I would like to make several comments about the excellent review
by Parsons et al, "Response of the Normal Eye to High-Dose
Radiotherapy," which appeared in the June issue of ONCOLOGY
(pp 837-852). In 1897, Chalupecky first described the effects
of ionizing radiation on the eye . A subsequent study by Birch-Hirschfeld
in 1908 identified the first case of a radiation-induced cataract
. Definitive investigations on the effects of ionizing radiation
on the eye began with the studies of Rohrschneider . He described
a gradient in radiosensitivity of the ocular structures extending
from the lens (the most sensitive tissue), through the conjunctiva,
cornea, uvea, and retina, to the least sensitive tissue, the optic
nerve. Poppe further elucidated the work of Rohrschneider .
Even though many clinicians have an almost morbid fear of the
harmful effects of irradiating the eye and orbit, modern, innovative
radiation therapy technologies have allowed for appropriate treatment
programs to be administered with a minimum of complications. The
magnitude of this potential problem in 1996 can best be appreciated
by noting the number of tumors for which a portion of the eye
or the complete ocular structures will be included within the
irradiated volume. These include 29,800 head and neck cancers,
14,700 central nervous system tumors, 1,900 primary eye tumors,
100,000 skin cancers, 3,000 tumors of other histologies (such
as rhabdomyosarcomas and lymphoma), and approximately 80,000 tumors
that have metastasized to orbital structures. Table 1 illustrates
the usual radiation doses used in the treatment of eye diseases.
The presence of complications, whether functional or cosmetic,
varies depending on a number of factors. These include:
- the cellular composition of the injured tissue (in the eye,
there is a broad diversity of tissues with differing types of
- the injured tissue's functional reserve to withstand the evolution
of a clinically apparent complication; and
- other factors, such as the vascular nutritional integrity
of the organ.
General Schema of Ocular Complications
These three factors underlie a general schema that can be applied
to the eye and orbital contents. Acute lesions represent primary
functional cell necroses affecting rapidly proliferating cells.
Acute radiation-induced lesions may be defined as effects that
occur either during the course of fractionated radiation therapy
or within several weeks following its completion. Such lesions
typically occur in the eyelid skin (blepharitis), conjunctiva
(conjunctivitis), and corneal epithelium (keratitis). With proper
medical management, recovery from these mild forms of radiation
injury generally occurs within several weeks after the completion
of the treatment.
Subsequent cellular recovery may be followed by delayed lesions,
which are predominantly stromal in pathogenesis. These lesions
may consist of edema followed by interstitial fibrosis. Pathogenic
mechanisms include endothelial damage in the microcirculation
with passage of proteinaceous fluid into the interstitial spaces
through the damaged vascular barrier.
Late effects may also occur coincidentally with permanent changes
in arterioles and small arteries. Late tissue complications, particularly
where there are few rapidly proliferating cells, are thought to
be due to the nutritional consequences of ischemic vascular damage.
Typical delayed radiation-induced effects on the eye include cataract
formation and radiation retinopathy. Such lesions commonly develop
after a latent interval of at least several months. However, the
latent period can vary widely--from a few months to many years--depending
on individual biologic factors and radiation dose. In general,
the higher the dose employed, the earlier the particular response
will be observed.
Factors Influencing the Development of Radiation Injury
Factors that influence the probability of radiation injury may
be categorized as technical and nontechnical. Technical factors
include human mistakes in the delivery of radiation therapy and
systematic errors, such as those due to inaccurate initial adjustment
of equipment, incorrect procedures, or unrecognized deviation
of a particular parameter over time. Estimates of the incidence
and significance of mistakes in the delivery of the radiation
therapy program range from 1% to 40%. The incidence varies according
to the type of treatment and the complexity of the treatment technique.
Strict attention to detail is mandatory in radiation therapy programs
for tumors in or around the eye, since precise and proper control
of the technical components of treatment will significantly reduce
the potential for radiation-induced complications.
The important technical factors are fraction size, protraction
(or length) of the course of treatment, hyperfractionation, type
of radiation employed (eg, beta, photon, electrons, neutrons),
the radiosensitivity of the tissues being irradiated, and the
Nontechnical factors that modify radiation tolerance include the
presence of a concurrent disease state that either compromises
the tissue's arterial blood supply (such as diabetes mellitus
and systemic hypertension) or increases the sensitivity of normal
tissues to radiation damage (such as ataxia and telangiectasia)
and simultaneous or sequential treatment with chemotherapeutic
agents that may also modify radiation tolerance. Merriam, Merriam
and Focht, and Merriam et al have summarized the reported clinical
complications according to the ocular tissue involved, the latent
period, and the dose responsible for each effect [5-8]. These
ocular complications from radiation therapy have also been summarized
by my colleagues and myself .
The paper by Parsons et al summarizes in elegant detail basic
data on the risks involved when radiation therapy is used for
tumors near the eye or optic nerves, whether these structures
are incidentally irradiated because of proximity of the tumor,
or are clinically involved within the volume being reirradiated
because of tumor extension. The authors define the influence of
radiation treatment volumes and doses required, as well as the
potential injury to critical structures within the orbital contents.
Clearly, the expression and severity of injury are dose dependent.
The data submitted by the authors clearly define the influence
of fractionation, fraction size, volume of tissue irradiated,
and total dose to that volume on the incidence of severe dry eye
syndrome, retinopathy, and optic neuropathy. The most important
point is the fact that the incidence of these complications begins
to increase steeply after doses of 40, 50, and 60 Gy, respectively.
The paper clearly documents the risks involved when the eye is
included in the radiation field. However, all efforts in the derivation
of treatment programs of tumors in and near the eye should maintain
the basic premise of affording the maximum potential for cure
with the minimum of complications. It is apparent that modern,
innovative technologies with three-dimensional reconstructed treatment
programs and treatment delivery will significantly reduce the
risks involved in radiation therapy for tumors in and near the
orbit; these new technologies allow for noncoplanar field set-ups
to adequately encompass the tumor but decrease the orbital structures
irradiated to an absolute minimum. When a patient has a curable
tumor, the treatment program should not be compromised to avoid
complications. Active medical management during treatment, as
well as continued management in the follow-up period, with intervention
when necessary, will significantly reduce the risk of complications
Luther W. Brady, MD, Department of Radiation Oncology,
and Nuclear Medicine,Medical College of Pennsylvania
1. Chalupecky H: Über die wirkung der röntgenstrahlen
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2. Birch-Hirschfeld GVA: Zur wirkung der röntgenstrahlen
auf das menschliche auge. Klin Mbl Augenheilk 46:129, 1908.
3. Rohrschneider W: Experimentelle untersuchungen über die
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III. Mitteilung: Veränderungen der linse der netzhaut und
des sehnerven nach röntgenbestrahlung. Graefes Arch Ophthal
4. Poppe E: Experimental investigation of the effects of roentgen
rays on the eye. Oslo 1942.
5. Merriam GR Jr: Late effects of beta radiation on the eye. AMA
Arch Ophthalmol 53:708, 1955.
6. Merriam GR Jr, Focht EF: A clinical study of radiation cataracts
and the relationship to dose. Am J Roentgenol 77:759, 1957.
7. Merriam GR Jr, Focht EF: A clinical and experimental study
of the effect of single and divided doses of radiation on cataract
production. Trans Am Ophthamol Soc 60:35, 1962.
8. Merriam GR Jr, Biavati BJ, Bateman JL, et al: The dependence
of RBE on the energy of fast neutrons: IV. Indications of lens
opacities in mice. Radiat Res 25:123, 1965.
9. Brady LW, Shields J, Augsburger J, et al: Complications from
radiation therapy to the eye, in Vaeth JM, Meyer JL (eds): Frontiers
of Radiation Therapy in Oncology, vol 23, pp 238-250. Basel, Karger,