Hand-foot skin reaction induced by multitargeted tyrosine kinase inhibitors

INTRODUCTION — Protein tyrosine kinase inhibitors (TKIs), which include selective and multikinase inhibitors, are a class of targeted anticancer medications approved for treatment of a number of solid tumors. The ability of TKIs to block molecular pathways specific to the proliferation of malignant cells has decreased the incidence of many of the adverse events caused by cytotoxic chemotherapy. However, TKIs bring their own set of specific dermatologic adverse events, which include [1]:

●Hand-foot skin reaction (HFSR)

●Seborrheic dermatitis-like eruption

●Subungual splinter hemorrhages

●Keratoacanthoma and squamous cell carcinomas

●Hair changes such as alopecia and changes in hair color and/or texture

●Keratosis pilaris-like eruption

HFSR is the most common cutaneous adverse event caused by TKIs. Although rarely life-threatening, it can impair patients' quality of life and may lead to dose reductions or premature discontinuation of cancer treatment. HFSR secondary to TKIs will be reviewed in this topic. Other cutaneous adverse reactions to molecularly targeted therapy or conventional chemotherapy agents are discussed separately.

●(See "Cutaneous adverse effects of conventional chemotherapy agents".)

●(See "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy".)

●(See "Acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors".)

EPIDEMIOLOGY

Incidence — The risk of developing HFSR varies depending on the specific drug used and type of malignancy [2-4]. The incidence rates of all-grade and high-grade HFSR range from 4.5 and 1.8 percent, respectively, in patients treated with pazopanib (a multitargeted tyrosine kinase inhibitor [TKI] used in the treatment of advanced renal cell carcinoma) to 60.5 and 20.4 percent, respectively, in patients taking regorafenib (a potent multitargeted TKI used in the treatment of advanced colorectal cancer) (table 1) [5]. A meta-analysis of 57 studies (24,956 patients) found an overall incidence of all-grade and high-grade HFSR associated with vascular endothelial growth factor receptor (VEGFR)-TKIs of 35 percent (95% CI 28.6-41.6) and 9.7 percent (95% CI 7.3-12.3), respectively [6]. The highest risk of all-grade HFSR was observed in patients with thyroid cancer and in patients receiving cabozantinib. The highest risk of high-grade HFSR was observed in patients with thyroid cancer and in patients receiving regorafenib.

Risk factors — The risk factors for the development of HFSR are largely unknown, and the reaction is generally considered unpredictable. In a study of patients with renal cell carcinoma treated with sorafenib, female sex, good performance status, presence of lung and liver metastases at baseline, involvement of two or more organs, baseline white blood cell count above 5.5 x 10⁹ cells/L, and week of therapy (with maximum risk at week 5) were predictive of grade 2 or greater HFSR [3].

The development of hypertension has been shown to be a risk factor for HFSR in patients treated with bevacizumab and/or sorafenib [7]. Polymorphisms of the VEGFR2 gene may also be associated with increased risk of developing HFSR [7].

Several genetic polymorphisms have been identified that increase risk of development of HFSR. Variants in the C-C motif chemokine ligand 5/C-C motif chemokine receptor 5 (CCL5/CCR5) pathway have been found to predict severe HFSR in patients with metastatic colorectal cancer treated with regorafenib [8].

Association of hand-foot skin reaction with survival — Several studies have noted an association between the development of HFSR and other skin toxicities from TKIs and increased tumor response rate and overall survival rate [7,9-11]. A Japanese prospective study examining patients with metastatic renal cell carcinoma treated with sorafenib found that the median progression-free survival was 4.6 months in patients with HFSR versus 1.5 months in patients without [11]. In a multivariate analysis, HFSR was the only predictive factor of progression-free survival, after adjusting for major patient clinical characteristics (eg, Eastern Cooperative Oncology Group performance status, Memorial Sloan-Kettering Cancer Center risk classification, lactate dehydrogenase). A study in Korea found that HFSR was a predictor of long-term survival (>2 years) in patients treated with sorafenib for unresectable hepatocellular carcinoma [12].

Similarly, a national registry-based study from the Czech Republic including 705 patients with metastatic renal cell carcinoma treated with sunitinib showed improved overall survival and progression-free survival in patients who developed HFSR compared with those who did not [10]. These findings have been confirmed in multiple studies of patients with metastatic renal cell carcinoma treated with sunitinib [13,14]. A study from Taiwan showed that in patients with soft tissue sarcoma treated with pazopanib, HFSR was an independent predictive factor for better treatment outcome [15], and the appearance of HFSR was found to independently predict prolonged, progression-free survival in patients on lenvatinib for hepatocellular carcinoma [16].

PATHOGENESIS — Although the exact mechanism leading to HFSR is unknown, it is thought that the inhibition of both the vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptors is necessary to cause HFSR. Inhibition of either one of these receptors alone rarely leads to HFSR [17]. Moreover, the observation that the incidence of HFSR increases when multikinase inhibitors are combined with VEGF receptor blockers such as bevacizumab and cediranib supports the theory that capillary microtrauma and/or inability to effectively repair vascular trauma at sites prone to mechanical and frictional stress results in drug extravasation and tissue damage [18]. Further supporting the importance of vascular competence in the pathogenesis of HFSR is its increased incidence in patients treated with regorafenib, which uniquely inhibits the endothelium-specific TIE-2 receptor (important for vascular remodeling) [17]. It was demonstrated via microarray analysis in a three-dimensional (3-D) epidermal model that sunitinib decreases expression of keratin 6A and serine protease inhibitor (SERPIN)B1 through inhibition of phosphorylated extracellular signal-regulated kinases (ERK)1/2 and phosphorylated p38 mitogen-activated protein kinase (MAPK) signaling pathways [19].

HISTOPATHOLOGY — The main histopathologic features described for HFSR are similar to hand-foot syndrome (HFS) caused by cytotoxic chemotherapy. They include dyskeratotic keratinocytes at various stages of necrosis, vacuolar degeneration of the basal layer, and mild perivascular or lichenoid infiltrate that is predominantly lymphocytic [20]. Necrotic subepidermal, intraepidermal, or subcorneal blisters can form followed by acanthosis with hyperkeratosis or parakeratosis. Cases of mild cystic degeneration of the eccrine coil and squamous metaplasia of the sweat glands have also been described [21]. While the histologic features of HFS and HFSR can be similar, HFSR is more likely to show an increased rate of epidermal replication resulting in papillomatosis and acanthosis [20].

CLINICAL MANIFESTATIONS — HFSR appears in the first two to four weeks of treatment with tyrosine kinase inhibitors (TKIs) [1]. It typically involves the palms and soles but can also occur in other friction-prone areas such as the interdigital web spaces and lateral aspects of the feet [18]. It has been reported in unusual areas of excessive friction such as the fingertips used to operate a mobile device and the stump of an amputee [22,23].

The typical appearance is that of focal, hyperkeratotic, callus-like lesions on an erythematous base in areas of pressure or friction such as the fingertips, heels and metatarsal areas, and over joints (picture 1A-C). These lesions can begin as bullae or blisters [17]. This clinical presentation differs from that of hand-foot syndrome (HFS) caused by cytotoxic chemotherapy, which typically presents with a diffuse erythema and scale involving the entire palm and sole (picture 2A-B) [18]. (See "Toxic erythema of chemotherapy (hand-foot syndrome)", section on 'Hand-foot syndrome'.)

HFSR lesions are usually painful; other symptoms may include paresthesia, tingling, burning, soreness of the palms and soles, and decreased tolerance of contact with hot objects [1]. In severe cases, HFSR can limit the patient's ability to care for or dress themselves. Long-term cutaneous sequelae have not been reported.

IMPACT ON QUALITY OF LIFE — Although HFSR is not life-threatening and is usually self-limiting, the symptom burden may significantly reduce the patient's health-related quality of life (HRQL) and lead to dose reductions or premature drug discontinuation. One study examining the data from 23 patients receiving sorafenib or sunitinib who completed the Skindex-16 (a self-reported, dermatology-specific quality of life [QoL] questionnaire) found a positive correlation between scores for symptoms and emotions and severity grade of HFSR, with the highest score reported for the symptoms domain [24].

Two instruments have been developed to assess specifically the HRQL in patients with hand-foot syndrome (HFS) and HFSR, the HFS-14 [25], which assesses functional implications, and the newer HFSR and quality of life (HF-QoL) questionnaire [26]. The latter evaluates the wider symptom burden, including physical well-being, activities of daily living, role function, social activities, emotional well-being, and mood. Although generally used in the setting of clinical trials, these instruments may be helpful in clinical practice to assess the patient's tolerance of treatment and overall clinical status.

DIAGNOSIS — The diagnosis of HFSR is usually straightforward, based upon the clinical appearance of hyperkeratotic plaques with painful erythema localized to areas of friction or pressure of the palms and soles (picture 1C) and history of tyrosine kinase inhibitor (TKI) use. A skin biopsy is not usually performed, due to the potential morbidity associated with this procedure on the hands or feet.

Grading of severity — Grading the severity of HFSR is important to guide the approach to treatment and to facilitate the communication between dermatologist and oncologist. In clinical trials and oncology practices, the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, is the most commonly employed scale to assess the severity of cutaneous adverse reactions to cancer treatment (table 2) [26,27]. Although HFSR is not included in CTCAE as its own category, "palmoplantar erythrodysesthesia" can be used to grade HFSR. It is also important to keep in mind the limitations of the CTCAE scale, which does not incorporate the patient's perception of severity or the potentially prolonged duration of HFSR [28].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of HFSR includes other eruptions occurring primarily on the hands and feet:

●Hand-foot syndrome (HFS) – In patients receiving both a targeted agent and a cytotoxic chemotherapeutic agent, this distinction may be important to guide the reduction of the appropriate medication, if indicated. While both can be associated with pain and paresthesias, HFS due to cytotoxic chemotherapy typically presents with diffuse erythema and desquamation (picture 2A-B), in contrast with the more focal hyperkeratotic lesions found in HFSR [18]. (See "Toxic erythema of chemotherapy (hand-foot syndrome)", section on 'Hand-foot syndrome'.)

●Contact dermatitis – Allergic or irritant dermatitis involving the hands and/or feet presents with erythema and scale that are often more diffuse than HFSR (picture 3) and are typically associated with pruritus rather than pain. (See "Irritant contact dermatitis in adults" and "Clinical features and diagnosis of allergic contact dermatitis".)

●Tinea pedis and manuum – Skin infection from dermatophytes of the genus Trichophyton is characterized by erythema and scaling. The involvement of the hand is typically unilateral, resulting in the so-called "two-feet, one hand syndrome" (picture 4). Dermatophyte infections are usually more pruritic than painful. A skin scraping from an affected area with a potassium hydroxide preparation will reveal fungal hyphae. (See "Dermatophyte (tinea) infections", section on 'Tinea pedis' and "Dermatophyte (tinea) infections", section on 'Tinea manuum'.)

●Psoriasis – Psoriasis may present with erythema and scale of the palms and/or soles (picture 5). However, it is often associated with characteristic nail changes, such as pitting (picture 6) and oil spots (picture 7), as well as symmetric plaques on other areas of the body (picture 8). Patients often have a history of psoriasis; however, if a new presentation is suspected, a skin biopsy may be needed to differentiate psoriasis from HFSR. (See "Psoriasis: Epidemiology, clinical manifestations, and diagnosis".)

●Dyshidrotic dermatitis (eczema) – This type of eczema presents with deep-seated vesicles and blisters typically located on the volar aspect of the hands and feet (picture 9A-C). In contrast with HFSR, dyshidrotic eczema is intensely pruritic and is not limited to areas of friction and pressure. (See "Acute palmoplantar eczema (dyshidrotic eczema)".)

MANAGEMENT — The approach to management of HFSR should be individualized, depending upon severity, impact on the patient's activities of daily living, and need to continue anticancer treatment with multitargeted tyrosine kinase inhibitors (TKIs). A multidisciplinary approach to care, including oncologist, dermatologist, podiatrist, and nursing care, can be helpful.

There are limited clinical trials specifically addressing the treatment of HFSR [29]. Treatment is generally based upon clinical experience, expert consensus, and local guidelines [17,21,29,30]. Our approach to management of HFSR is illustrated in the algorithm (algorithm 1).

General principles

Treatment of hyperkeratosis and skin inflammation — Topical keratolytic agents, such as creams or ointments containing topical urea 10 to 20%, can be applied focally to hyperkeratotic areas [17]. Caution should be used as these agents can cause irritation and discomfort if applied to nonintact skin. Keratolytic medications can be used for all grades of HFSR (algorithm 1). It is imperative that health care providers seek out any causes of friction in areas of HFSR; inspection of clothing and questioning regarding daily activities may be needed to identify potential exacerbating factors. (See 'Prevention' below.)

Topical corticosteroids may be helpful to reduce skin inflammation in patients with grade 2 or higher HFSR. Since palms and soles are areas at low risk of skin atrophy from topical corticosteroids, superpotent corticosteroids (group 1 (table 3)) can be safely used until cutaneous inflammation subsides. We typically use clobetasol propionate 0.05%, halobetasol 0.05%, or betamethasone dipropionate 0.05% in ointment, cream, or foam formulation, twice daily.

Treatment of pain — Topical analgesics such as topical lidocaine 4 to 6% in gels, creams, or patches can be used for symptomatic pain relief for grades 1 and 2 HFSR. Systemic pain medications such as nonsteroidal anti-inflammatory drugs, opioids, or gamma-aminobutyric acid (GABA) agonists (gabapentin or pregabalin) may be of use in grade 2 or higher HFSR, if no contraindications exist [17].

Prevention of infection — Although secondary infection in HFSR has not been described, given the patient's immunocompromised status, the disruption of the skin barrier by trauma or inflammation is a concern as a possible portal of entry for infection. Open or oozing areas of the skin may be treated with antiseptics (eg, potassium permanganate, chlorhexidine gluconate, diluted bleach) or topical antibiotics (eg, mupirocin 2%, gentamicin 1%) [17].

Other — Small studies and case reports suggest a beneficial effect of heparin-containing ointment [31], hydrocolloid dressing containing ceramide [32], vitamin E [33], narrowband ultraviolet B phototherapy [34], and topical sildenafil [35] in the treatment of HFSR. However, these treatments are rarely used due to the scant evidence of efficacy, costs, and limited accessibility of some of them.

Our approach — There is no evidence from randomized trials to determine the best reactive strategy for HFSR. Our approach, based upon clinical experience and expert consensus, is illustrated in the algorithm (algorithm 1) [17,21,29,30].

Patients with grade 1 hand-foot skin reaction — For mild, grade 1 HFSR (table 2), dose modifications are not needed (algorithm 1). Patients should avoid using hot water and should regularly apply keratolytic emollients containing topical urea 10% three times per day. (See 'Treatment of hyperkeratosis and skin inflammation' above.)

We generally reassess patients after two weeks of treatment. If the reaction has not improved or has worsened, patients are treated in the same way as those with grade 2 rash.  

Patients with grade 2 hand-foot skin reaction — For grade 2 HFSR, topical treatment includes a superpotent topical corticosteroid (group 1 (table 3)) to be applied to the erythematous areas (algorithm 1). We use clobetasol propionate 0.05% ointment, foam, or solution twice daily and lidocaine 4 to 6% cream or patches during the day.

Oral analgesics, including nonsteroidal anti-inflammatory drugs, opioids, or GABA agonists (eg, gabapentin, pregabalin) may be given as needed to reduce skin pain and discomfort. (See 'Treatment of hyperkeratosis and skin inflammation' above.)

We generally reassess patients after two weeks of treatment. If the reaction has not improved or has worsened, patients are treated in the same way as those with grade 3 rash [17,21].  

For grade 2 reaction that does not respond to treatment, the TKI dose can be decreased as per the prescribing information. If the HFSR does not improve, the TKI can be temporarily discontinued as for patients with grade 3 HFSR, until symptoms improve to grade 0 or 1, and then resumed at a lower dose as per prescribing information [17,21].

Patients with grade 3 hand-foot skin reaction — For patients with grade 3 or intolerable grade 2 reaction that does not respond to treatment, a temporary interruption of the TKI is indicated (algorithm 1). The TKI should be held for at least seven days or until toxicity resolves and then resumed at a lower dose as per the prescribing information. If the adverse reaction does not recur, dose escalation can be attempted.

Topical treatments and oral pain medications are continued as for grade 2.

PREVENTION — Prior to initiating treatment with multitargeted tyrosine kinase inhibitors (TKIs), we instruct patients to adopt prophylactic measures that may reduce the likelihood or severity of HFSR (algorithm 1). These include [17,21,29]:

●Urea 10% cream three times per day to palms and soles.

●Examining hands and feet for presence of calluses. Hyperkeratotic areas and calluses should be removed through a manicure and/or pedicure, using appropriately sterilized instruments. Keratotic skin can be gently exfoliated using a pumice stone.

●Keeping skin of hands and feet well-moisturized using bland emollients or topical urea-based creams, especially after washing.

●Seeking evaluation by an orthotist for an orthotic device is encouraged for patients with evidence of abnormal weight bearing.

●Avoiding exposing hands and feet to hot water, as this is believed to exacerbate symptoms.

●Avoiding constrictive footwear and excessive friction on the skin when applying lotions, getting massages, or performing everyday tasks such as typing or using handheld electronic devices.

●Avoiding vigorous exercise that places undue stress on the palms and/or soles of the feet, particularly during the first month of therapy.

●Wearing shoes with padded insoles throughout treatment to reduce pressure on the feet. Thick cotton gloves or socks can be worn to prevent injury and keep the palms and soles dry.

The use of a 10% topical urea cream for the prevention of HFSR has been evaluated in a randomized trial of 871 patients receiving sorafenib for advanced hepatocellular carcinoma [36]. In this study, patients were treated with 10% topical urea cream three times per day plus best supportive care or best supportive care alone excluding all creams. The incidence of any grade HFSR within 12 weeks of starting sorafenib was modestly but significantly lower with the topical urea cream (56 versus 74 percent, odds ratio [OR] 0.46, 95% CI 0.34-0.61) as was the incidence of grade (≥2) HFSR (21 versus 29 percent, OR 0.64, 95% CI 0.47-0.87). However, due to the lack of a placebo (vehicle) group, it is unclear whether the beneficial effect of treatment is associated with topical urea or the cream itself.

Another 12-week trial comparing urea 20% cream and placebo in 288 patients with hepatocellular carcinoma treated with sorafenib found a trend towards lower cumulative incidence of any-grade and severe HFSR in the urea group [37]. At 12 weeks, the patients using urea cream had a lower incidence of grade ≥2 HFSR and a significantly better quality of life (HF-QoL) score.

SUMMARY AND RECOMMENDATIONS

●Incidence – Hand-foot skin reaction (HFSR) is the most common cutaneous adverse reaction to treatment with multitargeted tyrosine kinase inhibitors (TKIs). The incidence rates of all-grade and high-grade HFSR vary, depending on the specific drug used and type of malignancy (table 1), and appear to be more common in females. (See 'Introduction' above and 'Epidemiology' above.)

●Clinical presentation – HFSR appears in the first two to four weeks of treatment with TKIs. It typically presents with focal, hyperkeratotic, callus-like lesions and erythema on the palms and soles (picture 1A-C) but can also occur in other friction-prone areas such as the interdigital web spaces and lateral aspects of the feet. (See 'Clinical manifestations' above.)

●Diagnosis – The diagnosis of HFSR is usually straightforward, based upon the clinical appearance and history of TKI use. The severity is graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 5.0 (table 2). (See 'Diagnosis' above.)

●Prevention – Prior to initiating treatment with multitargeted TKIs, instruct patients to adopt prophylactic measures that may reduce the likelihood or severity of HFSR, including hand and foot care to eliminate hyperkeratoses, podiatric consultation, minimization of friction and pressure, and use of emollients or topical urea 10 to 20% three times per day. (See 'Prevention' above.)

●Management – Reactive treatment is based upon clinical experience, consensus statements, and local guidelines. Our approach is illustrated in the algorithm (algorithm 1) (see 'Management' above):

•For patients with grade 1 HFSR (table 2), we suggest keratolytic moisturizers (Grade 2C). We use topical urea 10 to 20% creams or ointments and lidocaine 4 to 6% cream or patches. (See 'Patients with grade 1 hand-foot skin reaction' above.)

•For patients with grade 2 HFSR, we suggest super high-potency topical corticosteroids (group 1 (table 3)) and oral analgesics in addition to topical therapies as for grade 1 (Grade 2C). We use clobetasol propionate 0.05% ointment, foam, or solution twice daily. If the reaction does not improve, the TKI dose can be lowered as per the prescribing information until symptoms improve to grade 0 or 1 and then resumed at a lower dose as per prescribing information. (See 'Patients with grade 2 hand-foot skin reaction' above.)

•For patients with grade 3 HFSR or intolerable grade 2 HFSR that does not respond to treatment, we suggest to hold the TKI dose for at least seven days or until HFSR resolves (Grade 2C). In addition, we continue topical medications and oral analgesics as for grade 1 and 2. Once the toxicity has resolved, treatment with the TKI can be resumed at a lower dose. If the adverse reaction does not recur, dose escalation can be attempted. (See 'Patients with grade 3 hand-foot skin reaction' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Mario E Lacouture, MD, who contributed to an earlier version of this topic review.