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Journal of Clinical Oncology, Vol 26, No 15 (May 20), 2008: pp. 2582-2584 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.3387
Bilateral Eardrum Perforation After Long-Term Treatment With ErlotinibDepartment of Oncology, University College Hospital London, London, United Kingdom
Royal National Throat, Nose and Ear Hospital, London, United Kingdom
Wolfson Institute for Biomedical Research, University College London, London, United Kingdom A 58-year-old patient presented with cough and was found to have an abnormal chest x-ray. Computed tomography (CT) scan showed a 3-cm soft-tissue mass in the anterior segment of the right upper lobe. A positron emission tomography (PET)/CT scan showed an area of irregular 18-fluorodeoxyglucose (FDG) uptake corresponding to the 3-cm mass seen on CT and mediastinal FDG avid lymph node involvement. He underwent a limited wedge resection and sampling of right station 4 lymph node. Frozen section of lung showed a non–small-cell lung cancer with irregular glandular structures consistent with adenocarcinoma (Fig 1), and frozen section of mediastinal node showed metastatic involvement. Postoperatively, he developed extensive subcutaneous emphysema and required a rethoracotomy, bullectomy, pleurectomy and closure of air leak. He subsequently made a good recovery and was discharged home. A PET/CT scan assessment performed 2 months later was reported as showing disease progression with multiple FDG right paratracheal, right hilar, and subcarinal lymph nodes and also fresh lesions identified involving the upper and lower lobe of the lung. He was treated with four cycles of gemcitabine plus carboplatin chemotherapy. A PET/CT assessment scan showed disease response, with less intense FDG avid lymphadenopathy in the right paratracheal and hilar regions, and the previously noted lesions in the subcarinal region and lung lesions are no longer FDG avid. He remained well until 3 months later, when he presented with increasing shortness of breath. Chest x-ray showed disease progression with an enlarging right hilar mass, and he was commenced on the epidermal growth factor receptor (EGFR) inhibitor erlotinib at the dose of 150 mg daily. His symptoms responded within 1 week, but he developed a generalized acneiform rash, conjunctivitis, and diarrhea associated with erlotinib treatment. These responded to symptomatic treatments. Twelve months after the start of the erlotinib treatment, he noticed sudden bilateral hearing loss. There was no prior upper respiratory tract infection or travel by airplane, and the only medication he was taking was erlotinib. The neurologic examination was normal and there was no nystagmus. A PET/CT scan showed he remained in complete remission, and magnetic resonance imaging showed no evidence of brain metastases. On otoscopic examination, he was found to have bilateral small postero-superior perforations of the tympanic membranes (TMs) and attenuation of the distal long process of the incus on the right. Audiometry showed bilateral sensorineural hearing loss with bilateral additional conductive element. His overall thresholds were 50 dB on the left and 60 dB on the right. Dosage of erlotinib was reduced to 100 mg. At follow-up 6 months later, the right TM perforation was unchanged; the left side had healed (Fig 2). Decision was made jointly with the patient to continue erlotinib treatment at 100 mg daily because of the risk of relapse. At the last follow-up 25 months after starting erlotinib, the patient remains in complete remission, as evidenced by negative whole-body PET/CT scan.
Response to EGFR inhibitors is associated with EGFR mutations.1,2 We sequenced exons 18 to 21 of the EGFR gene using DNA extracted from tumor and normal lung tissues obtained at previous resection. Two missense mutations in exon 18 (G719C) and in exon 20 (S768I; marked by arrows) were identified in the tumor DNA but not in the germline DNA (Fig 3). It is possible that the double-point mutations identified here are associated with prolonged remission compared with single-point mutation, and more studies are required to confirm this observation. In addition, the occurrence and severity of skin rash is correlated with survival, as demonstrated with the patient here, suggesting that host factors are at least as important as tumor factors in determining survival.3 The main causes of bilateral TM perforation are infection, including middle ear infections and ear canal infection, and trauma, such as barotrauma and self-inflicted or iatrogenic perforation. Our patient had no signs of otitis externa or media when he first presented with bilateral eardrum perforations. There was no history of barotrauma or mechanical intervention that could affect the TMs. An important feature of TM perforation in our patient was its chronic course in the absence of infection, pointing toward the ongoing effect of the causative drug. Erlotinib significantly improves survival, tumor-related symptoms, and quality of life as compared with best supportive care in patients with advanced non–small-cell lung cancer after first- or second-line chemotherapy.4,5 The EGFR pathway is involved not only in the process of tumor growth and angiogenesis but also in proliferation of keratinocytes, fibroblasts, epithelial cells, and endothelial cells, and EGFRs are strongly expressed, mainly in the stratified squamous epithelium of the TMs of animals and humans.6-8 Interestingly, EGF application has been reported to improve healing of perforated eardrum in animals, and erlotinib administration to animal models after experimental TM perforation delayed eardrum healing.7,9-11 There is little information available on the effect of long-term erlotinib administration in normal human TM. We hypothesize that the mechanism of the TM perforation reported here is the inhibition of epithelial regeneration with long-term EGFR inhibition in TM. We believe that the left tympanic membrane healed eventually because of the decrease in the dose of erlotinib. Although the possibility of TM perforation caused by EGFR inhibitors can be postulated on the basis of in vitro and animal experiments, to our knowledge, this is the first report of this adverse effect in humans. Because the numbers of patients treated with erlotinib and other EGFR inhibitors is expected to increase significantly worldwide and a significant number of patients may remain on long-term treatment, TM perforation owing to EGFR inhibition is a differential diagnosis to consider if these patients present with sudden hearing loss. Physicians and patients should be aware of this possible adverse effect and take it into consideration when prescribing the drug.
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
ACKNOWLEDGMENTS We thank Tony Wright and Mary Falzon, MD, for help with the preparation of the photographs and Gerard Kingdon for help with submission. REFERENCES
1. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004 2. Paez JG, Janne PA, Lee JC, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304:1497-1500, 2004 3. Mohamed MK, Ramalingam S, Lin Y, et al: Skin rash and good performance status predict improved survival with gefitinib in patients with advanced non-small cell lung cancer. Ann Oncol 16:780-785, 2005 4. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123-132, 2005 5. Bezjak A, Tu D, Seymour L, et al: Symptom improvement in lung cancer patients treated with erlotinib: Quality of life analysis of the National Cancer Institute of Canada Clinical Trials Group Study BR21. J Clin Oncol 24:3831-3837, 2006 6. Jost M, Kari C, Rodeck U: The EGF receptor: An essential regulator of multiple epidermal functions. Eur J Dermatol 10:505-510, 2000[Medline] 7. O'Daniel TG, Petitjean M, Jones SC, et al: Epidermal growth factor binding and action on tympanic membranes. Ann Otol Rhinol Laryngol 99:80-84, 1990[Medline] 8. Somers T, Goovaerts G, Schelfhout L, et al: Growth factors in tympanic membrane perforations. Am J Otol 19:428-434, 1998[Medline] 9. Lee AJ, Jackler RK, Kato BM, et al: Repair of chronic tympanic membrane perforations using epidermal growth factor: Progress toward clinical application. Am J Otol 15:10-18, 1994[Medline] 10. Ramalho JR, Bento RF: Healing of subacute tympanic membrane perforations in chinchillas treated with epidermal growth factor and pentoxifylline. Otol Neurotol 27:720-727, 2006[CrossRef][Medline] 11. Kaftan H, Vogelgesang S, Lempas K, et al: Inhibition of epidermal growth factor receptor by erlotinib: Wound healing of experimental tympanic membrane perforations. Otol Neurotol 28:245-249, 2007[CrossRef][Medline]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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