CLINICAL INVESTIGATION Head and Neck Cancer SEVERE DRY EYE SYNDROME AFTER RADIOTHERAPY FOR HEAD-AND-NECK TUMORS NIRANJAN BHANDARE, M.S.,* VITALI MOISEENKO,PH.D., y WILLIAM Y. SONG,PH.D., z CHRISTOPHER G. MORRIS, M.S.,* M. T ARIQ BHATTI, M.D., x AND WILLIAM M. MENDENHALL, M.D.* *Department of Radiation Oncology, University of Florida College of Medicine, Gainesville, FL; y Vancouver Cancer Centre, Vancouver, BC, Canada; z University of California, San Diego, San Diego, CA; x Department of Ophthalmology and Medicine (Division of Neurology), Duke University Medical Center, Durham, NC Purpose: To investigate the incidence of severe dry eye syndrome (DES) after external beam radiotherapy for head-and-neck cancer and its dependence on the parameters relevant to external beam radiotherapy. Methods and Materials: The present retrospective study included 78 patients treated for primary extracranial head-and-neck tumors between 1965 and 2000, whose lacrimal apparatus/entire globe was exposed to fractionated external beam radiotherapy. The dose received by the major lacrimal gland was used for analysis. The end point of the present study was the ophthalmologic diagnosis of severe DES leading to vision compromise. Results: Of the 78 patients, 40 developed severe DES leading to visual compromise. The incidence of DES increased steadily from 6% at 35–39.99 Gy to 50% at 45–49.99 Gy and 90% at 60–64.99 Gy. With a mean of 0.9 years (range, 1 month to 3 years), the latency of DES was observed to be a function of the total dose and the dose per fraction. On univariate and multivariate analysis, the total dose (p < .0001 and p < .0001, respectively) and dose per fraction (p # .0001 and p = .0044, respectively) were significant. However, age, gender, and the use of chemoradiotherapy were not. The actuarial analysis indicated a 5-year probability of freedom from DES of 93% for doses <45 Gy, 29% for 45–59.9 Gy, and 3% doses $60 Gy. A logistic normal tissue complication probability model fit to our data obtained a dose of 34 and 38 Gy corresponding to a 5% and 10% incidence of DES. Conclusion: With a dose of 34 Gy corresponding to a 5% incidence of DES, the risk of severe DES increased, and the latency decreased with an increase in the total dose and dose per fraction to the lacrimal gland. The effect of chemo- radiotherapy and hyperfractionation on the risk of DES needs additional investigation. Ó 2012 Elsevier Inc. Dry-eye syndrome, Radiotherapy, Head-and-neck tumors. INTRODUCTION Dry eye syndrome (DES) is a disorder that results from deficiencies or defects in the components of lubrication that can lead to structural and functional abnormalities of the ocular surface. In 2007, the International Dry Eye Workshop defined DES as ‘‘a disease of tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to ocular surface. It is accom- panied by increased osmolarity of tear film and inflammation of the ocular surface’’ (1). External beam radiotherapy (EBRT) for head-and-neck tumors involving the orbit and the tissues adjacent to the orbit often delivers high radiation doses to the eye, including the adnexa; the lacrimal system, including the major and accessory lacrimal glands, lacrimal canaliculi, lacrimal sac, and nasolacrimal duct; the ocular surface, including the cornea and conjunctiva; the eyelids; the meibomian glands; and associated sensory and motor nerves. Radiation damage to the lacrimal system can lead to corneal abnormalities and ocular dysfunction. Although direct radiation damage to the corneal epithelium and endothelium (2) can be associated with an acute reaction, delayed DES, resulting from disordered ocular lubrication due to damage to the lacrimal glands, has been reported in patients who were persistently symptomatic after subsidence of the acute radiation reactions (3, 4). Although mild to moderate DES is often successfully manageable with supportive therapy, severe DES can result in ulceration and/or infection of the cornea, thickening of the corneal surface, corneal erosion, punctate keratopathy, epithelial defects, corneal abrasions, ulceration, neovascula- rization, scarring, thinning, perforation, and corneal necrosis, leading to irreversible corneal opacity with compromised vision, severe pain, and eye loss. Severe DES after EBRT for head-and-neck cancer is a sparsely reported ocular Reprint requests to: Niranjan Bhandare, M.S., Department of Radiation Oncology, University of Florida Health Science Center, P.O. Box 100385, 2000 SW Archer Rd., Gainesville, FL, 32610- 0385. Tel: (352) 265-8217; Fax: (352) 265-8417; E-mail: bhandn@ shands.ufl.edu Conflict of interest: none. Received Nov 8, 2010, and in revised form April 28, 2011. Accepted for publication May 16, 2011. 1501 Int. J. Radiation Oncology Biol. Phys., Vol. 82, No. 4, pp. 1501–1508, 2012 Copyright Ó 2012 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/$ - see front matter doi:10.1016/j.ijrobp.2011.05.026