Hand-foot syndrome (HFS) - palmar-plantar erythrodysaesthesia (PPE) associated with chemotherapeutic agents

Definition

Hand-foot syndrome (HFS), also known as palmar-plantar erythrodysaesthesia (PPE), is a common side effect associated with a number of chemotherapeutic drugs including capecitabine, fluorouracil, liposomal doxorubicin and cytarabine. A similar reaction, hand-foot skin reaction (HFSR) occurs with some kinase inhibitors e.g. pazopanib, sorafenib and sunitinib, however lesions tend to be more localised and hyperkeratotic, see figure below.^rr Hand-foot syndrome is characterised by the gradual onset of bilaterally symmetric reactions over the palms and soles including erythema, tenderness, pain, swelling, tingling, numbness, hyperpigmentation, pruritus, bullous lesions, dry rash, moist desquamation, ulceration and sensory impairment or paraesthesia.^r Although not life threatening, hand-foot syndrome impacts on quality of life and may result in sub-optimal dosing. Symptoms appear to be dose-dependent and palms are affected more than soles.

A summary of Hand-foot syndrome (HFS) versus Hand-foot skin reaction (HFSR)^r

© J Am Acad Dermatol 2014

Pathophysiology

The exact causative mechanism of hand-foot syndrome is unknown however there are a few theories postulating that:

• Higher expression of the fluoropyrimidine-activating enzyme thymidine phosphorylase in the tissues of the palmar surfaces, compared to other epithelioid surfaces, leading to increased concentrations of fluoropyrimidine in the hands and feet.^r
• Drug extravasation occurs from the microcapillaries of the hands and feet because of local trauma caused by normal daily activities, such as grasping and walking, and by exposure to increased temperatures such as hot water which further affects capillaries in the palms and soles causing drug accumulation in the tissues.^r
• Many chemotherapeutic drugs concentrate in the eccrine sweat glands or ducts, such as those found in the palms and soles; damage to these tissues occurs because of local drug accumulation.^r
• It may be due to damaged deep capillaries in the soles of the feet and palms of the hands, leading to a cyclooxygenase (COX) inflammatory-type reaction.^r
• Interaction of doxorubicin and copper ions creating reactive oxygen species, inducing apoptosis of keratinocytes.^r

Onset/duration

Hand-foot syndrome may occur days to weeks after commencing treatment with certain chemotherapeutic drugs. It most commonly develops after six weeks of treatment. The symptoms usually resolve within 2 weeks if the chemotherapeutic drug is stopped.

Symptoms and signs

• Assess baseline skin of patients hands and feet.
• Monitor changes in skin colour and texture of palms of hands and soles of feet throughout treatment.
• Monitor for associated symptoms such as numbness, tingling and pain throughout treatment.

Grading

* adapted from Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 November 27, 2017.
** instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc.
*** self care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not bedridden.

Prevention

The following pre-emptive measures have been investigated:^r

• premedication with oral/topical corticosteroid
• application of topical agents such as a topical emollient, urea-based creams or vitamin E cream
• nicotine patch
• COX-2 inhibitors in selected cases^r 
• avoiding exposure of hands and feet to heat and/or unnecessary pressure
• cooling hands and feet during treatment.
• oral pyridoxine is ineffective in prophylaxis.

Due to the lack of randomised controlled trials there is limited and/or conflicting evidence for the efficacy of most of these measures.^r 

Treatment

The most effective treatments for hand foot syndrome are usually:

• dose reduction and/or increasing the dosing interval of the causative chemotherapy drug (refer to individual treatment protocols for specific dose modifications)
• stopping the causative chemotherapy drug
• topical application of an emollient containing urea 10%
• administration of regular analgesia or as required
• consider referral to dermatologist for persistent symptoms.

Symptoms may be treated using topical wound care, cold compresses, moisturisers, topical corticosteroids and systemic analgesics. Pyridoxine daily has been tried but evidence for efficacy is limited to case reports.^rrr A randomised control phase II study investigated prophylactic urea-based cream in conjunction with sorafenib use for advanced hepatocellular carcinoma and found it effective in preventing and/or delaying the onset of HFSR compared to best supportive care.^r

Treatment algorithm

The following treatment algorithm has been developed by collating the currently available evidence for the treatment of hand foot syndrome in patients receiving chemotherapy.^rrr

The following interventions may assist in reducing the development and severity of hand-foot syndrome as well as reducing pain, discomfort and secondary infection resulting from hand foot syndrome. Patients should be advised to:

• gently apply an emollient to hands and feet daily; eg. an emollient containing urea 10%. Preparations containing urea moisturise dry skin by reducing water loss from the epidermis (upper layer of skin) resulting in softer and more supple skin
• bathe or shower in lukewarm water
• soak hands and feet in a basin of cold water for 15 minutes 3 to 4 times per day is possible
• avoid sun exposure and use a sunscreen SPF 30+ or greater
• avoid activities that cause excessive friction and rubbing of the skin surfaces 
• use barrier gloves when dealing with chemicals such as detergents and cleaning products
• wear cotton gloves
• wear thick cotton socks especially if standing for long periods
• avoid tight-fitting shoes
• avoid topical anaesthetic containing creams as they may exacerbate skin toxicity
• report any skin changes to their medical officer as soon as possible
• avoid exposure of hands and feet to heat.

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Bibliography

Son, H. S., W. Y. Lee, W. S. Lee, et al. 2009. "Compliance and effective management of the hand-foot syndrome in colon cancer patients receiving capecitabine as adjuvant chemotherapy." Yonsei Med J 50(6):796-802.

Read abstract

PURPOSE: Physicians and oncology nurses must continue to update their knowledge on treatment and treatment-related side effects, while searching for effective methods to prevent or manage side effects. The objective of our study was to describe the incidence and response to treatment of the hand-foot syndrome (HFS) and the compliance with treatment of patients with stage IIB, IIIA, IIIB, and IIIC colon cancer that were treated with capecitabine alone as adjuvant therapy.

MATERIALS AND METHODS: Between September 2005 and September 2006, 84 patients fulfilled the inclusion criteria and were included in this retrospective analysis of prospectively collected data.

RESULTS: The treatment compliance rate was 90.5% (76 out of the 84 patients). The HFS developed in 65 patients (77.4%). Thirty-three patients (50.7%) had grade 1 HFS, 22 patients (33.8%) had grade 2 HFS and 10 patients (15.5%) had grade 3 HFS, as their most severe episode. For Grade 1 patients, the dose was maintained, and skin barrier cream and moist exposed burn ointment (MEBO) were applied. For Grade 2 patients, either the dose was maintained or 25% of the dose was reduced; MEBO and supportive care were provided. For Grade 3 patients, one cycle of chemotherapy was interrupted followed by dose adjustment; MEBO and supportive care were provided.

CONCLUSION: HFS is manageable if both patients and oncology care teams are educated about HFS associated with capecitabine. The HFS is treated by patient education, preventive management, ointment application, conservative management, dose reduction, and interruption of chemotherapy administration.

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