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Journal of Clinical Oncology, Vol 24, No 36 (December 20), 2006: pp. 5786-5788 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.08.6868
Hand-Foot Syndrome and Seborrheic Dermatitis-Like Rash Induced by Sunitinib in a Patient With Advanced Renal Cell CarcinomaDepartments of Dermatology, Pathology, Hematology-Oncology, Chang Gung Memorial Hospital and University, Taipei, Taiwan A 56-year-old man with left renal cell carcinoma (RCC) presented with left flank mass in 1999. He underwent radical nephrectomy. Tumor recurred at paraaortic area, involving pancreas and duodenum in 2005. Second attempt to remove the tumor failed. He received interferon alfa therapy. Unfortunately, disease progression with lung metastases was noted in 2006. The patient received oral sunitinib (Sutent; Pfizer Inc, New York, NY) 50 mg in a 4-week-on/2-week-off regimen. In addition to general systemic effects, including asthenia, poor appetite, nausea, and diarrhea, the patient developed cutaneous reactions during the third week of the trial. Tender erythematous swelling over the finger tips and periungual area were observed. In addition, the patient had several blisters with erythematous halo over palms and soles, accompanied by tingling and a burning sensation over the lesion sites (Fig 1). These skin lesions resulted in difficulties during walking and handling objects. A skin biopsy on the left middle finger blister was performed. The histology demonstrated acanthosis, spongiform pustule, and an intraepidermal cavity filled with necrotic keratinocytes. The underlying dermis showed dilated vessels with mononuclear cell infiltrates and scattered neutrophils and rare eosinophils (Fig 2; magnification of x40 and x400 [inset]) . In addition to involvement of the limbs, the patient also had skin manifestations of sunitinib over the face with fissuring of both sides of the mouth and scaling erythema with greasy flakes over bilateral nasolabial folds and perioral area (Fig 3). These seborrheic dermatitis-like rashes disappeared after administration of topical 0.1% mometasone furoate ointment and discontinuation of sunitinib therapy. At the same time point, blisters on palms and soles resolved with desquamation.
Advanced and metastatic RCC is resistant to conventional chemotherapy. Few patients survive long-term after immunotherapy such as that with interleukin-2 and/or interferon, both of which are frequently associated with severe toxicities.1,2 Activation of the vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) kinase pathways is common in solid tumors such as RCC.3 Such activation is implicated in tumor angiogenesis and proliferation. Several new antitumor agents have been developed that target VEGF/PDGF receptors (VEGFR/PDGFR), such as low molecular weight tyrosine kinase inhibitors (TKIs) sunitinib,4 sorafenib,5 and the anti-VEGF antibody, bevacizumab.6 The appearance of hand and foot, tender erythematous blisters has been observed at doses of sunitinib 75 mg daily,4and at 50 mg daily in this case. These skin lesions induced by sunitinib were more localized and hyperkeratotic than that in hand-foot syndrome or palmar plantar erythrodysaesthesia produced by classic chemotherapy, such as that with cytarabine, fluorouracil, capecitabine, and doxorubicin.7 Previous experimental study has demonstrated that combined suppression of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms.8 Because sunitinib is a TKI that targets VEGFR-2 and PDGFR-ß, both of which are the major expression subtypes of VEGFR/PDGFR in capillary vasculature, it is hypothesized that TKIs act via direct anti-VEGFR and anti-PDGFR effects, which damage the capillary endothelium. While hand and foot surfaces are under pressure from walking or use, we propose that the affected vessels under the pressure points are prone to damage and clinically present as hand/foot, inflammatory, tender erythema, and blisters. Seborrheic dermatitis-like rash was observed in this sunitinib-treated patient. The involved areas were the scalp, eyebrows, nasolabial folds, and perioral area; presentations varied from slightly erythematous scaling to greasy flakes. These lesions faded after applying of a topical steroid and discontinuation of sunitinib. Many etiologies have been implicated in seborrheic dermatitis, such as imbalances in lipids and hormones, Malassezia species infection, immunocompromised status, and CD4 T-cell lymphopenia.9-11 Drugs with T-cell suppression and antiangiogenesis characteristics, such as thalidomide,12 reportedly induce seborrheic dermatitis. Sunitinib has marked antityrosine kinase activities against T-cell PDGF-ß receptors and antiangiogenesis effects,13 which in turn cause seborrheic dermatitis. In the past few years, TKIs targeting different receptors have shown their efficacy in the treatment of many types of cancer. Among them, epidermal growth factor receptors TKIs (eg, gefitinb, erlotinib) were best documented with dermatologic adverse effects, most frequently an acneiform eruption, but also xerosis, and paronychia.14 This report described a patient taking sunitinib who developed hand-foot syndrome and seborrheic dermatitis-like rashes, two entities that, to date, have debated pathophysiologies. Further study is warranted to clarify mechanisms of these two dermatologic manifestations. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
ACKNOWLEDGMENTS We thank Pfizer Limited for the Grant No. XMRPG 350111. This patient has participated in Protocol No. A6181037. REFERENCES
1. Negrier S, Escudier B, Lasset C, et al: Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma: Groupe Francais d'Immunotherapie. N Engl J Med 338:1272-1278, 1998 2. Medical Research Council Renal Cancer Collaborators: Interferon-alpha and survival in metastatic renal carcinoma: Early results of a randomised controlled trial. Lancet 353:14-17, 1999[CrossRef][Medline] 3. Stadler WM: Targeted agents for the treatment of advanced renal cell carcinoma. Cancer 104:2323-2333, 2005[CrossRef][Medline] 4. Faivre S, Delbaldo C, Vera K, et al: Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 24:25-35, 2006 5. Clark JW, Eder JP, Ryan D, et al: Safety and pharmacokinetics of the dual action Raf kinase and vascular endothelial growth factor receptor inhibitor, BAY 43-9006, in patients with advanced, refractory solid tumors. Clin Cancer Res 11:5472-5480, 2005 6. Yang JC: Bevacizumab for patients with metastatic renal cancer: An update. Clin Cancer Res 10:6367S-6370S, 2004 7. Lassere Y, Hoff P: Management of hand-foot syndrome in patients treated with capecitabine (Xeloda). Eur J Oncol Nurs 8:S31-S40, 2004 (suppl 1)[CrossRef][Medline] 8. Erber R, Thurnher A, Katsen AD, et al: Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. Faseb J 18:338-340, 2004 9. Gupta AK, Bluhm R: Seborrheic dermatitis. J Eur Acad Dermatol Venereol 18:13-26, 2004; quiz 19-20, 2004[CrossRef][Medline] 10. Wiwanitkit V: Prevalence of dermatological disorders in Thai HIV-infected patients correlated with different CD4 lymphocyte count statuses: A note on 120 cases. Int J Dermatol 43:265-268, 2004[CrossRef][Medline] 11. Oble DA, Collett E, Hsieh M, et al: A novel T cell receptor transgenic animal model of seborrheic dermatitis-like skin disease. J Invest Dermatol 124:151-159, 2005[CrossRef][Medline] 12. Hall VC, El-Azhary RA, Bouwhuis S, et al: Dermatologic side effects of thalidomide in patients with multiple myeloma. J Am Acad Dermatol 48:548-552, 2003[CrossRef][Medline] 13. Daynes RA, Dowell T, Araneo BA: Platelet-derived growth factor is a potent biologic response modifier of T cells. J Exp Med 174:1323-1333, 1991 14. Segaert S, Van Cutsem E: Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol 16:1425-1433, 2005
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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