Response of the Normal Eye to High Dose Radiotherapy

Introduction

Although primary tumors of the eye (eg, melanoma, retinoblastoma) and optic nerve (eg, glioma) are rare, tumors that involve tissues adjacent to these structures are relatively common. Because many of these tumors are best treated with radiation therapy, the visual apparatus frequently receives incidental irradiation. Tumors for which irradiation usually is employed include those of the nasal cavity and paranasal sinuses, nasopharynx, orbit (eg, lymphomas), and central nervous system (eg, pituitary), as well as advanced cancer of the eyelid and periorbital skin.

The manner in which radiation oncologists report ocular complications differs from the way in which such complications are reported in the surgical literature. Characteristically, radiation damage that leads to a marked reduction in visual acuity (typically after a latent interval of 1 to 3 years) has been scored by radiation oncologists as a "severe complication." In contrast, surgical sacrifice of the orbital contents (with immediate visual loss) has been regarded as an unfortunate by-product of complete tumor removal and not as a complication per se.

When tumors of the paranasal sinuses are irradiated, varying portions of the eye fall within the treatment fields, depending on the degree to which the orbit is invaded. When orbital invasion is extensive, all of the orbital contents are irradiated, including the eyeball and all of the lacrimal tissue.[1] If the administered dose is high, as is the case when a carcinoma is treated, a dry eye results; visual loss usually occurs within 6 to 10 months after treatment, due to degeneration of the anterior segment of the eye, with resultant corneal ulceration and opacification and possible endophthalmitis. Lower doses, as are used in the treatment of lymphomas, result in only mild symptoms of a dry eye and cataract formation, usually a correctable form of visual loss.

If orbital invasion is limited, so that most of the lacrimal tissue can be spared high-dose irradiation,[1,2] severe dry-eye problems do not occur, even when high doses are administered. If the dose to the eyeball itself is high, however, visual loss due to posterior segment degeneration (radiation retinopathy) may occur, usually after a 2- to 3-year latency period. If low total doses are used, patients usually remain asymptomatic in the follow-up period with regard to dry-eye complaints and retinal problems but are still at risk for cataract formation if the lens was irradiated.

Even when the orbial invasion has not occurred, it is often necessary to include a portion of the contiguous orbit and the medial one-fourth to one-third of the eyeball in the irradiation field[1] because of the anatomic configuration of the sinuses and because of possible subclinical disease extensions through the thin bony walls that separate the sinuses from the orbit. Although visual loss secondary to eyeball injury is rare in this setting, there is still a risk of blindness due to optic nerve injury, usually after a 1- to 6-year latency period; the magnitude of risk depends on the daily fraction size and total dose administered.

Patients who are to undergo high-dose eye or optic nerve irradiation should be evaluated before treatment by an ophthalmologist knowledgeable about radiation complications. Most potential visual complications can be anticipated during the treatment planning stage, and patients should understand these risks. Follow-up should be continued in the post-treatment period on a regularly scheduled basis of prophylaxis, not just when indicated by specific problems. Frequently, a number of ophthalmologic problems occur simultaneously (eg, dry-eye symptoms, cataracts, radiation retinopathy, and glaucoma), which makes assessment confusing and management difficult.

Before undertaking any specific treatment, the ophthalmologist should correlate the treatment details with the radiation therapist, because some pitfalls may be avoided by good communication. For example, if high-dose irradiation has been administered to the eyeball, cataract formation will almost certainly be accompanied by the development of radiation retinopathy. Unless measures have been taken to manage the radiation retinopathy, removal of the cataract may increase the incidence of neovascular glaucoma. Also, anterior-segment disease should be treated early and aggressively to avoid corneal complications. Even when vision is lost, vigorous attempts to save the eye are worthwhile for cosmetic reasons.

Between October 1964 and May 1989, 157 patients underwent radiotherapy at the University of Florida, Gainesville, for primary extracranial tumors that required irradiation of the eyes or optic nerves. All patients were followed for a minimum of 3 years. In this article, we will explore the various ophthalmologic complications that may occur in patients undergoing radiation therapy at these sites, based on our own experience, as well as a review of the literature.

Severe Dry-Eye Syndrome

When the orbit is extensively invaded by carcinoma, high-dose irradiation of the entire orbit is necessary, and generally results in severe dry-eye syndrome. Patients develop a red, painful, scratchy eye (foreign-body sensation) and photophobia. The drying effects of wind are particularly bothersome. Severe problems may produce corneal epithelial breakdown, ulceration with bacterial infection, vascularization, opacification, or perforation. Some patients develop iritis in association with corneal ulceration. Symblepharon (scarring of the conjunctival tissue) or phthisis bulbi (shrinking of the globe) are observed occasionally.

Most patients who develop severe dry-eye syndrome become severely symptomatic within 1 month after completion of irradiation. Corneal opacification and vascularization are often pronounced within 9 to 10 months after therapy is completed.

Various treatments have been administered in an attempt to control symptoms of severe dry-eye syndrome, including artificial tears, lubricating ointments, bandage contact lens, conjunctival flaps, or tarsorrhaphy. Topical steroids are occasionally used for iritis. Topical and/or systemic antibiotics are prescribed for treatment of corneal ulcers. Retrobulbar alcohol(Drug information on alcohol) injections may be used in a uninfected painful eye. Many patients eventually require enucleation or evisceration because of endophthalmitis with pain and perforation of the globe.

University of Florida Data

At the University of Florida, 33 patients with extracranial head and neck tumors received irradiation of an entire orbit. Most patients were treated with cobalt-60. The dose to the lacrimal apparatus was calculated at a depth of 1 cm from the anterior skin surface, the approximate depth of the major lacrimal gland. The end point of the study was severe dry-eye syndrome sufficient to produce visual loss secondary to corneal opacification, ulceration, or vascularization.

Follow-up in 13 patients who did not develop severe dry-eye complications ranged from 3 to 20 years (mean, 7.3 years; median, 4 years). Sixteen patients received 45 Gy or less and 17 patients received 57 Gy or more. There are no data in the mid-range of doses (45.01 to 56.99 Gy). All 17 patients who received doses of 57 Gy or more developed severe dry-eye syndrome, as compared with 3 (19%) of 16 patients who received 45 Gy or less.

Data From the Literature

There are limited data in the literature on the probability of dry-eye complications according to dose. Consideration of the data from Parsons et al [3], Morita and Kawake [4], Bessell et al [5], and Letschert et al[6] reveals that the exact clinical end points of the various studies were not always clearly defined and probably differ somewhat from study to study. The sigmoid dose-response curve that has been constructed should be considered a first approximation, and more data are needed, particularly along the steep portion of the curve. The probability of complications appears to increase steeply at doses above 40 Gy.