Ocular Complications of High-Dose Radiotherapy

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 [1]. A subsequent study by Birch-Hirschfeld in 1908 identified the first case of a radiation-induced cataract [2]. Definitive investigations on the effects of ionizing radiation on the eye began with the studies of Rohrschneider [3]. 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 [4].

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 cellular composition);
• 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 patient's age.

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 [9].

Summary

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 (Table 2).

Luther W. Brady, MD, Department of Radiation Oncology, and Nuclear Medicine,Medical College of Pennsylvania