Capecitabine-Induced Darkening of Hands and Feet
The darkening of the hands and feet secondary to capecitabine is called palmar-plantar erythrodysesthesia syndrome (PPES), also known as hand-foot syndrome (HFS). 1, 2, 3
Terminology and Clinical Presentation
The condition is formally termed palmar-plantar erythrodysesthesia syndrome (PPES) or hand-foot syndrome (HFS), and represents a cutaneous toxicity characterized by erythema, dysesthesia, pain, and skin changes affecting the palms and soles. 1, 2, 3
The FDA drug label describes HFS as "palmar-plantar erythrodysesthesia or chemotherapy-induced acral erythema," with median time to onset of 79 days (range 11-360 days) in patients receiving capecitabine monotherapy. 3
In Black patients specifically, capecitabine produces a distinct clinical pattern: hyperpigmentation of the palms and soles followed by keratoderma-like thickening that is not typically observed in white patients, and this can rapidly progress to severe grade 3 HFS with ulceration and infection, particularly in those with compromised peripheral vasculature. 4
Grading and Clinical Features
The FDA defines three grades of severity 3:
Grade 1: Numbness, dysesthesia/paresthesia, tingling, painless swelling or erythema of hands/feet, or discomfort that does not disrupt normal activities 3
Grade 2: Painful erythema and swelling of hands/feet with discomfort affecting activities of daily living 3
Grade 3: Moist desquamation, ulceration, blistering, or severe pain of hands/feet causing inability to work or perform activities of daily living 3
Important Clinical Distinctions
Classic HFS from capecitabine must be distinguished from hand-foot skin reaction (HFSR) caused by multikinase VEGFR inhibitors like sorafenib and sunitinib, as management nuances differ despite shared prevention principles. 2
Capecitabine-induced HFS has a reported incidence of approximately 50-60%, making it one of the most common dose-limiting toxicities of this agent. 2
The condition is usually bilateral, though rare unilateral presentations have been documented. 5
Management Implications
Treatment interruption and dose reduction remain the only evidence-based methods to effectively manage HFS, with dose interruption required for grade 2 or 3 toxicity until resolution to grade 1 or less, followed by dose reduction of 25-50% upon rechallenge. 2, 3, 6, 7
High-potency topical steroids (e.g., clobetasol 0.05%) applied twice daily are recommended for symptomatic management. 1, 2
Prophylactic measures include urea 10% cream applied three times daily to palms and soles before and during chemotherapy, avoidance of mechanical stress (prolonged walking, heavy lifting without cushioned footwear), and treatment of pre-existing hyperkeratosis. 1, 2