CORRESPONDENCE

Ocular Toxicity Related to Cetuximab Monotherapy in an Advanced Colorectal Cancer Patient

Giuseppe Tonini, Bruno Vincenzi, Daniele Santini, Diego Olzi, Alessandro Lambiase, Stefano Bonini

Affiliations of authors: Department of Medica1 Oncology, University Campus Bio-Medico, Rome, Italy (GT, BV, DS); Department of Ophthalmology, University Campus Bio-Medico, Rome, Italy (DO, AL, SB)

Correspondence to: Bruno Vincenzi, MD, University Campus Bio-Medico, Rome, Via E. Longoni n. 83,00155 Rome, Italy (e-mail: b.vincenzi{at}unicampus.it).

A 58-year-old Italian woman was diagnosed in December 1997 with colon adenocarcinoma. After resection and preoperative clinical evaluation for distant metastases, the disease was classified as pT4, pN1, cM0. She received six courses of adjuvant chemotherapy with 5-fluorouracil and folinic acid, according to the Mayo Clinic schedule (1). By October 2000, the disease had progressed to the liver, and the patient was therefore treated with 12 courses of irinotecan plus bimonthly, high-dose leucovorin and bolus and continuous infusion of 5-fluorouracil (FOLFIRI regimen), after which she attained a clinical partial response. However, 5 months after chemotherapy ended, disease progressed to the liver and to the lungs. The patient was then started on second-line chemotherapy with oxaliplatin plus bimonthly, high-dose leucovorin and bolus and continuous-infusion 5-fluorouracil (FOLFOX 4 regimen). Restaging after 12 courses of the second-line chemotherapy showed stable disease, so we decided to stop treatment and perform follow-up examination every 3 months. Six months after the FOLFOX 4 regimen was stopped, disease progression was identified, and the patient started chemotherapy with Raltitrexed plus irinotecan. However, the patient experienced grade 3 gastrointestinal toxicity, so treatment was stopped after the second cycle. Subsequently, we decided to test the primary tumor for epidermal growth factor receptor (EGFR) expression using immunohistochemical staining. The tumor stained positive for EGFR, so we began treating the patient with immunotherapy using cetuximab, a monoclonal antibody that specifically blocks EGFR activity (2). Cetuximab at standard dosages was started, and a mild, self-limiting cutaneous acneiform eruption was evident after just 1 week.

Three weeks after beginning cetuximab treatment, the patient reported bilateral ocular discomfort, characterized by itchiness all around both eyelids, photophobia, foreign body sensation, tearing associated with exfoliated skin, oil secretions, and crusty scaling. Visual activity, intraocular pressure, and fundus were normal upon ocular examination. However, the ocular surface was characterized by a corneal transparency and mild conjunctival hyperemia (Fig. 1). This clinical presentation is typical of squamous blepharitis, a condition that is related to meibomian gland dysfunction. Any other cause of squamous blepharitis, such as immune or allergic diseases and iatrogenic etiology, was excluded, and an infective pathogen was not identified. After 1-week delay of immunotherapy and topical antibiotic therapy (macrolides), all clinical signs and symptoms of squamous blepharitis disappeared. However, 2 weeks after immunotherapy was restarted, the same ocular manifestations recurred.



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Fig. 1. Clinical spectrum of the ocular side effects related to cetuximab monotherapy. (A, B) Details of the lower lid margin of a patient treated with cetuximab, highlighting aberrant meibomian gland function with abundant lipidic secretion. (C, D) Details of the upper lid margin of a patient treated with cetuximab, showing adherent squamous components of blepharitis.

 
Side effects from cetuximab treatment include acneiform eruptions, seborrheic dermatitis-like eruptions, and maculopapular rash, mostly on the face, trunk, and, less frequently, on the limbs (3). To our knowledge, this report represents the first description of cetuximab-related ocular side-effects. The pathogenesis of skin toxicity may be explained as follows. EGFR is expressed in the epidermis, the sweat gland apparatus, and hair follicle epithelium. Previous experimental studies have demonstrated that a centra1 role of EGFR physiology is in the norma1 differentiation and development of the hair follicle (4). The effects of cetuximab on the skin are likely to be a direct consequence of its interference with the EGFR signaling pathway. Among the potential candidates for proteins that are involved in the postreceptor effects of cetuximab, p27kip1 merits attention. p27kip1 is a negative growth regulator that binds to and inactivates cyclin-dependent kinase 2, thereby leading to cell cycle arrest in G1 (5,6). The ocular toxicity is a newly described cetuximab-related toxicity, so the pathogenesis is not clearly established. Meibomian glands are the sebaceous glands of the eye that secrete tears, similar to the sweat gland apparatus of the skin. We hypothesize that cetuximab targets the EGFR-expressing cells of meibomian glands and may consequently lead to altered secretive function.

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