Hand-foot syndrome (HFS) is a dose-limiting cutaneous reaction localized on the palms of the hands and/or the soles of the feet as a toxic side effect of some types of chemotherapy or biologic therapy drugs used to treat cancer. It is never life threatening but can interfere with patient’s daily activity.

It may also be referred to as:

• acral erythema

• palmar plantar erythema

• hand-to-foot syndrome

• Burgdorf reaction

• palmar-plantar erythrodysesthesia   

(erythodysestesia=tingling sensation  progressing to severe pain and tenderness with erythema and edema)

• chemotherapy-induced acral erythema

• palmar plantar dysaestesia

• palmar plantar erythroderma

• toxic erythema of the palms and soles

• hand-foot skin reaction

It was first described by Zuehlke in 1974 associated with mitotane (Lysodren) therapy for the hypernephroma and definied by Burdgorf in 1982.

It has been estimated that HFS occurs in 6-64% of patient treated with different chemotherapy regimens, in nearly 80% of cases with less severe grades and 5% severe grade condition.

The HFS appears to be predominantly drug and dose dependent (peak plasma drug concentration, total cumulative dose, administration schedule) in its onset and severity.

Patients with HFS usually first note a prodrome of dysesthesia (impairment of sensitivity, especially to touch) or paresthesia (skin sensation such as burning, pricking, itching or tingling), characterized by a tingling sensation on the palms and soles, which progress over several days to a burning pain and well-definied symmetric erythema (sometimes particularly on the pads of the distal phalanges) and edema (swelling), sometimes with a fine desquamation.

The hands are usually more severally affected than the feet, or may be the only area involved.

HFS can progress from mild to moderate symptoms:

• redness

• numbness

• tingling, 

• tenderness (sensitive to touch)

• thigtness of the skin

• bright redness (symmetrical and sharply defined)

• burning pain



• swelling

• peeling skin

to severe symptoms

• blisters, ulcers

• severe pain

• difficulty walking or using the hands (interfere with daily livings and activities such as holding objects, doing up bottons, walking)

• loss of fingerprints (capecitabine, as a possible result of peeling/flaking of the skin).

Usually two systems have been used for the classification of HFS: the NCI grading criteria and WHO grading criteria.
The NCI (National Cancer Institute) has a 3-grade classification system. The WHO (World Health Organisation) classification system is based on 4 grades.

Histologically, HFS has not specific findings: mild spongiosis, scattered necrotic and dysckeratotic keratinocytes, vacualar degeneration of the basal layer, papillary edema. A sparse superficial perivascular lymphohistiocytic infiltrate can be found in varying degrees in the epidermis. Basement membrane is intact and there is no damage to sweat gland or duct.

Some chemotherapy is more likely to cause HFS than others. The drugs known to cause HFS include:

• docetaxel

• pegylated liposomal doxorubicin (Doxil)

• doxorubicin (Adriamycin, Doxil)

• fluoruracil (5-FU)

• capecitabine (Xeloda)

• cytarabine (Ara-c)

• floxuridina (FUDF)

• idarubicin (Idamycin)

• ixabepilone (Ixempra)

• emitafur

• tegafur

• irinotecan

• paclitaxel

• 6-mercaptopurine

• 6-thioguanine

• pazopanib (Votrient)

• hydroxyurea (Hydrea)

• sunitinib (Sutent)

• sorafenib (Nexavar)

• vemurafenib ( Zelboraf)

• cisplatin

• interleukin-2 (high dose)

• EGFR/ protein kinase inhibitors

But not everyone who is treated with these medications develops HFS, and the severity of HFS can vary from person to person, even among people taking the same medication for the same form of cancer.

HFS ususally first appear within days treatment (sorafenib, sunitinib, pazopanib) or after two-three months with other chemotherapies.

HFA occurs when small amounts of drug leak out of capillaries (small blood vessels) in the palms of the hands and soles of the feet: it can damage the sorrounding tissues and cause a range of symptoms.

There are ways to manage symptoms of HFS and prevent it from worsening.

For a period of time following treatment (approximately one week after IV medication, much as possible during the time taking oral medication) it is important to avoid activities that rub the skin of palms and soles, put pressure on the palms and soles and/or expose to heat, modifying some of  normal daily activity, because of the  increase of the amount of drug in the capillaries and the amount of drug linkage.

The following tips may help, first of all reducing friction and heat:

• avoid prolonged heat exposure of hands and feet (heat increases the amount of medication in the blood vessels and can increase the linkage)

• avoid long exposure of hands and feet to hot water such as washing dishes (use tepid water), hot tub, steam room

• take lukewarm/cool showers or baths

• after washing or bathing pat the skin dry with a towel, don’t rub (friction can cause irritation and linkage)

• avoid saunas, sitting in the sun

• avoid massaging or rubbing feet and hands

• avoid strenuous physical activity such as running, aerobics, jumping, power walking, racquet sports, long periods of walking during the first weeks of treatments

• elevate hands and feet when sitting or lying down

• keep skin moist: gently apply mild skin care creams to keep hands and feet moist. Apply at night and wear loose-fitting cotton gloves and socks

• avoid rubbing or massaging too vigorously moisturizer to hands and feet to avoid friction. Apply liberally and often

• avoid lotions or creams containing perfumes, alcohol, glycerin

• wear loose fitting, well-ventilated shoe,

• avoid tight fitting socks and stockings

• do not go barefoot

• avoid using knives, because a chopping motion can cause excessive pressure and friction on the palms

• avoid tools as shovel, screwdrivers, hammers or gardening tools (squeezing the hand on a hard surface can trigger leakage)

• cool hands and feet placing palms or bottoms or feet in cool water or on cool compresses (wet towel) or ice packs or packages of frozen vegetables (avoid to apply it directly to the skin, wrap it in a towel)(help to cool the burning sensation). Alternate on and off for 15-20 minutes a timefrom

• stay away from harsch chemicals such as laundry detergents of cleaning products

• avoid alcohol intake

Because HFS can worsen  and have a considerable impact on the patient’s quality of life (QOL), disrupting patient’s ability to pursue normal daily activities, it is important to instruct patients regarding the possibility of HFS: they should be made aware of the first signs and symptoms.

HFS is manageable but if it is not recognized early and left untreated it can progress  rapidly from a mild cutaneous reactions to a painful, debilitating condition.

Early their communication to the doctor or  a member of the nursing staff help them to identify and grading of HFS, allowing care interventions to manage symptoms. In fact sooner implemented, there is a rapid reversal of signs and symptoms without conseguences.

In addition doctor can modify dose changing treatment schedule  with dose reduction, less frequent dosing or ultimately drug withdrawal until resolved or permanently if necessary to prevent worsening.

About treatment of HFS:

• emollient

• topical or systemic corticosteroid

• pain relievers (such as ibuprofen, naproxen, celecoxib, acetominophen)

• topical 99% diemethyl-sulfoxide

• celecoxib

Pyridoxine (vit B6) may be beneficial as preventing measure when drugs with a strong association with HFS are going to be administred.