What is the recommended management of palmar‑plantar erythrodysesthesia (hand‑foot syndrome) in a patient undergoing chemotherapy such as capecitabine, 5‑fluorouracil, cytarabine, docetaxel, sorafenib, or sunitinib?

Management of Palmar-Plantar Erythrodysesthesia (Hand-Foot Syndrome)

Begin prevention at chemotherapy initiation with behavioral modifications and urea 10% cream three times daily, escalate to high-potency topical steroids for grade 1-2 symptoms, and interrupt or reduce chemotherapy dosing for grade 3 or higher toxicity. 1

Understanding the Two Distinct Syndromes

You must first distinguish between two clinically different entities:

• Classic HFS (PPES) occurs with cytotoxic chemotherapy agents including capecitabine (50-60% incidence), 5-fluorouracil (6-34%), cytarabine (14-33%), docetaxel (6-58%), and doxorubicin (22-29%), presenting as dysesthesia, burning pain, swelling, and erythema that progresses to hyperkeratosis, blisters, and ulcerations 1

• Hand-Foot Skin Reaction (HFSR) occurs with multikinase VEGFR inhibitors like sorafenib (10-62%), sunitinib (10-50%), and regorafenib (47%), presenting as well-defined painful hyperkeratosis and calluses at pressure-bearing areas rather than diffuse palmar involvement 1

The distinction matters because treatment approaches differ slightly, though both follow similar prevention and grading principles. 1

Prevention Strategy (Grade 0)

Initiate these measures before starting chemotherapy:

• Avoid mechanical stress: no prolonged walking, heavy carrying without cushioned shoes and gloves, or repetitive friction to hands and feet 1

• Avoid chemical irritants: eliminate exposure to solvents, harsh soaps, and disinfectants 1

• Treat pre-existing hyperkeratosis before chemotherapy begins using professional podiatric debridement if needed 1, 2

• Apply urea 10% cream three times daily to palms and soles as prophylaxis 1

• Intensive skin care with emollient creams is essential and supported by level II evidence 1

Treatment Algorithm by Grade

Grade 1 (Minimal skin changes or dermatitis without pain)

• Continue chemotherapy at current dose and monitor closely for progression 1

• Apply high-potency topical steroid (e.g., clobetasol 0.05%) twice daily to affected areas 1, 2

• Increase urea concentration up to 40% for localized severe thickening 2

• Consider tazarotene 0.05-0.1% as first-line topical retinoid to reduce scaling, though this is often off-label 2

Grade 2 (Skin changes with pain limiting instrumental activities of daily living)

• Continue high-potency topical steroid twice daily 1

• Monitor closely for worsening—if reactions progress or fail to improve, dose interruption becomes necessary 1

• Professional podiatric debridement is indicated when lesions become too painful or thick for self-management 2

• Consider dose reduction of the chemotherapy agent at this stage to prevent progression 1, 3

Grade 3-4 (Severe pain, ulceration, or inability to perform self-care)

• Interrupt chemotherapy immediately until toxicity resolves to grade 1 or less 1, 4

• Reduce chemotherapy dose by 25-50% upon rechallenge 4, 3, 5

• Discontinue treatment permanently for grade 4 toxicity 1

• Provide aggressive supportive care: elevation, cold compresses, topical wound care, and pain management 5

Systemic Therapy for Refractory Cases

When topical measures fail after 4 weeks:

• Oral acitretin 25 mg daily demonstrates significant improvement in scaling, thickness, and erythema within 2 months for severe palmoplantar conditions, though this is primarily studied in non-chemotherapy-induced keratoderma 2

• COX-2 inhibitors show promise as the most effective systemic agents for HFS prevention and treatment, though large randomized trials are still needed 3

• Topical PUVA therapy 2-3 sessions weekly can be considered for refractory inflammatory cases, though long-term use increases skin cancer risk 2

Critical Clinical Pearls

The occurrence and severity of HFS correlates with chemotherapy response—patients developing HFS may actually have better tumor outcomes, making dose optimization rather than complete discontinuation preferable when possible. 1

Quality of life impact is disproportionate to the small body surface area affected, justifying aggressive intervention and systemic therapy when topical treatments fail. 1, 2

Docetaxel causes an atypical variant with dorsal hand and foot involvement (PATEO syndrome) rather than classic palmar-plantar distribution—recognize this pattern to avoid misdiagnosis. 1, 6

Early recognition is paramount—educate patients to report dysesthesia and tingling immediately, as intervention at grade 1 prevents progression to debilitating grade 3-4 toxicity requiring treatment discontinuation. 1, 3, 7

Common Pitfalls to Avoid

• Never dismiss early symptoms (tingling, dysesthesia) as minor complaints—these herald progression to severe toxicity if chemotherapy continues unmodified 4, 5, 7

• Avoid overdebridement of hyperkeratotic lesions, which makes underlying skin susceptible to increased blistering and tenderness 2

• Do not confuse HFS with simple edema from hormonal agents like letrozole, which lacks the inflammatory, painful, and progressive dermatologic features characteristic of chemotherapy-induced HFS 8

• Recognize that hyperpigmentation may be the primary presenting sign in patients with darker skin tones, making early grade 1 HFS harder to detect—maintain high clinical suspicion based on symptoms rather than relying solely on visible erythema 7