Hand-Foot Syndrome (HFS) Updated

Background

Hand-foot syndrome (HFS), also called palmar-plantar erythrodysesthesia (PPE), is a cutaneous complication associated with continuous fluorouracil therapy, oral capecitabine, and liposomal doxorubicin. 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. 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

Pathophysiology

Although its exact pathophysiologic mechanism 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, in which HFS is the consequence of an inflammatory reaction, which might result from overexpression of COX-2. These researchers noted that COX-2 is upregulated with the administration of chemotherapy, possibly leading to a COX inflammatory-type reaction.4

Because the condition primarily affects the palms of the hands and the soles of the feet, researchers have also postulated 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 be seen. More research is needed to determine the complete pathophysiology and pathobiology of this commonly seen 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 1).



Photos courtesy of Susan Moore.
*Grading and descriptions based on information from NCI CTCAE v4.03.6
ADLs = activities of daily living; HFS = hand-foot syndrome; PPE = palmar-plantar erythrodysesthesia.

There are few randomized clinical trial data that look at prevention and management of HFS. Selected trials of treatments studied in HFS are listed in Table 1.



DMSO = dimethylsulfoxide; HFS = hand-foot syndrome; MBC = metastatic breast cancer; PPE = palmar-plantar erythrodysesthesia.

Small case reports of treatment with oral corticosteroids, COX-2 inhibitor agents and topical nicotine patch have also been reported as interventions to ameliorate the symptoms of PPE; however, large prospective trials are needed to help refine the optimal therapy of this often-seen side effect. Therefore, treatment of HFS is largely symptomatic (Tables 2 and 3). 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
• Try cold compresses, which may be helpful
• Use topical emollients or other preparations containing urea or lanolin 2,3,14
• Use protective gloves if needed15

Additional Clinical Information

Several case reports have been published recently regarding another complication as a sequela of HFS with capecitabine. Two cases of acquired palmoplantar keratoderma were noted in patients with metastatic breast cancer, thought to be a sequential event of HFS.16 Another published report described HFS with scleroderma-like changes, also thought to be linked to the administration of 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 all new effects and toxicities thought to be drug related to FDA MedWatch (http://www.fda.gov/medwatch/).

Drs Saif and Elfiky18 report on differentiating HFS between the presentation of fluoropyrimidine-associated HFS in white and non-white patients. Three cases illustrating the disparities in white and non-white patients are discussed. The authors suggest a modified grading schema for non-white patients. An algorithm outlines pretreatment patient education and monitoring of skin changes during therapy.

Implications for Health Care Professionals

HFS can be painful and disruptive to patients’ quality of life.  However, the current literature on HFS is limited to the identification and treatment of HFS, with no existing reports on the effect of HFS on patients’ quality of life (QOL).19 More research is needed on the effect of HFS and QOL. Oncology health care providers 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, this communication of symptoms is crucial. Early reporting of HFS symptoms can assist nursing and physician staff in appropriate identification and grading of PPE, allowing care interventions to be implemented sooner. In most patients, the syndrome is completely reversible.20 However, significant HFS usually requires dose interruption, and if the syndrome persists, dose modification becomes necessary (Table 2).21 Although pyridoxine (50-150 mg/d) has been of use in some patient populations, others receive no benefit from the addition of this therapy.12,20  Table 3 outlines patient education for managing capecitabine-associated HFS.



Data from Xeloda® prescribing information.22

Based on information from NCI CTCAE v4.03 (page 18)6 and Wilkes and Doyle.23

Assessment Tools

Polovich et al include a description of HFS under Cutaneous Toxicity in Side Effects of
Cancer Therapy.24

Patient information for coping with HFS skin problems is available here.

Clinical Practice Guidelines

There are no evidence-based national clinical practice guidelines for management of HFS.

References

1. Clark AS, Vahdat LT. Chemotherapy-induced palmar-plantar erythrodysesthesia syndrome: etiology and emerging therapies. Support Cancer Ther. 2004;1:213-218.
2. 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.
3. Berg D. Capecitabine: a new adjuvant option for colorectal cancer. Clin J Oncol Nurs. 2006;10:479-486.
4. 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.
5. 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.
6. National Cancer Institute, Cancer Therapy Evaluation Program. Common Terminology Criteria for Adverse Events v4.03 (CTCAE). http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.
12. Lee S, Lee S, Chun Y, et al. Pyridoxine is not effective for the prevention of hand foot syndrome (HFS) associated with capecitabine therapy: results of a randomized double-blind placebo-controlled study. J Clin Oncol. 2007;25(18 suppl). Abstract 9007.
13. Morse MA. Supportive care in the management of colon cancer. Support Cancer Ther. 2006;3:158-170.
14. Wilkes GM. Therapeutic options in the management of colon cancer: 2005 update. Clin J Oncol Nurs. 2005;9:31-44.
15. Viale PH. Chemotherapy and cutaneous toxicities: implications for oncology nurses. Semin Oncol Nurs. 2006;22:144-151.
16. 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.
17. 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.
18. 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.
19. 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.
20. 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.
21. Gressett SM, Stanford BL, Hardwicke F. Management of hand-foot syndrome induced by capecitabine. J Oncol Pharm Pract. 2006;12:131-141.
22. Genentech USA, Inc. Xeloda prescribing information; 2010. http://www.gene.com/gene/products/information/xeloda/pdf/pi.pdf. 
23. Wilkes GM, Doyle D. Palmar-plantar erythrodysesthesia. Clin J Oncol Nurs. 2005;9:103-106.
24. Polovich M, White JM, Kelleher LO, eds. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. 3rd ed. Pittsburgh, PA: Oncology Nursing Society. 2009.

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