Hand-foot skin reaction induced by multitargeted tyrosine kinase inhibitors

INTRODUCTION — 

Vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR) inhibitors are a group of small molecule tyrosine kinase inhibitors (TKIs). They include selective and multikinase inhibitors, a class of targeted anticancer medications approved for the treatment of a number of solid tumors. (See "Overview of angiogenesis inhibitors", section on 'Antiangiogenic therapy of cancer'.)

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.

Hand-foot skin reaction (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 TKIs and other targeted anticancer therapies are discussed separately. Cutaneous reactions to conventional chemotherapeutic agents are also discussed separately.

●(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".)

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

●(See "Toxic erythema of chemotherapy (hand-foot syndrome)".)

EPIDEMIOLOGY

Incidence — The risk of developing HFSR varies depending on the specific drug used and type of malignancy (table 1) [1-3].

A meta-analysis of 57 studies that included nearly 25,000 patients treated with vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitors (TKIs) found a pooled incidence of 35 percent (95% CI 28.6-41.6) for all-grade HFSR and 9.7 percent (95% CI 7.3-12.3) for high-grade HFSR [4]. 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.

●Genetic factors – Several genetic polymorphisms have been identified that increase the risk of development of HFSR. Variant genes involved in the CCL5/CCR5 (C-C motif chemokine ligand 5/C-C motif chemokine receptor 5) pathway have been found to predict severe HFSR in patients with metastatic colorectal cancer treated with regorafenib [5]. Polymorphisms in the VEGFR2 and VEGFA genes may also be associated with increased risk of developing HFSR and better outcome [6,7].

●Patient-related factors

•In a study of patients with renal cell carcinoma treated with sorafenib, the factors predictive of grade 2 or greater HFSR included [2]:

-Female sex

-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

-Week of therapy (with maximum risk at week 5)

•The development of hypertension has been shown to be a risk factor for HFSR in patients treated with bevacizumab and/or sorafenib [6].

•It has been hypothesized that zinc deficiency may have a role in the development of HFSR [8].

PATHOGENESIS — 

Although the exact mechanism leading to HFSR is unknown, it is thought that the simultaneous inhibition of both the vascular endothelial growth factor receptor (VEGFR) and the platelet-derived growth factor receptor (PDGFR) is necessary to cause HFSR. Inhibition of either one of these receptors alone rarely leads to HFSR [9].

Moreover, the observation that the incidence of HFSR increases when multikinase inhibitors are combined with VEGFR blockers (eg, 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 [10].

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) [9].

It was demonstrated via microarray analysis in a three-dimensional (3D) 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 [11].

CLINICAL MANIFESTATIONS — 

HFSR appears in the first two to four weeks of treatment with a tyrosine kinase inhibitor (TKI) [12]. In a retrospective study of 102 patients treated with multikinase inhibitors, the median time to the development of HFSR was 18 days [13].

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 [10]. It has been reported in unusual areas of excessive friction, such as the fingertips used to operate a mobile device and the stump of a person with an amputation [14,15].

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 and picture 1B and picture 1C). These lesions can begin as bullae or blisters [9].

This clinical presentation differs from that of hand-foot syndrome caused by cytotoxic chemotherapy, which typically presents with a diffuse erythema and scale involving the entire palm and sole (picture 2A-B) [10]. (See 'Differential diagnosis' below and "Toxic erythema of chemotherapy (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 [12]. 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 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 [16].

Two instruments have been developed to specifically assess the HRQL in patients with hand-foot syndrome (HFS) and HFSR: the HFS-14, which assesses functional implications [17], and the newer hand-foot skin reaction and quality of life (HF-QoL) questionnaire [18]. 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.

IMPACT ON SURVIVAL — 

Multiple studies have noted an association between the development of HFSR and other skin toxicities from tyrosine kinase inhibitors (TKIs) and improved tumor response rate and overall survival rate [6,19-21].

●A Japanese prospective study of 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 HFSR [21]. 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).

●In another Japanese study of 97 patients receiving regorafenib for metastatic colorectal cancer, patients who developed grade ≥2 HFSR had a better overall and progression-free survival than those who had grade ≤1 HFSR [22].

●In a Chinese study of 435 patients with hepatocellular carcinoma treated with sorafenib, the development of grade ≥2 HFSR within 60 days of sorafenib initiation was associated with a decreased risk of death (adjusted hazard ratio 0.53, 95% CI 0.43-0.67) and progression (adjusted hazard ratio 0.74, 95% CI 0.58-0.96) [23].

●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 [24].

●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 [20]. These findings have been confirmed in multiple studies of patients with metastatic renal cell carcinoma treated with sunitinib [25,26].

●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 [27], and the appearance of HFSR was found to independently predict prolonged, progression-free survival in patients on lenvatinib for hepatocellular carcinoma [28].

DIAGNOSIS

Clinical — The diagnosis of HFSR is usually straightforward, based on the clinical appearance of hyperkeratotic plaques with painful erythema localized to areas of friction or pressure of the palms and soles (picture 1C) within days to a few weeks of initiating treatment with a tyrosine kinase inhibitor (TKI).

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 treatments (table 2) [18,29]. Although HFSR is not included in the 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 [30].

Skin biopsy and histopathology — A skin biopsy is not usually performed due to the potential morbidity associated with this procedure on the hands or feet. However, it may be necessary to rule out other skin conditions that may mimic HFSR. (See 'Differential diagnosis' below.)

The main histopathologic features described for HFSR are similar to hand-foot syndrome caused by cytotoxic chemotherapy. (See "Toxic erythema of chemotherapy (hand-foot syndrome)".)

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 [31]. 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 [32]. While the histologic features of hand-foot syndrome and HFSR can be similar, HFSR is more likely to show an increased rate of epidermal replication resulting in papillomatosis and acanthosis [31].

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis of HFSR includes other eruptions occurring primarily on the hands and feet.

●Hand-foot syndrome – 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, hand-foot syndrome 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 [10]. (See "Toxic erythema of chemotherapy (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 "Allergic contact dermatitis: Clinical features and diagnosis" and "Irritant contact dermatitis in adults".)

●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 (KOH) 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)".)

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 [9,32,33]:

●General foot care measures

•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 the 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.

●Topical urea – The use of a 10% to 20% urea-based cream three times per day on palms and soles may help promote skin hydration and prevent HFSR.

•In a randomized trial of 871 patients receiving sorafenib for advanced hepatocellular carcinoma, patients were treated with 10% topical urea cream three times per day plus best supportive care or best supportive care alone excluding all creams [34]. 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 0.46, 95% CI 0.34-0.61) as was the incidence of grade ≥2 HFSR (21 versus 29 percent, odds ratio 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 [35]. At 12 weeks, the patients using urea cream had a lower incidence of grade ≥2 HFSR and a significantly better quality of life (hand-foot skin reaction and quality of life [HF-QoL]) score.

•Another trial that included 129 patients undergoing treatment with sorafenib found that a 10% urea-based cream was more effective than moisturizers in maintaining skin hydration but did not reduce the incidence of HFSR [36].

●Topical clobetasol – In a preplanned analysis of a regorafenib dose optimization trial in 116 patients with metastatic colorectal cancer, patients received preemptive (n = 61) or reactive (n = 55) clobetasol 0.05% twice daily on the palms and soles [37]. The proportion of patients who did not develop HFSR was greater in the preemptive group than in the reactive group during the second cycle of regorafenib (33 versus 15 percent, respectively) but not during the first cycle. However, the absence of a placebo (vehicle) group does not allow firm conclusions to be drawn regarding the efficacy of topical clobetasol in preventing HFSR.

●Moisturizers plus hydrocolloid dressing – In a randomized intrapatient comparison study that included 50 patients treated with multitargeted TKIs, the proportion of patients developing grade ≥2 HFSR was significantly lower in the hydrocolloid dressing arm than in the control arm (20 versus 50 percent) [38].

●Zinc supplementation – In a small open-label randomized trial that included 65 patients undergoing treatment with regorafenib for metastatic colon cancer, patients were assigned to zinc supplementation with zinc gluconate 78 mg twice daily or no supplementation [39]. At eight weeks, the proportion of patients with grade 2/3 HFSR was lower in the supplementation group than in the no supplementation group (12.5 and 33 percent, respectively). The proportion of patients who had a dose reduction during the first eight weeks of treatment was similar in the two groups (69 and 64 percent, respectively).

●Celecoxib – In a randomized trial, 116 patients with advanced hepatocellular carcinoma were assigned to treatment with sorafenib alone or sorafenib plus celecoxib 200 mg twice daily [40]. Patients in the sorafenib plus celecoxib group were less likely to develop grade 2/3 HFSR (29 versus 64 percent, hazard ratio 0.38, 95% CI 0.21-0.70) and to require dose reduction or interruption (15.5 versus 46.6 percent).

MANAGEMENT — 

There is limited evidence from clinical trials to determine the best management strategy for HFSR. Treatment is generally based on clinical experience, expert consensus, and local guidelines [9,32,33,41,42]. Management should be individualized depending on severity, impact on the patient's activities of daily living, and need to continue anticancer treatments. A multidisciplinary approach to care, including oncologist, dermatologist, podiatrist, and nursing care, can be helpful.

General principles

Treatment of hyperkeratosis and skin inflammation

●Topical keratolytic agents – Topical keratolytic agents, such as creams or ointments containing topical urea 10% to 20%, can be applied focally to hyperkeratotic areas [9]. 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 clinicians 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' above.)

●Topical corticosteroids – 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 (NSAIDs), opioids, or gamma-aminobutyric acid (GABA) agonists (gabapentin or pregabalin), may be used in grade 2 or higher HFSR if no contraindications exist [9].

Tyrosine kinase inhibitor dose modification/interruption — For most patients experiencing HFSR, dose modification or interruption of current tyrosine kinase inhibitor (TKI) treatment is not necessary. However, the drug dose can be decreased or temporarily interrupted in patients with grade ≥2 HFSR that does not respond to treatment. (See 'Patients with grade 3 hand-foot skin reaction' below.)

Our approach — Our approach is based on the HFSR severity according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 (table 2) and is illustrated in the algorithm (algorithm 1) [9,32,33,41].

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.)

Topical analgesics such as topical lidocaine 4% to 6% in gels, creams, or patches can be used for symptomatic pain relief.

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, dose modifications are generally not needed. 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 NSAIDs, 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 [9,32].

For grade 2 reaction that does not respond to treatment, the TKI dose can be decreased as per the prescribing information until symptoms improve to grade 0 or 1 and then resumed at a lower dose as per 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 [9,32].

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.

Other treatments — Several other treatments have been used for HFSR. However, there is limited evidence of efficacy to support their routine use.

●Zinc supplementation – A cohort study suggests that zinc supplementation may improve HFSR in patients receiving vascular endothelial growth factor receptor (VEGFR)-TKIs [43]. In this study, which included 80 patients, supplementation with elemental zinc 10 mg per day improved HFSR by at least one grade in 38 of 47 patients (81 percent) with grade 2/3 reaction. None of the patients interrupted TKI treatment.

●Other therapies – Small studies and case reports suggest a beneficial effect of several treatments for HFSR. These include:

•Heparin-containing ointment [44]

•Hydrocolloid dressing containing ceramide [45]

•Vitamin E [46]

•Narrowband ultraviolet B (NBUVB) phototherapy [47]

•Topical sildenafil [48]

•Acitretin [49]

•Traditional Chinese herbal preparations [13,50,51]

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. Lesions can start as bullae. (See 'Clinical manifestations' above.)

●Diagnosis – The diagnosis of HFSR is usually straightforward, based upon the clinical appearance and history of TKI use. A skin biopsy is generally not needed for the diagnosis. 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, we 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 – Management of HFSR is individualized and based on severity (table 2), impact on patient's activities of daily living, and the need to continue anticancer therapy (algorithm 1). Key components include topical therapies for hyperkeratosis and skin inflammation, treatment of pain, and assessment of the need for dose modification or temporary interruption of TKI therapy. (See 'Management' above.)

•Treatment of pain – Topical analgesics (eg, topical lidocaine) can be used for symptomatic pain relief for grades 1 and 2 HFSR. Systemic analgesics, such as nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, or gamma-aminobutyric acid (GABA) agonists (gabapentin or pregabalin), may be used in grade 2 or higher HFSR. (See 'Treatment of pain' above.)

•Grade 1 hand-foot skin reaction – For patients with grade 1 HFSR, we suggest keratolytic moisturizers rather than topical corticosteroids (Grade 2C). We typically use topical urea 10% to 20% creams or ointments. (See 'Patients with grade 1 hand-foot skin reaction' above.)

•Grade 2 hand-foot skin reaction – For patients with grade 2 HFSR, we suggest super high-potency topical corticosteroids (group 1 (table 3)) in addition to topical keratolytic moisturizers (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.)

•Grade 3 hand-foot skin reaction – For patients with grade 3 HFSR or intolerable grade 2 HFSR that does not respond to treatment, we suggest holding the TKI dose for at least seven days or until HFSR resolves (Grade 2C). In addition, we continue topical medications as for grade 1 and 2 and pain treatment. Once the skin 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.)

•Other treatments – Several other treatments have been used for HFSR, including oral zinc supplementation, hydrocolloid dressings, and traditional Chinese herbal preparations. However, the limited evidence for their efficacy does not support their routine use. (See 'Other treatments' above.)

ACKNOWLEDGMENT — 

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