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Journal of Clinical Oncology, Vol 25, No 15 (May 20), 2007: pp. 2140 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.4045
Temporal Dependence of the Effect of Radiation on Erlotinib-Induced Skin RashSkin and Eye Reactions to Inhibitors of EGFR and Kinase S, Department of Dermatology, Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center; and the Department of Radiation Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL To the Editor: We write in response to Drs Sankha Mitra and Richard Simcock's article1 concerning epidermal growth factor receptor inhibitor (EGFRI)–induced rash in areas of radiotherapy. These authors describe an interesting case in which the characteristic papulopustular rash to the EGFRI erlotinib developed diffusely on the upper body, but spared a previously irradiated site. The clinical presentation described in this report underscores the need for a better understanding of skin toxicities unique to combined EGFRI-radiation therapies, and can be explained by reasons presented in this letter. A papulopustular rash involving the face and upper trunk develops in approximately 74% of patients receiving the orally administered reversible quinazoline EGFR tyrosine kinase inhibitor erlotinib.2 Clinical and experimental data suggests that this rash is mechanism based—the inhibition of the EGFR in basal epidermal keratinocytes and the outer root sheath of the hair follicle leads to growth arrest and subsequent inflammation.3 Thus, EGFR harboring cells are critical in the initiation of the pathological sequence of events, and areas with a high density of these cells (pilosebaceous units in the head and upper body) are frequently affected, whereas locations devoid of such appendages (palms and soles) are uniformly spared. Skin cells are relatively radiosensitive because they originate from a basal layer of actively proliferating stem cells. Acute radiation dermatitis can become clinically apparent within days of the first treatment. Time to onset and severity of reaction are dependent on multiple factors, including fraction size, area being treated, beam type, patient age, and previous or concurrent treatments.4 In contrast, chronic effects of radiation in skin develop months or years after exposure. Previously irradiated areas are notable for a conspicuous absence of hair follicles and sebaceous glands and fibrosis. These changes occur as a result of depletion of basal layer stem cells with apoptosis, leading to inflammation and subsequent transforming growth factor beta–mediated fibrosis.5 These changes explain the absence of rash in previously radiated skin, as EGFR-expressing cells that could initiate the pathological process are now decreased or absent. Supporting this thought, the patient in Mitra and Simcock's article1 had received radical radiotherapy approximately 1 year before administration of erlotinib. Conversely, data suggests that EGFR inhibitors, such as erlotinib, act as radiosensitizers in epithelial cells,6 an effect used advantageously in the clinic with the use of combined therapies. We present an 84-year-old white female with stage IV non–small-cell lung cancer who received palliative radiation to the sternum and upper mediastinum. A dose of 30 Gy was delivered in 10 fractions during 2 weeks using 6-MV photons from the front and 10-MV photons from the back. A 1-cm bolus was placed over her sternal mass to increase surface dose to the area. Immediately after the completion of radiation, she was placed on erlotinib at 150 mg a day. After 5 days of therapy, she developed a mild (grade 1) papulopustular rash on her face, but a severe, confluent area of tender papulopustules on the middle of her chest, the area irradiated a few days previously (Fig 1A). Therapy for the rash was initiated with doxycycline at 50 mg twice a day and the topical calcineurin inhibitor pimecrolimus, which resulted in resolution of facial and chest lesions at 2 weeks (Fig 1B).
Thus, the timing of radiation with respect to the administration of EGFRI will lead to different results in tumors and skin, as has been reported with other radiosensitizers, such as paclitaxel and docetaxel.7 This time dependency is of importance for therapeutic as well as supportive care regimens, as optimal antitumor efficacy may be associated with increased toxicities, in which case pre-emptive or early therapy against cutaneous adverse effects may be of benefit to ensure continued therapy and quality of life. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author or 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: N/A Stock: N/A Honoraria: Mario E. Lacouture, OSI Pharmaceuticals, Imclone Systems Research Funds: N/A Testimony: N/A Other: N/A
ACKNOWLEDGMENTS Support for M.E.L. by a Zell Scholarship from the Robert H. Lurie Comprehensive Cancer Center. REFERENCES 1. Mitra SS, Simcock R: Erlotinib induced skin rash spares skin in previous radiotherapy field. J Clin Oncol 24: 28-29, 2006[CrossRef] 2. Perez-Soler R, Saltz L: Cutaneous adverse effects with HER1/EGFR-targeted agents: Is there a silver lining? J Clin Oncol 23: 5235-5246, 2005 3. Lacouture ME: Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer 6: 803-812, 2006[CrossRef][Medline] 4. Sitton E: Early and late radiation-induced skin alterations: Part I: Mechanisms of skin changes. Oncol Nurs Forum 19: 801-807, 1992[Medline] 5. Bentzen SM: Preventing or reducing late side effects of radiation therapy: Radiobiology meets molecular pathology. Nat Rev Cancer 6: 702-713, 2006[CrossRef][Medline] 6. Harari PM, Huang S: Radiation combined with EGFR signal inhibitors: Head and neck cancer focus. Semin Radiat Oncol 16: 38-44, 2006[CrossRef][Medline] 7. Hymes SR, Strom EA, Fife C: Radiation dermatitis: Clinical presentation, pathophysiology, and treatment 2006. J Am Acad Dermatol 54: 28-46, 2006[CrossRef][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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