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Corneal edema with a systemic epidermal growth factor receptor inhibitor

2017; Elsevier BV; Volume: 52; Issue: 3 Linguagem: Inglês

10.1016/j.jcjo.2016.11.018

1715-3360

Roland Hӧllhumer, Greg Moloney, Kiran Jacob,

NF-κB Signaling Pathways

Epidermal growth factor receptors (EGFRs) are expressed on the ocular surface and play an important role in the maintenance of the corneal and conjunctival epithelium. Non–small cell lung cancer has been associated with abnormalities in the expression of this receptor, which led to targeted therapy for these patients.1Saint-Jean A. de la Maza M.S. Morral M. et al.Ocular adverse events of systemic inhibitors of the epidermal growth factor receptor: 5 cases.Ophthalmology. 2012; 119: 1798-1802Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar EGFR inhibitors, including erlotinib and gefitinib, target the tyrosine kinase enzyme and have been shown to confer a 6.4% overall survival in patients with stage IIIB and IV non–small cell lung cancer.2Meerbeeck J.V. Galdermans D. Bustin F. et al.Survival outcomes in patients with advanced non-small cell lung cancer treated with erlotinib: expanded access programme data from Belgium (the TRUST study).Eur J Cancer Care. 2014; 23: 370-379Crossref PubMed Scopus (8) Google Scholar The most common side effects of the EGFR inhibitor erlotinib include rash, diarrhea, anorexia, fatigue, nausea, and vomiting.1Saint-Jean A. de la Maza M.S. Morral M. et al.Ocular adverse events of systemic inhibitors of the epidermal growth factor receptor: 5 cases.Ophthalmology. 2012; 119: 1798-1802Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, 3Methvin A.B. Gausas R.E. Newly recognized ocular side effects of erlotinib.Ophthal Plast Reconstr Surg. 2007; 23: 63-65Crossref PubMed Scopus (39) Google Scholar Ocular side effects develop in 17.8% of patients and include dry eye, trichomegaly, ectropion, keratitis, corneal ulceration, and perforation.3Methvin A.B. Gausas R.E. Newly recognized ocular side effects of erlotinib.Ophthal Plast Reconstr Surg. 2007; 23: 63-65Crossref PubMed Scopus (39) Google Scholar This case report illustrates a form of corneal toxicity secondary to a systemic EGFR inhibitor. A 70-year-old male patient was referred with a subacute onset of corneal edema. He had a background of metastatic non–small cell lung cancer that was positive for an EGFR mutation on biopsy. At presentation he had been on an EGFR receptor inhibitor, erlotinib, at a dose of 150 mg a day for 20 months. On ocular examination his visual acuity was 6/6 OD and 6/60 OS, with normal intraocular pressures bilaterally. On slit-lamp examination his right cornea had early signs of deep stromal edema. His left cornea had punctate epithelial erosions, deep stromal edema, and Descemet's membrane folds (Fig. 1). There were no features of intraocular inflammation, trichomegaly, or ectropion. After discussion with his oncologist, the patient was switched to gefitinib, and corneal edema resolved completely within 6 days. At 1 month his visual acuity had returned to 6/9 OS. This case illustrates a complication of corneal edema after the use of an EGFR inhibitor, erlotinib. To our knowledge this is the first case report of this complication. Saint-Jean et al.1Saint-Jean A. de la Maza M.S. Morral M. et al.Ocular adverse events of systemic inhibitors of the epidermal growth factor receptor: 5 cases.Ophthalmology. 2012; 119: 1798-1802Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar describe 2 cases of corneal toxicity (epithelial defects and corneal melt) in patients receiving erlotinib who were treated with intensive carboxymethylcellulose-based tear supplements. One patient continued an uninterrupted course of erlotinib with full resolution of symptoms, whereas the second, who was also treated with concurrent ciprofloxacin, had erlotinib withheld for 2 weeks with full resolution of corneal signs. Erlotinib was then recommenced without recurrence of corneal changes. Our patient received lubrication without any clinical improvement. Chow et al.4Chow V.W. Jhanji V. Chi S.C. Erlotinib-related corneal melting.Ophthalmology. 2013; 120: 1104Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar describe a patient with corneal melt secondary to erlotinib who did not improve despite cessation of the agent and application of intensive lubrication with carboxymethylcellulose and lanolin. The patient received punctal plugs in the upper punta and cautery of the lower puncta in an attempt to improve the tear film integrity; however, the corneal changes persisted. Resolution was finally achieved after initiating 20% autologous serum drops. Morishige et al.5Morishige N. Katabe N. Morita Y. et al.Spontaneous healing of corneal perforation after temporary discontinuation of erlotinib treatment.Case Rep Ophthalmol. 2014; 5: 6-10Crossref PubMed Scopus (15) Google Scholar describe perforation despite the use of punctal plugs. An argument may be made against the use of punctal plugs because this may increase the concentration of the drug in the tear film with worsened toxicity. The erlotinib was stopped, and a bandage contact lens was placed. In 2 days the patient had complete resolution of the corneal defects. The erlotinib was then recommenced at half of the previous dose without any subsequent complication. This suggests that there may be benefit to interrupting a course of erlotinib to avoid more invasive measures to rectify the corneal defects. More severe corneal damage may require surgical intervention. Cyanoacrylate glue, multilayered amniotic membrane grafts, and patch grafts have been attempted as salvage procedures.1Saint-Jean A. de la Maza M.S. Morral M. et al.Ocular adverse events of systemic inhibitors of the epidermal growth factor receptor: 5 cases.Ophthalmology. 2012; 119: 1798-1802Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar Our patient had features of keratoconjunctivitis sicca and bilateral corneal edema. It is interesting that the edema resolved completely when changed to gefitinib, as this is also a tyrosine kinase inhibitor. As other cases have shown, patient symptoms may resolve and show no recurrence even if recommenced on therapy. It would be interesting to elucidate the underlying mechanisms of the ocular sequelae. As the use of EGFR inhibitors increases, awareness among ophthalmologists and oncologists about ocular side effects becomes increasingly important. There is no single treatment of the ocular sequelae that is universally effective, although cessation of the EGFR inhibitor seems to make a significant difference. Early recognition of corneal toxicity is essential to ensure early initiation of management. The authors have no proprietary or commercial interest in any materials discussed in this article.