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Journal of Clinical Oncology, Vol 23, No 22 (August 1), 2005: pp. 5273-5275 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.01.9570
Abnormal Hair Growth in a Patient With Head and Neck Cancer Treated With the Anti-Epidermal Growth Factor Receptor Monoclonal Antibody CetuximabDepartment of Medical Oncology, Institute of Hematology and Oncology (ICMHO), and the Department of Dermatology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Hospital Clínic, Barcelona, Spain. To the Editor: Cetuximab (C225; Erbitux; ImClone Systems Inc, New York, NY) is a chimeric monoclonal antibody directed selectively against the epidermal growth factor receptor (EGFR).1 Cetuximab has recently been approved for the treatment of patients with EGFR-overexpressing metastatic colorectal cancer. Moreover, in clinical trials cetuximab has shown promising activity in different neoplasms, including head and neck cancer.2,3 Due to the important role of the EGFR in skin homeosthasis, cutaneous reactions are a common adverse effect of cetuximab, mainly an acneiform follicular eruption. Other less frequent dermatologic events are small oral aphthous ulcers, seborrheic dermatitis-like eruptions, paronychia, desquamation, pruritus, or one reported case of trichomegaly (abnormally long eyelashes).4-6 In this letter, we report a case of diffuse and abnormal hair growth of the chest apparently related to cetuximab therapy. Based on a biopsy performed in the thoracic skin of this patient, we describe its histopathologic and molecular correlations. A 66-year-old white man underwent supraglottic laringectomy due to a stage III supraglottic squamous cell carcinoma. Three months later, the patient developed local progression, and a total laryngectomy plus a modified radical neck dissection was performed. Four months later, the patient presented with a second local relapse. Chemotherapy with carboplatin plus tegafur was administered with no response, and the patient was then included in a clinical trial with weekly cetuximab (400 mg/m2/intravenous [IV] followed by 250 mg/m2/IV) plus carboplatin area under the plasma concentration time curve 5 mg · min/mL IV once every 4 weeks. After 1 year of continuous treatment, physical examination revealed abnormally long and thick hair distributed diffusely on the chest. Hormonal serum levels were normal and the patient was not receiving any treatment other than carboplatin plus cetuximab. A punch biopsy of the abnormal hair area revealed disoriented and short inserted hair follicles associated to an irregular architecture in keratinocytes of the inner and outer root sheaths, associated to a faint lymphocytic inflammatory infiltrate (Fig 1A). An immunohistochemical analysis for the phosphorylated form of EGFR7 showed absence of phosphorylated-activated EGFR in the epidermal keratinocytes and very faint staining in the altered hair follicles, suggesting a major inhibition of EGFR achieved during cetuximab treatment (Fig 1B). After 15 months of treatment, the patient achieved complete response and presented persistent grade 3 folliculitis and abnormal hair growth on the chest. At that time, cetuximab and carboplatin were discontinued. Three months later, the abnormal hair growth and the acneiform follicular eruption resolved.
In previous articles,7,8 histopathologic, clinical, and molecular effects of cetuximab and EGFR tyrosine kinase inhibitors have been reported in the skin of patients after a few weeks of treatment. This has been of help to understand the biologic activity of these drugs. However, the clinical and biologic effects of chronic treatment with EGFR-interacting agents are less characterized due to the more limited experience with long-term use of these drugs. Our patient did not exhibit other known reasons for developing abnormal hair growth. A possible role of carboplatin in this hair abnormality may not be ruled out, however, no reports of a similar nature are available regarding this drug. Furthermore, the disappearance of the excessive hair growth after cessation of treatment further supports cetuximab's potential role in the growth of abnormal hair. A possible explanation for this abnormal hair growth lies in the role of EGFR in hair cycle regulation. EGFR is a major regulator of the epithelium-mesenchymal interactions and plays an important role in regulating the transformation from anagen or growth phase to catagen or regressive phase.9 Cetuximab-induced inhibition of the EGFR in hair follicles may alter the growth cycle of the hair follicle and halt the anagen-catagen transformation. This would result in the hair follicles remaining in an aberrant anagen phase, consequently leading to abnormal hair growth. With the increasing use of cetuximab in cancer patients, it will be of interest to see if an effect similar to the one reported in this letter is observed in additional patients. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES
1. Mendelsohn J, Baselga J: Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 21:2787-2799, 2003
2. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004 3. Trigo J, Hitt R, Koralewski P, et al: Cetuximab monotherapy is active in patients with platinum-refractory recurrent/metastasic squamous cell carcinoma of the head and neck: Results of a phase II study. Proc Am Soc Clin Oncol 23:487, 2004 (suppl, abstr 5502) 4. Busam KJ, Capodieci P, Motzer R, et al: Cutaneous side-effects in cancer patients treated with the antiepidermal growth factor receptor antibody C225. Br J Dermatol 144:1169-1176, 2001[CrossRef][Medline]
5. Monti M, Mancini LL, Ferrari B, et al: Complications of therapy and a diagnostic dilemma case: Cutaneous toxicity induced by cetuximab. J Clin Oncol 21:4651-4653, 2003 6. Dueland S, Sauer T, Lund-Johansen F, et al: Epidermal growth factor receptor inhibition induces trichomegaly. Acta Oncol 42:345-346, 2003[CrossRef][Medline]
7. Albanell J, Rojo F, Averbuch S, et al: Pharmacodynamic studies of the epidermal growth factor receptor inhibitor ZD1839 in skin from cancer patients: Histopathologic and molecular consequences of receptor inhibition. J Clin Oncol 20:110-124, 2002
8. Albanell J, Codony-Servat J, Rojo F, et al: Activated extracellular signal-regulated kinases: Association with epidermal growth factor receptor/transforming growth factor 9. Hansen LA, Alexander N, Hogan ME, et al: Genetically null mice reveal a central role for epidermal growth factor receptor in the differentiation of the hair follicle and normal hair development. Am J Pathol 150:1959-1975, 1997[Abstract]
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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expression in head and neck squamous carcinoma and inhibition by anti-epidermal growth factor receptor treatments. Cancer Res 61:6500-6510, 2001
