|Year : 2014 | Volume
| Issue : 2 | Page : 140-142
Capecitabine-induced hand-foot syndrome
Shilpa Y Krishnegowda, Sudhir N Kumar
Department of Dermatology, Venereology and Leprosy, Adichunchanagiri Institute of Medical Sciences, Affiliated to Rajiv Gandhi Institute of Medical Sciences, Karnataka, India
|Date of Submission||01-Nov-2014|
|Date of Acceptance||10-Dec-2014|
|Date of Web Publication||29-Jan-2015|
Sudhir N Kumar
MD, Department of Dermatology, Venereology and Leprosy, Affiliated to Rajiv Gandhi Institute of Medical Sciences, Adichunchanagiri Institute of Medical Sciences, Karnataka - 571448
Source of Support: None, Conflict of Interest: None
Capecitabine is an oral fluoropyrimidine carbamate and a prodrug of 5- fluorouracil, used in treatment of colorectal and breast carcinoma, which fail to respond to standard chemotherapies. A variety of muco-cutaneous adverse effects has been recognized. The pathogenesis of such manifestations still remains an enigma though various theories have been proposed. We report a case of localized cutaneous hyperpigmentation of the palms and soles secondary to capecitabine in a woman that underwent sigmoidectomy and was in her second cycle of chemotherapy. Since these drugs causing HFS has become commoner in its use in the recent years, due to its relative ease in administration and the relative unawareness of this syndrome among dermatologists makes it a prudent topic to be reported.
Keywords: Capecitabine, hand - foot syndrome, 5 - fluorouracil, dose - dependent
|How to cite this article:|
Krishnegowda SY, Kumar SN. Capecitabine-induced hand-foot syndrome. Egypt J Dermatol Venerol 2014;34:140-2
| Introduction|| |
Capecitabine is an oral prodrug of 5-fluorouracil, used in the treatment of colorectal and breast carcinomas, which are recalcitrant to standard chemotherapies . Capecitabine is less frequently encountered with mucocutaneous side effects. Hand-foot syndrome (HFS) is dose related and is infrequently a life-threatening complication in some patients when appropriate measures are not undertaken. In the past decade, various attempts have been made to describe this entity. Here, we are presenting a case of HFS caused by capecitabine.
| Case report|| |
A 50-year-old female patient was referred to us for the development of blackish pigmentation over both the hands and feet, associated with numbness and tingling sensation. She was diagnosed with adenocarcinoma of the sigmoid colon (stage T 3 N 0 M X ) for which sigmoidectomy with transverse colostomy was performed. She was advised chemotherapy with intravenous oxaliplatin and oral capecitabine. Two courses of oxaliplatin, 180 mg in 500 ml of 5% dextrose as a slow infusion over 3 h, along with oral capecitabine at a daily dosage of 2500 mg given in divided doses for 2 weeks was given. A week after the second course, she developed diffuse hyperpigmentation of both hands and feet, more at the finger tips and was associated with tingling and numbness [Figure 1],[Figure 2] and [Figure 3]. No desquamation, ulceration, or mucosal pigmentation was noticed. Nails showed longitudinal melanonychia. She was a diabetic patient on regular treatment. Systemic examination did not reveal any abnormality. As the patient's only concurrent medications were ranitidine, domperidone, and oxaliplatin, for which hyperpigmentation as a side effect was not known, HFS was attributed to capecitabine. She was then instructed to apply emollients and reassurance was given.
|Figure 1: Hyperpigmentation of the palms, mainly seen over the finger tips.|
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|Figure 2: Hyperpigmentation of the hands mainly over the finger tips (dorsal view).|
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| Discussion|| |
HFS, otherwise known as Burgdorf's reaction, chemotherapy-induced acral erythema, or palmoplantar erythrodysesthesia, was first described by Lokich and Moore in 1984 ,. HFS is distinctive but not a less frequent side effect of capecitabine . Many other cytotoxic drugs such as 5-fluorouracil, cytarabine, doxorubicin, epirubicin, hydroxyurea, cyclophosphamide, and docetaxel have been implicated to cause HFS .
Capecitabine is converted by the enzyme thymidine phosphorylase to its active metabolite and prodrug form 5-fluorouracil. As the enzyme thymidine phosphorylase is more in certain tumors, it paves way for targeted approach of the drug towards these sites, lessening the side effects of its parent drug 5-fluorouracil ,,. It was first approved for treatment of metastatic solid tumors of colon and breast in 2001 .
HFS is a dose-dependent side effect. The drug accumulates in the stratum corneum of the palms and soles, which is rich in eccrine glands, resulting in local injury due to toxic quantities of the drug . Other proposed pathogenetic factors include stimulation of melanogenesis through raised melanocyte stimulating hormone, decreased tyrosinase inhibitors, formation of stable drug-melanin complex, increased photosensitivity, and increased enzyme activity resulting in higher concentration of active metabolite in these areas ,. The initial manifestations of HFS are discomfort over the hands, paresthesias, dysesthesias, burning sensation, pain, and tenderness on holding objects, which may progress to swelling and erythema of the thenar and hypothenar eminences over the next few days, resulting in difficulty in daily activities. Blisters may be seen in very severe cases and the condition resolves with desquamation within 2 weeks of stoppage of the medication . Nail disorders are reported in less than 5% of patients receiving capecitabine alone, which include photo-onycholysis, fragility, and longitudinal melanonychia ,. The other cutaneous side effects of capecitabine include lentigenes, inflammation of actinic keratoses, toxic epidermal necrolysis, and sclerodermatous changes ,.
The proposed classification systems for HFS have been shown in [Table 1] ,. According to the present classification systems, our patient with hyperpigmentation and dysesthesia fall under grade 1 of HFS. Diabetes may act as a risk factor for the rapid progression in HFS grades due to poor peripheral circulation . Narasimhan and colleagues observed HFS to be more frequent among black patients, and in these patients signs and symptoms were usually masked by progressive hyperpigmentation and thickening of palms and soles, which may be associated with stiffness and loss of function [Table 1]. Histopathology is usually nonspecific with focal spongiosis and atypia in the epidermis, whereas the dermis shows scanty mononuclear cell infiltrates. Rarely, vacuolar degeneration in basal layer with nuclear pleomorphism may be seen . Severe liver disease and acute graft versus host disease, which present as acral erythemas, should be differentiated from HFS. Elevated liver enzymes, absence of pain, and desquamation differentiates severe liver disease from HFS. Acute onset, reddening of dorsal aspect of fingers, presence of pruritus, tenderness, and spotty erythema help differentiate acute graft versus host disease from HFS.
|Table 1: The various proposed classification systems for hand-foot syndrome|
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The treatment of HFS varies according to the grades. Grade 1 and 2 patients may be treated symptomatically with emollients, cold compressors, and topical corticosteroids. Grade 3 needs either discontinuation or reduction of dosage by 25-50%, with intensive topical care. In patients with grade 4 HFS, complete stoppage of therapy is required to avoid recurrences or worsening of the existing condition . Avoidance of sunlight, heat, and elevation of hands and feet may relieve symptoms . Oral pyridoxine has shown some benefit in patients on 5-fluorouracil therapy .
The increasing frequency of use of oral capecitabine in recent years and the relative unawareness of this condition among dermatologists makes it prudent to be reported. Patients with Asian descent are also prone for HFS and it is not only a black population-based condition. Our patient, although diabetic, did not have any acute progression.
| Acknowledgements|| |
Conflicts of interest
| References|| |
Food and Drug Administration. Capecitabine approved in second-line metastatic breast cancer. Rockville, MD: National Press Office; 2001. 10.
A, Vasani R, Medhekar S, Thakre M, Saple DG. Hand-foot syndrome due to capecitabine. Indian J Dermatol 2008; 53
SD, Kim HJ, Hwang SJ, Kim YJ, Nam SH, Kim BS. Hand-foot syndrome with scleroderma-like change induced by the oral capecitabine: a case report. Korean J Intern Med 2007; 22
G, Cameli N, Romano MC, Mariano M, Panariello L, Bianca D, Monfrecola G. Chemotherapy and skin reactions. J Exp Clin Cancer Res 2012; 31
üller J, Cassidy J, Dumont E, Roos B, Durston S, Banken L, et al.
Preferential activation of capecitabine in tumor following oral administration to colorectal cancer patients. Cancer Chemother Pharmacol 2000; 45
M, Ura M, Nishida M, Sawada N, Ishikawa T, Mori K, et al.
Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. Eur J Cancer 1998; 34
Cutsem E, Twelves C, Cassidy J, Allman D, Bajetta E, Boyer M, et al.
Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 2001; 19
ález VM, Mathe AD, Munoz AS, Bas CA, Coppola F, Casas G, et al.
Cutaneous manifestations of new oncologic drugs: epidermal growth factor receptor inhibitors and 5-fluorouracil prodrugs. Dermatol Argent 2008; 14
Boston L, Pan TD, Mcdonald C. Alopecia and cutaneous complications. Abeloff M, Armitage J, Niederhuber J, Kaston M, Mckenna WG, eds Clinical oncology. 3rd ed. London, UK: Churchill-Livingstone; 2004. 796-803.
Zekri J, Abdel Ghany EM. Hyperpigmentation of the tongue, palms and soles: rare side effect of capecitabine. J Cancer Res Ther 2013; 1
Capecitabine (Xeloda). In: Physician′s desk reference
. 55th ed. Montvale: Medical Economics Inc.; 2001; 2606-2809.
Lal HS. Hand and foot syndrome secondary to capecitabine. Indian J Dermatol Venereol Leprol 2014; 80
Minisini AM, Tosti A, Sobrero AF, Mansutti M, Piraccini BM, Sacco C, Puglisi F Taxane-induced nail changes: incidence, clinical presentation and outcome. Ann Oncol 2003; 14
Narasimhan P, Narasimhan S, Hitti IF, Rachita M. Serious hand-and-foot syndrome in black patients treated with capecitabine: report of 3 cases and review of the literature. Cutis 2004; 73
Vukelja SJ, Lombardo FA, James WD, Weiss RB. Pyridoxine for the palmar-plantar erythrodysesthesia syndrome. Ann Intern Med 1989; 11: 688-689.
[Figure 1], [Figure 2], [Figure 3]