Toxic erythema of chemotherapy (hand-foot syndrome)

INTRODUCTION — The term "toxic erythema of chemotherapy" (TEC) was proposed in 2008 as a unifying, descriptive, diagnostic entity for the various clinical and histopathologic reaction patterns with significant overlapping features reported with chemotherapy [1]. The clinical presentation most frequently seen involves the hands and feet, hence the name "hand-foot syndrome" (HFS), which has been known by a variety of terms including acral erythema, palmar-plantar erythrodysesthesia, palmar-plantar erythema, toxic acral erythema, toxic erythema of the palms and soles, Burgdorf's reaction, and periarticular thenar erythema with onycholysis (PATEO) syndrome [2].

Originally reported in patients receiving high-dose cytarabine for acute leukemia, HFS has been frequently described in patients receiving pegylated liposomal doxorubicin, capecitabine (an oral fluoropyrimidine that is converted in vivo to fluorouracil, providing prolonged tissue exposure), or fluorouracil, although many other drugs have been implicated (table 1) [2-7].

Multitargeted tyrosine kinase inhibitors, such as sorafenib, sunitinib, and other kinase inhibitors that target angiogenesis, are associated with a high incidence of a hand-foot skin reaction, but the clinical and histologic patterns differ from the classic HFS that develops with conventional cytotoxic agents. Hand-foot skin reaction is discussed in detail elsewhere. Other adverse effects of conventional chemotherapeutic agents are also discussed separately.

●(See "Hand-foot skin reaction induced by multitargeted tyrosine kinase inhibitors".)

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

FREQUENCY AND CAUSATIVE AGENTS — TEC occurs in approximately 6 to over 60 percent of patients treated with the chemotherapeutic agents most frequently implicated (eg, doxorubicin, pegylated liposomal doxorubicin, fluoropyrimidines [fluorouracil, capecitabine], cytarabine, docetaxel); frequency varies depending on the specific agent, dose, and mode of administration [2,8,9]. However, TEC may occur with many other drugs (table 1). At least in the case of cytarabine, capecitabine, and doxorubicin, TEC is dose related. Drug formulations and administration schedules that result in sustained serum levels over time are more frequently associated with TEC.

As an example, pegylated liposomal doxorubicin is associated with a higher frequency of TEC than the nonencapsulated form of doxorubicin, particularly with initial doses greater than 40 mg/m² [10]. TEC is often the dose-limiting toxicity with certain chemotherapeutic agents (eg, capecitabine) [11].

PATHOGENESIS — The pathogenesis of TEC is not well understood. A direct toxic effect of the chemotherapeutic agent on eccrine coils (which are in highest density on the palms and soles) has been proposed. However, there is no direct evidence to support this theory as microscopic evidence of damage to the eccrine sweat glands or ducts is only infrequently reported [12,13].

TEC most often develops in patients who have neither undergone hematopoietic cell transplantation nor received blood products [14]. Finally, the occasional co-occurrence of facial erythema/edema, papular rash, and fever has led some to view this as a type I (immunoglobulin E [IgE]-mediated) allergic reaction, though TEC is often delayed by two to three weeks following chemotherapy rather than within 24 hours (as is usually seen with type I reactions) [15].

For patients treated with capecitabine, at least some data suggest that expression of the capecitabine-activating enzyme thymidine phosphorylase (TYMP) is significantly greater in the skin of the palms compared with skin on the lower back, providing higher tissue levels of the active moiety to this area [16]. Furthermore, the proliferative rate of epidermal basal cells in the palm was also higher compared with skin from the back, suggesting that palmar skin might be more sensitive to the local action of cytotoxic drugs.

Fluoropyrimidine toxicity may be associated with genetic polymorphisms of dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthase (TYMS), genes that encode for two enzymes that are involved in metabolism [17]. Although genetic tests are available that sequence the entire DPYD gene and identify some TYMS polymorphisms that predispose to excess hematologic and gastrointestinal toxicity, genetic testing is not considered standard of care prior to initiating fluoropyrimidine therapy (at least in North America). (See "Clinical presentation and risk factors for chemotherapy-associated diarrhea, constipation, and intestinal perforation", section on 'Testing for DPYD and TYMS variants'.)

CLINICAL PRESENTATION

Timing — Symptoms of TEC often develop one to three weeks after chemotherapy administration but may occur sooner, often within five to seven days with capecitabine.

Hand-foot syndrome — When TEC affects the hands and feet (HFS), it is often most pronounced over the fat pads of the proximal phalanges (picture 1A-B). Most cases are of grade 1 or grade 2 severity (table 2) [9].

●Clinical presentation – Affected patients initially complain of a tingling sensation, which is followed by the development of edema and tender, symmetric erythema. Skip areas may occur as can extension to the dorsal surfaces of the extremities. Affected areas may develop pallor, blistering, and desquamation [18-20]. Cutaneous and oral hyperpigmentation have been described in patients with darkly pigmented skin who have capecitabine-associated HFS [21,22].

●Impact on quality of life – HFS is a painful condition and may limit daily activities such as walking or grasping objects. Functional impairment is a component of the grading system for severity of HFS (table 2).

●Clinical course – HFS is dose related and usually resolves within two to four weeks after discontinuation of the causative agent.

Clinical variants — Variants of TEC include:

●Malignant intertrigo – TEC may also occur in intertriginous sites (previously known as malignant intertrigo) with involvement of the axillary folds, antecubital/popliteal fossae, neck, inguinal folds, buttocks, and genitals, mimicking a symmetric drug-related intertriginous and flexural exanthema [23-25]. Occasionally, it may be misdiagnosed as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) [26]. (See "Exanthematous (maculopapular) drug eruption", section on 'Intertriginous and flexural reaction pattern'.)

Involvement of the ears is commonly seen with cytarabine, giving rise to the phrase "Ara-C (cytarabine) ears."

●PATEO syndrome – Periarticular thenar erythema with onycholysis (PATEO) syndrome, a variant of TEC, was originally described in 2003 as HFS associated with taxanes (paclitaxel, docetaxel) that is accentuated over the dorsum of the hands (particularly the hypothenar eminence) or base of the thumb [27-30]. Distinct nail changes, including onycholysis, can occur due to cytotoxicity to the nail matrix. PATEO syndrome can additionally affect the skin around the Achilles tendon. (See "Cutaneous adverse effects of conventional chemotherapy agents", section on 'Onycholysis'.)

●Fixed erythrodysesthesia plaque – Another presumed variant of TEC, termed "fixed erythrodysesthesia plaque," is characteristic of intravenous injections of docetaxel [31-33]. This lesion develops as a fixed, solitary, erythematous plaque proximal to the infusion site that does not involve the palms or soles. It usually resolves with desquamation, leaving an area of hyperpigmented skin five to six weeks later.

●Stevens-Johnson syndrome/toxic epidermal necrolysis-like presentation – A particularly severe bullous variant resembling SJS/TEN, progressing to full-thickness epidermal necrosis and sloughing, has been reported following cytarabine or high-dose methotrexate, particularly in children [34-39].

Fingerprint loss — One potential consequence of capecitabine-associated TEC is the loss of fingerprints [40-43]. Patients on long-term therapy should be advised of this potential adverse effect, since it may be an impediment in situations in which fingerprint identification is necessary (eg, international travel).

However, an important point is that fingerprint loss is not permanent. In a prospective cohort study of 66 patients who were undergoing treatment with capecitabine or a tyrosine kinase inhibitor and who were fingerprinted at baseline, within 6 to 10 weeks after treatment initiation, and after treatment discontinuation, nine patients (14 percent) had severe loss of fingerprints [43]. Loss was unrelated to the severity of TEC in this study. Complete recovery of fingerprints occurred in all three patients who were able to participate in post-treatment assessments within two to four weeks after treatment discontinuation.

DIAGNOSIS

Clinical — The diagnosis of TEC is usually clinical, based on medication history and clinical presentation.

Skin biopsy and histopathology — A skin biopsy is not routinely performed in patients with TEC, as the histopathologic changes are generally nonspecific. A vacuolar interface dermatitis with basilar squamatization and necrotic keratinocytes is most commonly seen, with superficial dermal edema and a mild, perivascular lymphocytic infiltrate (picture 2) [8,44]. Epidermal dysmaturation resembling squamous cell carcinoma in situ may be observed (picture 3) [45]. Changes in the adnexal structures, including vacuolar changes in the epithelium, neutrophilic infiltration or necrosis of eccrine glands, or squamous syringometaplasia, have also been described (picture 4) [46-49].

The pathologic differential diagnosis includes acute graft-versus-host disease (in the appropriate clinical setting) and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). The distinction of TEC from graft-versus-host disease and SJS/TEN is important since the treatments are distinct. Unfortunately, a biopsy may not be able to distinguish among these entities in a clinically relevant timeframe. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease", section on 'Skin' and "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

TREATMENT — The main treatment for TEC is drug interruption or dose modification, depending on the severity of the reaction, in combination with topical corticosteroids and supportive treatment.

●Drug interruption/dose modification – For patients who develop severe (grade 2 or 3 [depending on the drug] (table 2)) HFS, subsequent chemotherapy doses should be reduced to avoid recurrence. Based upon the severity of the reaction, the hazard of rechallenge, and the clinical situation, it may be necessary to discontinue therapy entirely and switch to an alternative regimen if one is available.

●Topical corticosteroids – We suggest super high-potency topical corticosteroids (group 1 (table 3)) for the treatment of severe HFS (grade 2 or 3) in combination with supportive treatment. Topical corticosteroids are applied twice daily to the involved areas.

●Supportive treatments – Supportive treatment includes wound care for erosions and ulcerations, emollients and topical keratolytics for hyperkeratotic areas, and analgesics for pain control [2].

A small, phase 2A trial (21 patients) found that topical heparin (1000 international units/g) applied four times daily to the hands and feet of patients with grade ≤2 capecitabine-induced HFS reduced HFS severity by at least 1 grade in 90 percent of patients, with a median response time of three weeks [50]. However, these findings need to be confirmed in larger studies.

PROGNOSIS — TEC usually resolves with superficial desquamation of involved areas within two to four weeks after discontinuation of the causative agent. There are usually no long-term sequelae, although palmoplantar keratoderma may develop as a result of longstanding HFS [51].

PREVENTION

●Topical urea – In patients who will be treated with fluoropyrimidines, the local application of a topical urea 10% cream may help prevent HFS. The urea-based cream is applied to hands and feet three times per day and should be reapplied after washing hands. At low concentrations (2% to 10%), topical urea acts as a humectant that increases the hydration of the stratum corneum and is generally well tolerated. Urea up to 30% acts as an emollient and keratolytic, with urea greater than 30% functioning mostly as a keratolytic. These higher concentrations can be useful in instances of chronic reactions that lead to skin thickening [52]. The prophylactic benefit of topical urea treatment has not been demonstrated for other chemotherapy agents. However, given the low risk for toxic effects, a therapeutic trial is reasonable for patients at risk of developing HFS with other drugs.

The efficacy of topical urea with or without lactic acid for the prevention of HFS has been evaluated in a few randomized trials and meta-analyses with conflicting results. Moreover, as the included studies included a variety of interventions as comparators but not vehicle, the benefit of urea cream versus emollient cream remains uncertain:

•A 2022 meta-analysis of four randomized trials found that prophylactic treatment with urea was associated with a reduced risk of developing grade 2 or higher HFS or hand-foot skin reaction (odds ratio [OR] 0.62, 95% CI 0.49-0.79). However, subgroup analysis of only HFS demonstrated reduced risk of all-grade HFS (OR 0.44, 95% CI 0.22-0.90) but not grade 2 or higher HFS (OR 0.78, 95% CI 0.29-2.09) [53].

•A meta-analysis of three trials of prophylactic urea cream for capecitabine-induced HFS did not find it effective in reducing the risk of all-grade HFS (risk ratio [RR] 0.81, 95% CI 0.52-1.26) as well grade 2 or greater HFS (RR 0.74, 95% CI 0.41-1.32) [54].

●Topical diclofenac – A randomized trial that included 263 patients with breast or gastrointestinal cancer undergoing capecitabine treatment evaluated the efficacy of topical diclofenac applied to the palms and dorsa of the hands twice daily in preventing HFS [55]. At 12 weeks, fewer patients in the topical diclofenac gel group developed grade 2 or higher HFS than those in the vehicle group (3.8 versus 15 percent).

●Celecoxib – In a 2014 meta-analysis of randomized trials (140 patients), oral celecoxib 200 to 400 mg twice daily for 12 to 18 weeks significantly decreased the risk of all-grade and grade ≥2 HFS (OR 0.37, 95% CI 0.19-0.71; and OR 0.47, 95% CI 0.29-0.78, respectively) [56]. These results were confirmed in a 2022 meta-analysis [53].

However, celecoxib is known for its potential cardiovascular adverse effects with long-term use and upper gastrointestinal risk of bleeding. In our view, the benefit-to-risk ratio is not favorable when considering the use of celecoxib for the prevention of HFS. (See "NSAIDs: Adverse cardiovascular effects".)

●Pyridoxine – Early studies suggesting symptomatic improvement from pyridoxine in patients with HFS led to interest in the use of this vitamin as a preventive agent [57,58]. However, in four separate phase 3 trials in which patients receiving capecitabine-based chemotherapy or pegylated liposomal doxorubicin were randomly assigned to either pyridoxine (at a dose of 150 or 200 mg daily) or placebo, pyridoxine did not prevent this complication, lessen its severity, or permit higher doses of chemotherapy to be administered [59-62]. Whether higher daily doses of pyridoxine might confer greater protection against HFS is uncertain [63,64]. The results of three meta-analyses suggest that there is inadequate evidence to make any recommendation about using pyridoxine (at any dose) for the prevention of chemotherapy-induced HFS [53,56,65].

●Other – Other treatments that have been used in a limited number of patients include:

•Regional cooling (not indicated for drugs administered as continuous infusion) [66,67]

•Antiperspirants [68]

•Topical sildenafil [69]

•Topical silymarin [70] and other herbal products [71]

However, none of these treatments have been evaluated in high-quality studies.

●Avoidance of friction injuries – Patients should be counseled on avoidance of friction injuries to the hands and feet. For example, patients should avoid using a pumice stone for exfoliation of hyperkeratotic skin and should wear proper fitting shoes with socks.

SUMMARY AND RECOMMENDATIONS

●Definition – The term "toxic erythema of chemotherapy" (TEC) refers to various cytotoxic cutaneous reactions that can occur with conventional chemotherapy. The clinical presentation most frequently seen involves the hands and feet (hand-foot syndrome [HFS], also called palmar-plantar erythrodysesthesia or acral erythema). (See 'Introduction' above.)

●Causative agents – Drugs most frequently associated with TEC include doxorubicin, pegylated liposomal doxorubicin, fluoropyrimidines (fluorouracil, capecitabine), cytarabine, and docetaxel. However, TEC may occur with many other drugs (table 1). (See 'Frequency and causative agents' above.)

●Clinical presentation

•Hand-foot syndrome – Symptoms of HFS typically develop one to three weeks after chemotherapy administration. Affected patients initially complain of a tingling sensation, which is followed by edema and tender, symmetric erythema most pronounced over the fat pads of the distal phalanges (picture 1A-B). Transient fingerprint loss can occur in HFS associated with capecitabine. HFS is dose related and usually resolves within two to four weeks after discontinuation of the causative agent. (See 'Hand-foot syndrome' above.)

•Clinical variants – Clinical variants include malignant intertrigo; periarticular thenar erythema with onycholysis (PATEO) syndrome associated with taxanes; fixed erythrodysesthesia plaque proximal to the infusion site, characteristic of intravenous docetaxel; and a severe bullous variant resembling Stevens-Johnson syndrome/toxic epidermal necrolysis. (See 'Clinical variants' above.)

●Diagnosis – The diagnosis of TEC is usually clinical. (See 'Diagnosis' above.)

●Treatment – The main treatment for TEC is drug interruption or dose modification, depending on the severity of the reaction (table 2). For patients with severe HFS (grade 2 or 3), we suggest super high-potency topical corticosteroids (group 1 (table 3)), rather than other topical agents, in combination with supportive treatment (Grade 2C). Supportive treatment includes wound care for erosions and ulcerations, emollients, topical keratolytics for hyperkeratotic areas, and oral analgesics for pain control. (See 'Treatment' above.)

●Prevention – For patients undergoing treatment with fluoropyrimidines, we suggest topical urea preparations or topical diclofenac for the prevention of HFS (Grade 2C). The 2% to 10% urea-based cream is applied to the hands and feet three times per day and should be reapplied after washing hands. Topical diclofenac is applied to the hands and feet twice daily. Although oral celecoxib has been shown to be effective for the prevention of HFS, the associated risks of cardiovascular adverse effects and upper gastrointestinal bleeding make it an unsuitable prophylactic treatment. (See 'Prevention' above.)