Another installment of Clinical Quandaries is presented by Karen Férez-Blando, MD, and colleagues of a 45-year-old man with a diagnosis of intermediate-risk stage IV clear cell renal carcinoma who develops grade 2 hand-foot skin reaction on sunitinib therapy.
A man, age 45 years, was diagnosed with intermediate-risk stage IV clear cell renal carcinoma (lung and lymph node metastases). He was prescribed first-line systemic treatment with sunitinib (Sutent) 50 mg per day (each cycle: 4 weeks on, 2 weeks off). Upon day 22 of his second sunitinib cycle, he came to the oncology clinic complaining of difficulty walking due to bilateral sole pain. He described initial tingling sensations, which then became burning and painful, with symmetrical erythema and edema of the soles, without blisters. These turned into painful plaques with yellowish discoloration and hyperkeratosis on pressure-bearing areas. He denied fever or other symptoms. The pain limited his instrumental activities of daily living, but not his self-care activities of daily living. Total body skin examination disclosed hyperkeratotic plaques on the undersurface of the great toes and heels of both feet, predominantly at sites of pressure (Figure 1); no blisters, crusts, ulcers, or fissures were found. No relevant findings were found upon physical examination of his hands, mucosae, and scalp. A diagnosis of grade 2 hand-foot skin reaction (HFSR) was made.
Besides oral analgesics, which of the following is the best treatment for this patient?
Hand-foot syndrome (HFS) is a well-described cutaneous adverse event (AE) of certain chemotherapeutic agents, like capecitabine, docetaxel, 5-fluorouracil, and pegylated liposomal doxorubicin. It was first described in 1974 by Zuelke; alternative names for this AE include acral erythema, palmar-plantar erythrodysesthesia, and Burgdorf reaction.1 Clinical dermatological manifestations may include erythema, edema, dryness, blisters, fissures, ulcers, and/or desquamation. Varying degrees of paresthesia, dysesthesia, and pain can accompany such changes.2 Although palms and soles are the most commonly affected areas, changes in the dorsal surfaces and nails can occur.3
With the advent of targeted therapies such as multikinase inhibitors (MKIs), a novel profile of cutaneous AEs has emerged. Since the MKI-related skin changes affecting the palms and soles differ from the ones caused by chemotherapy, the term HFSR is used when referring to the MKI-induced syndrome.4 The differences between HFS and HFSR are summarized in Table 1. HSFR has been associated with various MKIs, including regorafenib (Stivarga), cabozantinib (Cabometyx), sorafenib (Nexavar), sunitinib, axitinib (Inlyta), and pazopanib (Votrient).5 Although it isn’t life-threatening, HFSR can lead to cessation of therapy, dose reduction, and impaired quality of life.6
HFSR affects 31.2% to 79.4% of patients using MKIs.7-9 The frequency of all-grade HFSR differs greatly among the MKIs—for instance, the frequency with regorafenib is 46% to 84%; with cabozantinib, 35%; sorafenib, 10% to 62%; and sunitinib, 10% to 28%. The corresponding frequencies for grade 3 or greater HFSR are 20.4%, 9.5%, 2% to 36%, and 4% to 12%, respectively. Notably, the incidence of HFSR from a specific MKI can vary among tumor types, as different doses might be indicated for them.1,10,11
HFSR has several risk factors. In a meta-analysis of randomized controlled trials involving 24,956 patients, the main risk factors for HFSR were:
(A) Tumor type. The highest risk was with thyroid cancer, with a relative risk (RR) of 12.62; the RR for renal cell carcinoma was 8.10.
(B) MKI used. Cabozantinib represented the highest RR with 12.10; the RR with sunitinib was 2.97.
(C) Dosing. Severity and frequency of HFSR positively correlated with the dosage of MKI.12
(D) Additional risk factors. These include female sex, good performance status, preexisting calluses, poorly fitting shoes, and repeated friction to the hands and feet.5
The pathogenesis of HFSR is still unclear. Proposed mechanisms include direct cytotoxic effect of the MKIs to the epidermis, eccrine secretion of MKI, and MKI-induced deficient capillary maintenance in high-friction areas.9,13
A crosstalk between vascular endothelial cells and keratinocytes has also been suggested as an etiological mechanism. In this model, MKI triggers the release of soluble heparin-binding epidermal growth factor from vascular endothelial cells. This stabilizes sirtuin 1, an essential keratinization inducer in keratinocytes, hence causing hyperkeratinization.
HFSR typically appears within the first 2 to 4 weeks of treatment initiation, with severity also likely to peak early.7,14,15 HFSR clinical presentation can be divided into several phases. In the prodromal phase, the patient notices dysesthesia, which progresses over several days to burning pain; palms and soles become symmetrically erythematous and edematous. The inflammatory phase follows: A well-defined symmetrical erythema and tense bullae appear on the palms and soles. The hyperkeratotic phase is next: Localized well-demarcated painful yellowish hyperkeratotic patches overlie erythematous base pressure-bearing areas.5 The patient can experience paresthesia, dysesthesia, and pain, which may be out of proportion to the clinical appearance of the lesions. Finally, the resolution phase is characterized by excessive desquamation and fissures.1,5,16,17 Other concomitant alterations have been described, including scalp dysesthesia, angular cheilitis, perianal rashes, and facial erythema resembling seborrheic dermatitis. It is uncertain whether the pathophysiology is the same.1
Several prophylactic measures have been described. It is recommended that before initiating treatment with a kinase-targeted therapy, a patient’s hands and feet should be examined for existing hyperkeratotic lesions and, if present, debrided by a podiatrist or dermatologist. Patients should take measures to ensure that their skin remains extremely moisturized, utilizing 10% urea cream, and to avoid friction as much as possible (summarized in Table 2), and these measures should be maintained even if HFSR occurs.4,7,9,16 Answer A is therefore incorrect: Hot compresses and scrubbing the lesions (no matter how hyperkeratotic they look) will worsen HFSR.
Patients who use 10% urea cream prophylactically, 3 times a day, have lower rates of HFSR. This was observed in a randomized, open-label trial that included 871 patients with hepatocellular carcinoma being treated with sorafenib. The use of urea-based cream extended the time to the first occurrence of HFSR, and it improved patient quality of life compared with best supportive care.18 Other topical keratolytic agents (ammonium lactate 6%-12%; salicylic acid 5%-10%) can be used to treat focal hyperkeratosis. Higher concentrations of keratolytics (urea 40%) might be implemented once HFSR is established.16 In addition, celecoxib has been suggested to lower incidence rates of HFSR. In an open-label prospective study of 116 patients with advanced hepatocellular cancer, patients who received sorafenib with celecoxib achieved lower grade 2 and grade 3 HFSR incidence rates compared with those who received sorafenib alone.19 Finally, a retrospective study found that prophylactic oral dexamethasone 2 mg, taken once a day, delayed dose modifications of regorafenib and decreased the incidence of grade 3 HFSR (3.2% in the experimental population vs 25.7% in the controls).20
After establishing a diagnosis of HFSR, treatment should be individualized using the National Cancer Institute’s Common Terminology Criteria for Adverse Effects. HFSR of grade 1 is characterized by minimal changes, such as erythema, edema, or hyperkeratosis without pain, and it can be treated with topical lidocaine 2% to 6% in gel, cream, or patch form. In grade 2 HFSR, painful skin changes (eg, blisters, erythema, hyperkeratotic plaques) limit instrumental daily life activities, and grade 3 HFSR is characterized by severe skin changes (eg, moist desquamation, ulceration, blistering, fissures, or local injury causing infectious complications) and pain that limits self-care activities of daily life.5,16,21 Treatment of grade 2 and 3 HFSR involves pain control with systemic medications, including nonsteroidal anti-inflammatory drugs and opioids or γ-aminobutyric acid antagonists.7,17
Superpotent topical steroids, such as clobetasol propionate ointment 0.05% or fluocinonide 0.05%, are recommended for treatment of the inflamed, erythematous areas.7,15 Topical steroids induce vasoconstriction, promote antimitotic actions, and have anti-inflammatory activity.22 No studies have compared the different strengths of topical steroids in HFSR. Superpotent ones are usually recommended since the percutaneous absorption in hyperkeratotic or lichenified lesions on the palms and soles is diminished.23,24 Clobetasol, due to its superior potency, has also proved effective in treating “steroid-resistant dermatosis.”25 The vehicle also matters; an ointment base, not cream, is preferred for infiltrated, lichenified lesions. An ointment’s occlusive effect increases the hydration of the stratum corneum, enhancing the drug’s penetration.26-28 Answer B is therefore incorrect: Hydrocortisone 1% cream is a low-potency steroid. Steroids are an adjuvant to and not a substitute for the aforementioned supportive measures. Answer C is therefore incorrect: Superpotent steroids are not recommended as HFSR monotherapy.
Other translational studies have suggested treatment with sildenafil, heparin-containing ointments,29 and narrowband UV-B phototherapy,23 but more research is needed.15 In a randomized multicenter phase 2 trial, patients with metastatic renal cell carcinoma who were being treated with sorafenib found that hydrocolloid dressing containing ceramide improved symptom management of HFSR.24 An ongoing phase 3 randomized trial is investigating this therapy.30 Several other therapy trials with topical sildenafil (NCT03229512), tazarotene (NCT04071756), and nicotinamide (NCT04242927) are ongoing.
The option of holding MKI, as a measure to improve HFSR, should be reserved for severe cases (grade 3) or refractoriness to supportive measures. When holding is needed, most HFSR treatment algorithms recommend holding MKI for 7 days (or until HFSR symptoms resolve), then resuming at a lower dose. If HFSR worsens or does not improve, dose interruption or discontinuation is suggested. If severe HFSR recurs despite supportive measures, therapy should be discontinued.7 Answer E is therefore incorrect: For grade 2 HFSR, try supportive measures before discontinuing the MKI. D, then, is the best answer.
Prognosis for patients with HFSR is good, since this AE is reversible and treatable. It has been suggested that HFSR occurrence is a predictor of prolonged survival. In individuals with renal cell carcinoma treated with sunitinib and sorafenib, HFSR is associated with significantly better progression-free survival (PFS).7,16 A similar observation was made in patients with metastatic colorectal cancer treated with regorafenib who experienced severe HFSR.31
The patient was treated with a high-potency topical steroid (clobetasol 0.05% ointment twice daily) and a keratolytic agent (urea 40% cream once daily), which improved the symptoms to grade less than or equal to 1 in 2 weeks. Clobetasol was tapered after 2 weeks. Rechallenge courses with urea were given when hyperkeratosis relapsed. Supportive care recommendations were reinforced. Sunitinib dose did not need to be delayed or adjusted. The patient had a partial response in his first CT response evaluation, which is maintained to this day (Figure 2). He has had a PFS of 12 months to date, with no grade greater than or equal to 2 HFSR recurrence.
Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
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31. Kobayashi K, Kawakami K, Yokokawa T, et al. Association of hand-foot skin reaction with regorafenib efficacy in the treatment of metastatic colorectal cancer. Oncology. 2019;96(4):200-206. doi:10.1159/000495989