patients should also be advised to wear cotton socks, non-constrictive footwear, and to avoid excessive trauma/pressure to the hands and feet. If symptoms of HFSR are severe, recalcitrant to standard conservative therapy, and affecting activities of daily living, dose reduction and/or discontinuation of targeted therapy and/or chemotherapeutic agents should be considered in the management of HFSR.

Wilhelm SM, et al. (2011). Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. Jul 1; 129(1):245–55.

Grothey A, et al. (2014). Optimizing treatment outcomes with regorafenib: personalized dosing and other strategies to support patient care. The Oncologist. Jun; 19(6):669–80.

A 60-year-old man presents with localized tender plaques of hyperkeratosis and a surrounding erythematous halo on the weight-bearing plantar aspect of his feet after beginning cancer treatment. Which medication is responsible for this cutaneous presentation and what is the name of this reaction? 

A 60-Year-Old Man Presents With Plantar Hyperkeratosis & Erythema

Shivani Tripathi, MD

Milan Anadkat, MD