Sparing of previously irradiated skin from erlotinib-induced acneiform rash

Abstract

To the Editor: Erlotinib is a human epidermal growth factor receptor type 1 (Her1/EGFR) thyrosine kinase inhibitor used in the treatment of non–small cell lung cancer (NSCLC) and pancreatic cancer.1Cohen M.H. Johnson J.R. Chen Y.F. Sridhara R. Pazdur R. FDA drug approval summary: erlotinib (Tarceva) tablets.Oncologist. 2005; 10: 461-466Crossref PubMed Scopus (340) Google Scholar, 2Moore M.J. Goldstein D. Hamm J. Figer A. Hecht J. Gallinger S. et al.Erlotinib plus gemcitabine compared to gemcitabine alone in patients with advanced pancreatic cancer. A phase III trial of the National Cancer Institute of Canada Clinical Trials Group [NCIC-CTG]. American Society of Clinical Oncology 2005 Annual Meeting Proceedings (abstract 1).J Clin Oncol. 2005; 23: 1PubMed Google Scholar Typically appearing within the first 2 weeks, the major physical manifestation of erlotinib toxicity is a cutaneous rash, seen in almost 70% of patients; the face, neck, and upper torso are commonly involed.3Perez-Soler R. Saltz L. Cutaneous adverse effects with HER1/EGFR-targeted agents: is there a silver lining?.J Clin Oncol. 2005; 23: 5235-5246Crossref PubMed Scopus (449) Google Scholar We report a patient with NSCLC developing a typical acneiform rash sparing the area of previous radiotherapy. A 43-year-old male patient was admitted to the hospital with fatigue and a cough. A computed tomographic scan of his thorax showed an 86 mm × 75 mm mass in the left upper lobe, with multiple mediastinal and hilar lymphadenopathies. Biopsy was consistent with NSCLC. No evidence of distant metastasis was present. Treatment with gemcitabin plus cisplatin was commenced, and radiotherapy to the mass and mediastinum was applied between the third and fourth cycles. After the sixth cycle, the mass and the lymphadenopathies had largely regressed. With the patient's approval, treatment with erlotinib was started. After 2 weeks of erlotinib treatment, a typical acneiform rash developed on the face, trunk, and upper extremities. The skin overlying the areas of previous radiotherapy, however, was spared, on both the anterior and posterior sides of the trunk (Fig 1). We performed skin biopsies from the acne-spared, previously irradiated skin and from the neighboring affected nonirradiated skin. Histologic examination revealed suppurative folliculitis destroying follicular epithelium and adnexial structures in the nonirradiated skin specimen. Although eccrine glands and piloerector muscles were normal, there was no follicular structure in the previosly irradiated skin specimen (Fig 2). We performed EGFR staining to see if EGFR expression was altered in the radiated area. No difference was seen between irradiated and nonirradiated skin. In both specimens, moderate intracytoplasmic and membranous EGFR staining of basal epidermal cells and follicular epithelium were observed. Four months after treatment began, the irradiated area remained acne-free and showed no signs of disease progression. Rash is a common adverse affect of Her1/EGFR-targeted agents. Histology of the lesions associated with erlotinib, cetuximab, and gefitinib are similar, indicating a class effect of Her1/EGFR inhibitors. The pathogenesis of the rash is not completely understood. Her1/EGFR is expressed by normal keratinocytes, skin fibroblasts, and in the outer root sheath of the hair follicle. A neutrophilic infiltrate has been reported in dermal tissue, particularly the infundibular part of the hair follicle, but the sebaceous glands are not affected.3Perez-Soler R. Saltz L. Cutaneous adverse effects with HER1/EGFR-targeted agents: is there a silver lining?.J Clin Oncol. 2005; 23: 5235-5246Crossref PubMed Scopus (449) Google Scholar Histologic analysis of rash samples from patients receiving cetuximab showed lymphocytic perifolliculitis or suppurative superficial folliculitis without any infectious etiology.4Busam K.J. Capodieci P. Motzer R. Kiehn T. Phelan D. Halpern A.C. Cutaneous side-effects in cancer patients treated with the antiepidermal growth factor receptor antibody C225.Br J Dermatol. 2001; 144: 1169-1176Crossref PubMed Scopus (391) Google Scholar The skin changes may start within the first hours of radiotherapy and might last for months, or they may be permanent. The estimated D50 follicle dose is around 40 Gy.5Lawenda B.D. Gagne H.M. Gierga D.P. Niemierko A. Wong W.M. Tarbell N.J. et al.Permanent alopecia after cranial irradiation: dose-response relationship.Int J Radiat Oncol Biol Phys. 2004; 60: 879-887Abstract Full Text Full Text PDF PubMed Scopus (82) Google Scholar The patient received 45 Gy total to the tumor bed, while the skin received 18.5 Gy. In the present case, we have shown that sparing of irradiated skin from erlotinib-related acneifom rash seems to be caused by radiation-induced follicular loss, and EGFR expresion is not altered.