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Response of the Normal Eye to High Dose Radiotherapy

Response of the Normal Eye to High Dose Radiotherapy

ABSTRACT: Radiation therapy of tumors near the eye or optic nerves often requires incidental irradiation of these structures, even when they are not clinically involved by tumor. Depending on the radiation treatment volume and dose required, radiation injury to the lens, lacrimal apparatus, retina, or optic nerve may result. The time to expression and severity of injury are dose-dependent. This paper reviews the results of 157 patients who were followed for a minimum of 3 years after radiotherapy for primary extracranial tumors at the University of Florida, in which the lacrimal gland, lens, retina, and/or optic nerve(s) received irradiation. This review shows that, after treatment at approximately 1.8 to 2.0 Gy per fraction, the incidence of severe dry-eye syndrome, retinopathy, and optic neuropathy appears to increase steeply after doses of 40, 50, and 60 Gy, respectively. [ONCOLOGY 10(6):837-852, 1996]

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 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.

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