Hand-Foot Syndrome (HFS)

blowes posted on August 13, 2010 01:00

Background

Hand-foot syndrome (HFS; also known as palmar-plantar erythrodysesthesia [PPE]) is a cutaneous complication associated with continuous fluorouracil therapy and oral capecitabine (therapies used in the treatment of CRC) and is seen with several other agents used in the treatment of various cancers. First reported in 1974, this complication was noted in patients receiving antimetabolites and some chemotherapy antibiotics.1 The median time to onset of HFS with capecitabine is approximately 79 days, ranging from 11 to 360 days. In patients with CRC, HFS is the most frequently reported side effect of oral capecitabine (> 50% of patients) and is the dose-limiting side effect for this agent.2,3

Pathobiology

Although the exact mechanism of action is not known, some researchers have theorized that HFS may be related to the crushing of deep capillaries in the soles of the feet and palms of the hands, which may cause drug extravasation into those same capillaries, causing the symptoms of this condition. Another report, by Lin et al,4 describes a different mechanism of action, in which HFS is a consequence of an inflammatory reaction that may result from overexpression of COX-2. These researchers note that COX-2 is upregulated with chemotherapy administration, possibly leading to a COX inflammatory-type reaction.3

Because the condition primarily affects the palms of the hands and the soles of the feet, researchers have also postulated a theory that HFS is caused by the accumulation of drug in the eccrine sweat or the eccrine sweat glands of the hands and feet, causing the damage characteristic of this toxicity.1 Histologically, changes in keratinocytes and vacuolar degeneration of the basal layer are seen, with scattered necrotic areas noted.5 Dilated blood vessels and papillary edema may also appear. However, more research is needed to determine the complete mechanism of action of this common cutaneous side effect.

Physical Presentation

Symptoms may include

Numbness

Tingling

Swelling

Dryness, cracking, edema

Erythema

Pain, blistering, or even desquamation (Figure 1)

Skin reactions may not be noted until the second week of therapy. To control or relieve symptoms, dose reduction or temporary drug cessation may be required (Table 2).

Figure 1. Toxicity Grading Scale*: HFS

Images courtesy of Susan Moore, RN, MSN, ANP, AOCN.
*Data from the National Cancer Institute Cancer Therapy Evaluation Program (page 15).6

Few randomized clinical trial data look at the prevention and management of HFS.

Table 1 - Selected trials of treatments for HFS

Study Author	Study Design	Results	Recommendations
Lauman et al⁷	Retrospective study in which patients were evaluated in 3 arms: capecitbine alone, pyridixoine prophylaxis with capecitabine, and pyridoxine to alleviate symptoms of HFS	Patients who took pyridoxine > 200 mg/d had better symptom control of their HFS than patients who took less than that amount	Patients may need higher doses of pyridoxine to ameliorate the symptoms of HFS

Fabian et al⁸	Phase 2 trial of metastatic CRC patients receiving continuous 5-FU; 5 of 25 patients with HFS received pyridoxine 50 or 150 mg/d when moderate HFS noted	4 of 5 patients who received pyridoxine had reversal of HFS without interruption of the 5-FU, and no adverse effect on clinical response was noted	Large, controlled trials are needed
Karo et al⁹	Small trial of 5 patients with metastatic breast cancer treated with docetaxel and capecitabine; all patients developed grade 2-3 HFS. Vitamin E therapy 300 mg/d PO was given without dose reduction of therapy	After 1 week, HFS symptoms began to disappear	It could be of interest to consider vitamin E as a preventive drug with HFS-associated agents
Yamamoto et al¹⁰	Patients on capecitabine were followed for HFS symptoms; 42 episodes of grade 2 toxicity were identified; all patients received oral vitamin E BID during chemotherapy	Reduction in desquamation, pain, and comfort level of all the patients improved; neurologic symptoms improved as well. All patients were able to complete chemotherapy without interruption or delay; 38 of 42 did not develop cutaneous manifestation, and 4 had grade 1 toxicity	Vitamin E minimized drug delays and schedule interruptions and maintained the dose density of therapy

Cin et al¹¹	13 patients with HFS used bag balm topically in a nonblinded study	12 of 13 reported improvement of symptoms after bag balm; 55% were able to continue chemotherapy without dose delay or reduction	Large placebo-controlled trials are needed to determine the effectiveness of bag balm
Lopez et al¹²	Topical DMSO was given to 2 patients undergoing chemotherapy with liposomal doxorubicin who developed grade 3 HFS	With topical DMSO 4 times daily for 14 days, HFS resolved over a period of 1-3 weeks	Small study; patients must be treated in a prospective trial to definitively document therapeutic efficacy

In small case reports, treatment with oral corticosteroids (not topical), with COX-2 inhibitors, or sometimes with a nicotine patch has ameliorated HFS symptoms; however, large prospective trials are clearly needed to help refine the optimal therapy of this frequent side effect. Therefore, HFS treatment is largely symptomatic. Patients should be instructed to

Avoid immersion in hot water, which could exacerbate symptoms
Avoid activities that may increase pressure in affected areas, such as high-impact exercise
Avoid tight clothing, vigorous skin rubbing, and sun exposure13
Apply cold compresses, which may help
Use topical emollients or other preparations containing urea or lanolin2,3,14 (Table 3)
Use protective gloves if needed15

Additional Clinical Information

Several case reports have been published recently regarding another complication associated with HFS from capecitabine. In patients with metastatic breast cancer, 2 cases of acquired palmoplantar keratoderma were noted, thought to be a sequela of HFS.16 Another published report described HFS with scleroderma-like changes, also thought to be linked to oral capecitabine, with hyperpigmentation of the palms and soles.17 These cases should be noted as single reports, and more information is needed before these side effects can be conclusively linked to capecitabine. Nurses should continue to be vigilant and report to FDA MedWatch (http://www.fda.gov/medwatch/) all new effects and toxicities thought to be drug related.

Drs Saif and Elfiky18 report on differentiating between the presentation of fluoropyrimidine-associated HFS in white and nonwhite patients. Three cases illustrating the disparities between white and nonwhite patients are discussed. The authors suggest a modified grading schema for nonwhite patients. An algorithm outlines pretreatment patient education and monitoring of skin changes during therapy. (See Reference 18 within the reference list for a link to the full-text article without charge.)

Nursing Implications

HFS can be painful and disruptive to patients’ quality of life. However, the current literature on HFS is limited to identification and treatment, with no existing reports on the effect of HFS on patients’ quality of life (QOL).19 More research on that effect is needed. Oncology nurses should instruct patients regarding the possibility of HFS and the need for early communication of symptoms. Because capecitabine is an oral therapy administered at home, symptom communication is crucial. Early reporting of HSF symptoms can assist nursing and physician staff in appropriate grading of HFS and sooner implementation of care interventions. In most patients, the syndrome is completely reversible.20 However, significant HFS usually requires dose interruption, and if the syndrome persists, dose adjustment becomes necessary.21 Although pyridoxine (50-150 mg/d) has been useful in some patient populations, others receive no benefit from adding this therapy.20 Additionally, because this an oral therapy, adherence may be a concern. Nurses may assess patients’ adherence by suggesting that they bring their medication bottles to clinic visits for pill counts.

Table 2. Capecitabine Dose Modification Table

Toxicity NCI CTCAE v3.0*	During a Course of Therapy	Dose Adjustment for Next Treatment Cycle, % of Starting Dose
Grade 1	Maintain dose level	Maintain dose level
Grade 2
1st appearance	Interrupt until resolved to grade 0-1	100%
2nd appearance	Interrupt until resolved to grade 0-1	75%
3rd appearance	Interrupt until resolved to grade 0-1	50%
4th appearance	Discontinue treatment permanently
Grade 3
1st appearance	Interrupt until resolved to grade 0-1	75%
2nd appearance	Interrupt until resolved to grade 0-1	50%
3rd appearance	Interrupt until resolved to grade 0-1
Grade 4
1st appearance	Discontinue permanently or If physician deems it to be in the patient's best interest to continue, interrupt until resolved to grade 0-1	50%

Data from Xeloda prescribing information.22
Data from the National Cancer Institute Cancer Therapy Evaluation Program.6

Assessment Tools

Polovich et al include a description of HFS under Cutaneous Toxicity in Side Effects of Cancer Therapy.23
Guidelines for coping with HFS skin problems are available here

Clinical Practice Guidelines

Evidence-based national guidelines do not currently exist.

Table 3. Patient Management of Hand-Foot Syndrome: Capecitabine Related

Grade	Clinical Feature	Functional Status	Suggested Interventions
1	Numbness, paresthesia, dysesthesia, tingling, painless swelling or erythema of the hands and/or feet	Activities of daily living generally unaffected	Call nurse or doctor when symptoms first appear. Do not “wait and see.” Skin care: § Reduce friction and pressure: kneeling for long periods of time; leaning on elbows; power walking, jogging, or regular walking for long periods of time; using hand tools; gardening § Wear sunscreen; avoid exposure to heat § Use mild soap to bathe; pat (don’t rub) skin dry § Keep shower and bath water lukewarm to cool; avoid hot tubs and long exposure to hot water § Keep skin moist; gently apply moisturizing creams or topical emollients. Apply at night and wear loose-fitting cotton gloves; avoid rubber ones (dishwashing gloves), since they retain heat § Put hands and feet in cool water to relieve symptoms Clothing: § Wear comfortable, loose-fitting clothes, shoes, and gloves § Do not go barefoot; wear shoes or slippers when possible
2	Painful erythema and swelling of the hands and/or feet, skin remains intact	Activities of daily living more difficult
3	Moist desquamation, ulceration, blistering, or severe pain of the hands and/or feet, tissue breakdown	Activities of daily living interrupted: unable to work; difficulty walking and using hands

Data from the National Cancer Institute Cancer Therapy Evaluation Program (page 18)6 and Wilkes and Doyle.24

References

Clark AS, Vahdat LT. Chemotherapy-induced palmar-plantar erythrodysesthesia syndrome: etiology and emerging therapies. Support Cancer Ther. 2004;1: 213-218.

Viale PH, Fung A, Zitella L. Advanced colorectal cancer: current treatment and nursing management with economic considerations. Clin J Oncol Nurs. 2005;9:541-552.

Berg D. Capecitabine: a new adjuvant option for colorectal cancer. Clin J Oncol Nurs. 2006;10:479-486.

Lin E, Morris JS, Ayers GD. Effect of celecoxib on capectabine-induced hand-foot syndrome and antitumor activity. Oncology (Williston Park). 2002;16 (suppl): 31-37.

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.

National Cancer Institute Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events v3.0. http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf. Page 15. Accessed March 19, 2010.

Lauman MK, Mortimer J. Effect of pyridoxine on the incidence of palmar plantar erythrodysesthesia (PPE) in patients receiving capecitabine. Proc Am Soc Clin Oncol. 2001;20:392a. Abstract 1565.

Fabian CJ, Molina R, Slavik M, et al. Pyridoxine therapy for palmar-plantar erythrodysesthesia associated with continuous 5-fluorouracil infusion. Invest New Drugs. 1990;8:57-63.

Karo IO, Sahin B, Erkisi M. Palmar-plantar erythrodysesthesia due to docetaxel-capecitabine therapy is treated with vitamin E without dose reduction. Breast. 2006;5:414-424.

Yamamoto D, Yamamoto C, Tanaka K. Novel and effective management of capecitabine induced hand foot syndrome. J Clin Oncol. 2008;26(suppl):734s. Abstract 20615.

Cin SF, Tchen N, Oza AM, et al. Use of “bag balm” as topical treatment of palmar-plantar erythrodysesthesia syndrome (PPES) in patients receiving selected chemotherapeutic agents. Proc Am Soc Clin Oncol. 2001;20:409a. Abstract 1632.

Lopez A, Wallace L, Dorr R, et al. Topical DMSO treatment for pegylated liposomal doxorubicin-induced palmar-plantar erythrodysesthesia. Cancer Chemother Pharmacol. 1999;44:303-306.

Morse MA. Supportive care in the management of colon cancer. Support Cancer Ther. 2006;3:158-170.

Wilkes GM. Therapeutic options in the management of colon cancer: 2005 update. Clin J Oncol Nurs. 2005;9:31-44.

Viale PH. Chemotherapy and cutaneous toxicities: implications for oncology nurses. Semin Oncol Nurs. 2006;22:144-151.

Do JE, Kim YC. Capecitabine-induced diffuse palmoplantar keratoderma: is it a sequential event of hand-foot syndrome? Clin Exp Dermatol. 2007;32:519-521.

Lee SD, Kim HJ, Hwang SJ, et al. Hand-foot syndrome with scleroderma-like change induced by the oral capecitabine: a case report. Korean J Intern Med. 2007;22:109-112.

Saif MW, Elfiky AA. Identifying and treating fluoropyrimidine-associated hand-and-foot syndrome in whites and non-white patients. J Support Oncol. 2007;5:337-343. http://www.supportiveoncology.net/journal/articles/0507337.pdf

Keating KN, Anderson RT, O’Leary JJ. Hand-foot syndrome: symptom assessment and the impact on quality of life—a review of the peer-reviewed literature. J Clin Oncol. 2008;26(suppl):739s. Abstract 20685.

Janusch M, Fischer M, Marsch WCH. et al. The hand-foot syndrome: a frequent secondary manifestation in antineoplastic chemotherapy. Eur J Dermatol. 2006; 16:494-499.

Gressett SM, Stanford BL, Hardwicke F. Management of hand-foot syndrome induced by capecitabine. J Oncol Pharm Pract. 2006;12:131-141.

Xeloda prescribing information. Genentech USA, Inc. 2009. Available here. Accessed March 19, 2010.

Polovich M, White JM, Kelleher LO, eds. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. Pittsburgh, PA: ONS Publishing Division; 2005:208.

Wilkes GM, Doyle D. Palmar-plantar erythrodysesthesia. Clin J Oncol Nurs. 2005;9:103-106.

Key Definitions

cyclo-oxygenase (COX)—an enzyme that catalyzes the conversion of arachidonic acid to prostaglandins and is inactivated by aspirin and other NSAIDs
desquamation—peeling off in the form of scales; scaling off, particularly of skin
dysesthesia—impairment of sensitivity, especially to touch
emollient—agent that softens or soothes the skin
erythema—abnormal redness of the skin due to capillary congestion (as in inflammation)
erythrodysesthesia—condition caused by continuous infusion therapy or certain oral chemotherapies resulting in a tingling sensation of the palms and soles, progressing to severe pain and tenderness with erythema and edema
paresthesia—skin sensation such as burning, prickling, itching, or tingling
pyridoxine—vitamin B6, found especially in cereals
vacuolar degeneration—formation of nonlipid vacuoles in cytoplasm, most frequently due to accumulation of water by cloudy swelling