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Journal of Clinical Oncology, Vol 25, No 3 (January 20), 2007: pp. 341-343 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.08.9565
Hand-Foot and Stump Syndrome to SorafenibDepartment of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL
Division of Hematology/Oncology, Department of Medicine, Northwestern University, Feinberg School of Medicine, Chicago, IL
Skin and Eye Reactions to Inhibitors of EGFR and Kinases (SERIES) Clinic and Cancer Skin Care Program, Robert H. Lurie Comprehensive Cancer Center and Department of Dermatology, Northwestern University, Feinberg School of Medicine, Chicago, IL A 47-year-old white man, who had an above-the-knee amputation of his left leg, was treated with single-agent sorafenib 400 mg orally twice daily for metastatic renal cell carcinoma. The patient regularly wore a prosthesis that encases his left stump. After approximately 8 weeks on sorafenib, the patient developed a tingling sensation of bilateral hands, his right sole, and his left stump. These quickly progressed to well-demarcated, tender, erythematous, scaling lesions on his palms, right sole (Fig 1) and left stump (Fig 2). Painless distal subungual splinter hemorrhages were also seen in all of his fingernails. Based on clinical findings and history, a diagnosis of hand-foot and stump syndrome (HFSS) secondary to sorafenib therapy was made.
Like hand-foot syndrome, the mechanism by which sorafenib induces the HFSS variant remains only speculative. However, the observed results of this case indicate a possible relationship between the direct toxic effect of the chemotherapeutic drug delivered by the high concentration of eccrine glands in the palms and right sole, and the hyperhidrosis of the encased left stump, which may have contributed to the development of the HFSS on these sites and supporting the notion of anticancer agents in eccrine sweat leading to alterations in skin.1 Features of the acral skin, such as the temperature gradient, the vascular anatomy, the rapidly dividing epidermis, and the highest number of eccrine sweat glands, favor such a hypothesis.2,3 In a study looking at 10 patients treated with doxorubicin, a well described culprit for HFS, Jacobi et al5 measured the fluorescence of the drug qualitatively using a dermatologic laser scanning microscope in one male patient before and after intravenous treatment of doxorubicin on several body surface areas.4 Doxorubicin fluorescence was detected in the uppermost part of the skin on the palmar-plantar surfaces, deep in sweat ducts, and around their openings in the upper skin layers.4 This result suggests that the chemotherapeutic agent was delivered by the sweat to the skin surface. Other cutaneous adverse effects that can be caused by sorafenib warrant attention, including a seborrheic dermatitis-like rash, alopecia, stomatitis, splinter hemorrhages, and inflammation of actinic keratoses.5 The splinter hemorrhages may possibly be explained by the blockade of the vascular endothelial growth factor receptor, which might impair the intrinsic repair mechanisms of delicate injury-prone spiral capillaries.6 Depigmentation of terminal hairs has also been witnessed in clinical practice, occurring in as few as 8 weeks. In mice, blockade of c-kit signaling leads to complete but reversible hair depigmentation with inhibition of melanocyte proliferation and differentiation.7 Multitargeted tyrosine kinase inhibitors can induce a variety of dermatologic adverse events, which require early recognition and effective management,8 in order to ensure continued lifesaving antineoplastic therapy. It is anticipated that observations such as the one described here, will contribute to a better understanding and further investigations towards the optimization of multitargeted therapies. Authors' Disclosures of Potential Conflicts of Interest Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: Mario E. Lacouture, Bayer Pharmaceuticals Stock: N/A Honoraria: N/A Research Funds: N/A Testimony: N/A
REFERENCES
1. Horn TD: Antineoplastic chemotherapy, sweat, and the skin. Arch Dermatol 133:905-906, 1997 2. Susser WS, Whitaker-Worth DL, Grant-Kels JM: Mucocutaneous reactions to chemotherapy. J Am Acad Dermatol 40:367-398, 1999; quiz 399-400, 1999 3. Guillot B, Bessis D, Dereure O: Mucocutaneous side effects of antineoplastic chemotherapy. Expert Opin Drug Saf 3:579-587, 2004[CrossRef][Medline] 4. Jacobi U, Waibler E, Schulze P: Release of doxorubicin in sweat: First step to induce the palmar-plantar erythrodysesthesia syndrome? Ann Oncol 16:1210-1211, 2005 5. Lacouture ME, Desai A, Soltani K, et al: Inflammation of actinic keratoses subsequent to therapy with sorafenib, a multitargeted tyrosine-kinase inhibitor. Clin Exp Dermatol 31783-785 2006[CrossRef][Medline] 6. Robert C, Soria JC, Spatz A, et al: Cutaneous side-effects of kinase inhibitors and blocking antibodies. Lancet Oncol 6:491-500, 2005[CrossRef][Medline] 7. Botchkareva NV, Khlgatian M, Longley BJ, et al: SCF/c-kit signaling is required for cyclic regeneration of the hair pigmentation unit. FASEB J 15:645- 658, 2001 8. Lacouture ME, Basti S, Patel J, et al: The SERIES clinic: An interdisciplinary approach to the management of toxicities of EGFR inhibitors. J Support Oncol 4:236-238, 2006[Medline]
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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