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Developing strategies to treat chemotherapy-induced palmar-plantar erythrodysesthesia

Although there are no proven or established methods to prevent PPE, patients can be advised to avoid trauma, pressure and heat exposure.

Issue: October 1, 2006

ByLisa K. Lohr, PharmD, BCPS, BCOP

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Chemotherapy treatments can cause a wide variety of dermatological side effects, ranging from alopecia and rash to folliculitis and pigmentation changes. One potentially severe dermatologic reaction is palmar-plantar erythrodysesthesia. This syndrome is also known as acral erythema, hand-foot syndrome and Burgdorf’s reaction.

Symptoms

The symptoms of this condition often begin with a tingling sensation in the palms of the hands and the soles of the feet. This can progress to erythematous swollen hands and feet, accompanied by sensitivity to touch and moderate to severe pain. The affected areas may develop blisters and bullae with desquamation before healing occurs, and the hands are often more severely affected than the feet. The lesions usually heal within a few weeks. The syndrome will recur in most patients who are retreated with the same chemotherapy. The severity of symptoms is graded according to tools developed by WHO and the NCI. These tools utilize factors such as pain, paresthesias and functional restrictions.

The etiology of palmar-plantar erythrodysesthesia has not been determined. Some postulated explanations include a direct toxic effect of the chemotherapy on the epidermal cells, local drug accumulation and inflammation, and chemotherapy leakage from small vessels in the hands and feet that are subjected to the pressure of work and walking. The reported incidence of PPE varies widely; it affects as many as 60% to 70% of patients receiving certain chemotherapy agents. Some antineoplastic agents are more likely to cause PPE than others.

Causes of PPE

The incidence and severity of PPE seem to be related to peak drug concentration, sustained drug levels, total cumulative dose and later cycles of chemotherapy treatments. The most likely causative agents are cytarabine, doxorubicin, liposomal doxorubicin (Doxil, Alza), fluorouracil and capecitabine (Xeloda, Roche). The table lists other agents that are believed to cause PPE.

As many as 33% of patients receiving high doses of cytarabine (>1 g/m²) are at risk. PPE occurs 34% of the time when fluorouracil is prescribed. These reactions are also more likely with protracted infusions than with bolus dosing. Reactions tend to occur around a cumulative dose of 1.85 g/m². They also seem to occur more frequently in women and older patients. The most frequent incidence of PPE, up to 57%, occurs with capecitabine, which is a prodrug of fluorouracil, since daily administration mimics drug exposure of protracted fluorouracil infusions.

PPE also occurs after anthracycline therapy. There is a 29% incidence of PPE with doxorubicin and the incidence increases at higher doxorubicin doses or when the drug is combined with fluorouracil. Liposomal doxorubicin (especially when given at high doses, in multiple cycles or more frequently) has been implicated in up to 40% of patients.

Preventing PPE

Unfortunately, there are no established methods to prevent PPE or to identify patients at higher risk. Patients can be advised to avoid trauma, pressure and heat exposure to the hands and feet before and after drug exposure. Some researchers suggest cooling the hands and feet during drug administration to reduce blood flow to these areas. Others have suggested that pyridoxine (vitamin B6) can help reduce PPE symptoms, with higher doses (200 mg to 300 mg daily) more effective than lower doses. However, better prospective trials are needed to confirm this effect before the treatment can be widely recommended. Other unproven treatments include topical or systemic corticosteroids, vitamin E and topical 99% dimethyl sulfoxide application.

If PPE occurs, the primary treatment is to discontinue the offensive agent, reduce the dose or slow the infusion, except for fluorouracil. Supportive therapy with cool compresses, elevation of the hands or feet and topical wound care should also be recommended. Affected hands and feet should be kept well hydrated and protected with emollients, petroleum jelly or similar products. Systemic analgesia may be necessary in moderate to severe cases. In most situations, PPE should heal within two to four weeks.

For more information:

• Lisa K. Lohr, PharmD, BCPS, is a Clinical Pharmacy Specialist in Oncology at Fairview University Medical Center in Minneapolis, and is the section editor for Pharmacology on Hem/Onc Today’s editorial board.
• Wyatt AJ, Leonard GD, Sachs DL. Cutaneous reactions to chemotherapy and their management. Am J Clin Dermatol. 2006;7:45-63.
• Wilkes GM, Doyle D. Palmar-plantar erythrodysesthesia. Clin J Oncol Nurs. 2005;9:103-106.
• Nagore E, Insa A, Sanmartin O. Antineoplastic therapy-induced palmar plantar erythrodysesthesia (“hand-foot”) syndrome. Incidence, recognition and management. Am J Clin Dermatol. 2000;1:225-234.