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Journal of Clinical Oncology, Vol 24, No 16 (June 1), 2006: pp. e28-e29 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.1631
Erlotinib Induced Skin Rash Spares Skin in Previous Radiotherapy FieldRoyal Sussex County Hospital, Brighton and Sussex University Hospital National Health Service Trust, Brighton, United Kingdom To the Editor: A 56-year-old male, ex-smoker presented with a T1N0M0 moderately differentiated adenocarcinoma of the right lung in November 2002. He had a right upper lobectomy with clear resection margins. None of the 11 lymph nodes removed had any evidence of cancer. A computed tomography (CT) scan done in February 2004 showed a 3 cm mass in the right paratracheal region. Staging investigations including a positron emission tomography (PET)–CT scan suggested that the paratracheal lymph node was the only site of recurrent disease. He had four cycles of paclitaxel at 175 mg/m2 plus carboplatin (area under the curve, 5) every 3 weeks without any significant adverse effects. Thereafter, in August 2004 he had a right posterolateral thoracotomy for excision of the mediastinal mass. The mass was in contact with the right main bronchus, right pulmonary artery, and superior vena cava, but a complete macroscopic resection was achieved. Histopathology revealed a lymph node completely replaced by poorly differentiated carcinoma with tumor extending superficially beyond the capsule and present at the circumferential margins. Staging investigations suggested no evidence of lung cancer. He had radical radiotherapy to the mediastinum to a dose of 64 Gy in 32 fractions over 6.5 weeks with 6 MV photons in two phases. In the first phase, he had two rectangular fields to the mediastinum from the front and back to a dose of 40 Gy in 20 fractions over 4 weeks. Phase II followed phase I and was completed in November 2004. Subsequently, he completed three cycles of gemcitabine (1,000 mg/m2 intravenously days 1 and 8) and cisplatin (70 mg/m2 intravenous infusion day 1) every 4 weeks without any significant adverse effects. He was well for approximately 3 months until August 2005 when he had a fainting attack. A magnetic resonance image of the brain suggested three small intracranial metastases. A PET-CT scan showed there was no extracranial cancer. He received whole-brain radiotherapy to a dose of 30 Gy in 10 fractions over 2 weeks with erlotinib (Tarceva; Roche, Basel, Switzerland) 150 mg orally once daily. Thereafter, he had gamma knife radiotherapy to each of the intracranial metastases to a single dose of 19 Gy. He is presently asymptomatic. The patient had continued to receive erlotinib for 3 weeks when he developed severe skin rashes. The rashes were treated with emollients and doxycycline. The rashes were extensive across his face, neck, and anterior and posterior chest. Surprisingly, the rashes had completely spared part of the skin of his anterior and posterior chest that had been included in his previous radiotherapy field. This was obvious when the radiotherapy fields are highlighted with skin marker pen (Figs 1, 2, 3, and 4.)
There is a high incidence of rash in patients treated with agents that inhibit HER1/epidermal growth factor receptor (EGFR). Phase I data shows that the rash is dose related.1-3 Data from several clinical trials with EGFR-targeted agents show a positive correlation between rash and response and/or survival.4,5 There is limited data on the etiology of the rash. Busam et al6 reported on a histologic analysis of rash samples from 10 patients receiving cetuximab, and concluded that this rash is characterized by a lymphocytic perifolliculitis or suppurative superficial folliculitis, but has no infectious etiology. They hypothesized that suppurative inflammation occurs in response to follicular rupture. As we have little knowledge of why HER1/EGFR inhibitors can cause inflammatory rash, studies to clarify the relationship between rash etiology and HER1/EGFR inhibition are urgently required. Agents that reverse HER1/EGFR inhibition in the skin might be able to prevent the rash.7 Multiple reports support the view that EGFR blockade radiosensitizes carcinoma cells in both in vitro and in vivo settings.8,9 The first phase III randomized trial evaluating EGFR inhibitors as radiosensitizers in patients with locally advanced head and neck cancer was strongly positive, indicating significant potential of this class of agents to improve outcome with radiotherapy.10 The radiation-induced activation of EGFR is associated with increased tumor cell proliferation, and treatment with EGFR inhibitors prevents the radiation-induced activation of EGFR and the proliferative response.11 The reasons why erlotinib-induced skin rash should spare previously radiated skin needs to be explored further. This report of an interesting observation will hopefully stimulate additional research into the mechanism of interaction of EGFR inhibitors with radiation. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES
1. Ranson M, Hammond L, Ferry D, et al: ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: Results of a phase I trial. J Clin Oncol 20:2240-2250, 2002 2. Herbst R, Maddox AM, Rothenberg ML, et al: Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: Results of a phase I trial. J Clin Oncol 20:3815-3825, 2002 3. Hidalgo M, Siu L, Nemunaitis J, et al: Phase I and pharmacologic study of OSI-774, an epidermal growth factor receptor tyrosine kinase inhibitor, in patients with advanced solid malignancies. J Clin Oncol 19:3267-3279, 2001 4. Clark G, Perez-Soler R, Siu L, et al: Rash severity is predictive of increased survival with erlotinib HCI. Proc Am Soc Clin Oncol 22:196, 2003 (suppl; abstr 786) 5. Saltz L, Kies M, Abbruzzese JL, et al: The presence and intensity of the cetuximab-induced acne-like rash predicts increased survival in studies across multiple malignancies. Proc Am Soc Clin Oncol 22:204, 2003 (suppl; abstr 817) 6. 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] 7. Pérez-Soler R, Delord JP, Halpern A, et al: HER1/EGFR inhibitor-associated rash: Future directions for management and investigation outcomes from the HER1/EGFR inhibitor rash management forum. The Oncologist 10:345-356, 2005 8. Raben D, Bianco C, Helfrich B, et al: Interference with EGFR signaling: Paradigm for improving radiation response in cancer treatment. Expert Rev Anticancer Ther 2:461-471, 2002[CrossRef][Medline] 9. Bianco C, Tortora G, Bianco R, et al: Enhancement of antitumor activity of ionizing radiation by combined treatment with the selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 (Iressa). Clin Cancer Res 8:3250-3258, 2002 10. Bonner J, Harari PM, Giralt J, et al: Cetuximab prolongs survival in patients with locoregionally-advanced squamous cell carcinoma of head and neck: A phase III study of high dose radiation therapy with or without cetuximab. J Clin Oncol 22:489s, 2004 (suppl; abstr 5507) 11. Huang SM, Li J, Armstrong EA, et al: Modulation of radiation response and tumor-induced angiogenesis after epidermal growth factor receptor inhibition by ZD1839 (Iressa). Cancer Res 62:4300-4306, 2002
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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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