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Hand and Foot Syndrome – a common side effect of chemotherapy

May 23, 2019

This article was jointly published in Podiatry Now Journal (June 2019 22(6): 8-11) & on the blog here.

 

 

Outline

 

Hand and foot syndrome is a relatively common side effect of patients undergoing chemotherapy, particularly those taking cytarabine, doxorubicin and 5-fluorouracil (including its prodrug, capecitabine). The condition ranges from paraesthesia affecting the palms and soles to painful blistering and fissures. Patients with this condition may present in the podiatry clinic seeking advice or treatment. The author presents a recent case of a 70-year-old female with metastatic breast cancer undergoing chemotherapy with capecitabine and discusses the background to this unusual condition, rarely documented within podiatry texts.

 

 

Case

 

A 70-year old female presented to the podiatry clinic with a history of soreness, blistering and fissuring affecting both plantar surfaces of her feet (Figure 1). Medically, she had been diagnosed with breast carcinoma three years previously. Following a recent scan, she was discovered to have developed advanced metastatic disease and had been prescribed a course of capecitabine. Within a few days of taking the drug she developed erythema, paraesthesia and shortly afterwards fissuring of her hands and feet. Blisters appeared around both halluces (Figure 2).  Based history and assessment, a diagnosis of hand foot syndrome was made.

 

 

 

 

What is hand foot syndrome?

 

Hand Foot Syndrome (HFS) is a common condition which may develop in cancer patients undergoing chemotherapy. The condition may develop within a day or sometimes after a few weeks of treatment. Initially, patients typically complain of tingling or burning in their hands and feet. They may also describe sensations such as walking on hot sand or gravel (1). Shortly afterwards the palmoplantar surfaces develop a symmetrical erythema accompanied by oedema which may limit movements of the digits. In time, the skin may develop scale and fissure. In severe cases, it may progress to blistering and skin ulceration. Extreme symptoms associated with HFS can have an adverse effect on the patient’s activity levels and quality of life (2). The condition is almost exclusive to the palms and soles, occurring below the line of Wallace, although lesions arising on the dorsa of the hands, face and trunk have been reported  (3). In a small number of cases, some patients may only exhibit limited or no erythema and only a fine scale on the palms and soles (4). The condition is said to be non-life threatening although reports of digital amputation have been published (5) and one case where a patient with HFS and diabetes died following sepsis secondary to a pseudomonas infection occurring on her feet (6).

 

 

 

Aetiology

 

The condition is caused as a side effect of chemotherapy treatment. HFS was first discussed in 1974 by Zuehlke (7) in patients taking mitotane for adrenal gland tumours, and latterly in 1991 by Baack & Burgdorf (8) who also observed the condition caused by other chemotherapy agents describing the condition as a “chemically induced acral erythema”  (3). Latterly the condition was formally titled “Palmar Plantar Erythrodysaesthesia (PPE)” but also “Hand Foot Syndrome”. A range of drugs have been known to cause the condition including anthracycline antibiotics, cytarabine, docetaxel but especially  5-fluorouacil  and  its prodrug, capecitabine (9). Newer agents such as multikinase inhibitors (MKI), such as sorafenib and sunitinib, are also known to provoke the condition  (10, 11) although some authors differentiate the condition caused by MKI’s as “Hand-foot-skin reaction” on the basis of histological differences and claiming these drugs are more likely to cause hyperkeratosis over pressure points with accompanying erythema rather than a confluent, symmetrical erythema and scale of classic HFS (6). The appearance of HFS is dose dependent and it arises most frequently at peak drug concentration  although the total cumulative dose can also predict it occurrence (4). Most cases arise within the first or second cycle of treatment, with HFS occurring most severely in the second cycle of chemotherapy  (12).

 

 

 

 

The incidence of HFS is difficult to determine as no formal work has studied this aspect. However, Nagore (4) reviewing published case series has suggested between 6-64% of patients may develop HFS whilst undergoing chemotherapy. Walko and Lindley (13) in their review specifically of 5-FU and capecitabine patients reported 55% of patients developed HFS during chemotherapy whilst Chu  (14) reported a rate of nearly 34% in patients receiving sorafenib. The condition is reported to be more common in older patients receiving chemotherapy, particularly females, in those with diabetes and in more active patients (15) .

 

 

 

 

The exact cause of the condition remains unknown, although several theories have been suggested. Firstly, accumulation of metabolites of the drugs is particularly high in keratinocytes of the palms and soles due to the abundance of the enzyme thymidine phosphorylase in these areas (16) which can rapidly degrade capecitabine to its metabolites leading to toxic effects (9). Other theories postulate that cytotoxic drugs are more readily secreted by the eccrine sweat glands, particularly numerous across the palmar and plantar surfaces, causing the skin reaction to occur (17). Mechanical damage to the plantar surface through activity may lead to minor capillary damage and leakage of metabolites leading to HFS (18), potentially explaining why the condition is more prevalent in active patients.  

 

Histological examination of the skin has been undertaken and pathological changes in the tissues can be observed as vacuolation and degeneration of cells within the basal layer and infiltration around blood vessels with lymphocytes, dermal oedema and degeneration of basal keratinocytes and apoptosis of epidermal keratinocytes (19).

 

Assessment of HFS

 

Two grading systems have been proposed for research and clinical purposes. The first is the National Cancer Institute (NCI) Grading of HFS. Based on three grades (table 1):

 

 

 

The second is the World Health Organisations grading system (Table 2).

 

 

 

 

 

In addition, a Hand-Foot Skin Reaction and Quality of Life Questionnaire has been developed specifically to measure the impact of the disease (20).

 

 

Management of HFS

 

Specific measures to improve the symptoms of HFS have been explored but ultimately cessation of chemotherapy or dose reduction is the key to resolving the condition. HFS will normally fully resolve within 2-3 weeks after treatment has ended. However, during therapy, it has been recommended that if symptom levels reach 2 to 3 on the NCI grading system (table 1) that treatment with capecitabine could be suspended until the HFS resolves whereupon it can be recommenced without affecting the clinical outcome of treatment (21) however, this is not true of other chemotherapy agents where suspension of treatment may lead to a decrease in their performance.

 

Studies have been undertaken to investigate treatments which may reduce the effects of the disease. Firstly, supplemental vitamin B6 (pyridoxine) which had been reported to improve symptoms. Subsequent meta-analyses have consistently reported there is no clinical evidence to support this claim  (22, 23). The use of a urea-based cream has also been investigated in one study but showed no benefit over a placebo cream  (24). The use of topical steroids has been proposed (25) but no trials have been undertaken to date.

 

 

Supportive Measures

 

In addition, a range of supportive measures have been documented. Overall, the evidence for these interventions is variable and for most, they have not been fully investigated but small-scale studies and case reports suggest they maybe be a useful adjunct. Suzuki and colleagues  (26) in a study of patient compliance for treating HFS, produced a list of suggested measures to reduce the effects of the condition (table 3).

 

 

 

 

 

Conclusion

 

Despite its absence within the podiatric literature, Hand-Foot Syndrome is a well-documented side-effect of chemotherapy treatment, particularly with the agents 5-Fluoruracil and its prodrug, capecitabine. Symptoms can range from erythema and swelling of the palmo-plantar surfaces to blistering and skin breakdown. Suspension or cessation of treatment is always curative within a week or two but where this is not an option, supportive measures have been suggested.

 

 

 

 

 

 

References

 

 

1.            Webster-Gandy JD, How C, Harrold K. Palmar–plantar erythrodysesthesia (PPE): A literature review with commentary on experience in a cancer centre. European Journal of Oncology Nursing. 2007;11(3):238-46.

2.            Scheithauer W, Blum J. Coming to grips with hand-foot syndrome. Insights from clinical trials evaluating capecitabine. Oncology (Williston Park). 2004;18(9):1161-8, 73; discussion 73-6, 81-4.

3.            Demircay Z, Gurbuz O, Alpdogan TB, Yucelten D, Alpdogan O, Kurtkaya O, et al. Chemotherapy-induced acral erythema in leukemic patients: a report of 15 cases. Int J Dermatol. 1997;36(8):593-8.

4.            Nagore E, Insa A, Sanmartín O. Antineoplastic Therapy—Induced Palmar Plantar Erythrodysesthesia (‘Hand-Foot’) Syndrome. Am J Clin Derm. 2000;1(4):225-34.

5.            Guenova E, Weber H, Voykov B, et al. Palmar-plantar erythrodysesthesia secondary to sunitinib treatment resulting in necrotic foot syndrome aggravated by background diabetic vascular disease. Arch Dermatol. 2008;144(8):1081-2.

6.            Hoesly FJ, Baker SG, Gunawardane ND, Cotliar JA. Capecitabine-induced hand-foot syndrome complicated by pseudomonal superinfection resulting in bacterial sepsis and death: Case report and review of the literature. Arch Dermatol. 2011;147(12):1418-23.

7.            Zuehlke RL. Erythematous eruption of the palms and soles associated with mitotane therapy. Dermatologica. 1974;148(2):90-2.

8.            Baack BR, Burgdorf WH. Chemotherapy-induced acral erythema. J Am Acad Dermatol. 1991;24(3):457-61.

9.            Do JE, Kim YC. Capecitabine-induced diffuse palmoplantar keratoderma: is it a sequential event of hand–foot syndrome? Clin Exp Dermatol. 2007;32(5):519-21.

10.          Lacouture ME, Reilly LM, Gerami P, Guitart J. Hand foot skin reaction in cancer patients treated with the multikinase inhibitors sorafenib and sunitinib. Ann Oncol. 2008;19(11):1955-61.

11.          Nakamura M, Miyachi Y. Sunitinib-induced subungual splinter haemorrhage and acral erythema. Eur J Dermatol. 2008;18(3):344-5.

12.          Abushullaih S, Saad ED, Munsell M, Hoff PM. Incidence and severity of hand-foot syndrome in colorectal cancer patients treated with capecitabine: a single-institution experience. Cancer Invest. 2002;20(1):3-10.

13.          Walko CM, Lindley C. Capecitabine: A review. Clin Ther. 2005;27(1):23-44.

14.          Chu D, Lacouture ME, Fillos T, Wu S. Risk of hand-foot skin reaction with sorafenib: a systematic review and meta-analysis. Acta Oncol. 2008;47(2):176-86.

15.          Yokokawa T, Kawakami K, Mae Y, Sugita K, Watanabe H, Suzuki K, et al. Risk Factors Exacerbating Hand-Foot Skin Reaction Induced by Capecitabine plus Oxaliplatin with or without Bevacizumab Therapy. Ann Pharmacother. 2015;49(10):1120-4.

16.          Asgari MM, Haggerty JG, McNiff JM, Milstone LM, Schwartz PM. Expression and localization of thymidine phosphorylase/platelet-derived endothelial cell growth factor in skin and cutaneous tumors. J Cutan Pathol. 1999;26(6):287-94.

17.          Mrozek-Orlowski ME, Frye DK, Sanborn HM. Capecitabine: nursing implications of a new oral chemotherapeutic agent. Oncol Nurs Forum. 1999;26(4):753-62.

18.          Lipworth AD, Robert C, Zhu AX. Hand-Foot Syndrome (Hand-Foot Skin Reaction, Palmar-Plantar Erythrodysesthesia): Focus on Sorafenib and Sunitinib. Oncology. 2009;77(5):257-71.

19.          Lou Y, Wang Q, Zheng J, Hu H, Liu L, Hong D, et al. Possible Pathways of Capecitabine-Induced Hand-Foot Syndrome. Chem Res Toxicol. 2016;29(10):1591-601.

20.          Anderson RT, Keating KN, Doll HA, Camacho F. The Hand-Foot Skin Reaction and Quality of Life Questionnaire: An Assessment Tool for Oncology. Oncologist. 2015;20(7):831-8.

21.          Blum JL, Jones SE, Buzdar AU, LoRusso PM, Kuter I, Vogel C, et al. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol. 1999;17(2):485-93.

22.          Chen M, Zhang L, Wang Q, Shen J. Pyridoxine for prevention of hand-foot syndrome caused by chemotherapy: a systematic review. PLoS ONE. 2013;8(8):e72245.

23.          Jo SJ, Shin H, Jo S, Kwon O, Myung S-K. Prophylactic and therapeutic efficacy of pyridoxine supplements in the management of hand–foot syndrome during chemotherapy: a meta-analysis. Clin Exp Dermatol. 2015;40(3):260-70.

24.          Wolf SL, Qin R, Menon SP, Rowland KM, Jr., Thomas S, Delaune R, et al. Placebo-controlled trial to determine the effectiveness of a urea/lactic acid-based topical keratolytic agent for prevention of capecitabine-induced hand-foot syndrome: North Central Cancer Treatment Group Study N05C5. J Clin Oncol. 2010;28(35):5182-7.

25.          Brown J, Burck K, Black D, Collins C. Treatment of cytarabine acral erythema with corticosteroids. J Am Acad Dermatol. 1991;24(6 Pt 1):1023-5.

26.          Suzuki S, Nawata S, Inada Y, Sato D, Kusano J, Ichikura D, et al. A cross-sectional survey of methods for controling hand-foot syndrome in patients receiving capecitabine treatment. Molecular and clinical oncology. 2018;9(4):443-8.

 

 

 

 

 

 

 

 

 

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