Ocular Complications of High-Dose Radiotherapy

I would like to make several comments about the excellent reviewby Parsons et al, "Response of the Normal Eye to High-DoseRadiotherapy," which appeared in the June issue of ONCOLOGY(pp 837-852). In 1897, Chalupecky first described the effectsof ionizing radiation on the eye [1]. A subsequent study by Birch-Hirschfeldin 1908 identified the first case of a radiation-induced cataract[2]. Definitive investigations on the effects of ionizing radiationon the eye began with the studies of Rohrschneider [3]. He describeda gradient in radiosensitivity of the ocular structures extendingfrom the lens (the most sensitive tissue), through the conjunctiva,cornea, uvea, and retina, to the least sensitive tissue, the opticnerve. Poppe further elucidated the work of Rohrschneider [4].

Even though many clinicians have an almost morbid fear of theharmful effects of irradiating the eye and orbit, modern, innovativeradiation therapy technologies have allowed for appropriate treatmentprograms to be administered with a minimum of complications. Themagnitude of this potential problem in 1996 can best be appreciatedby noting the number of tumors for which a portion of the eyeor the complete ocular structures will be included within theirradiated 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 (suchas rhabdomyosarcomas and lymphoma), and approximately 80,000 tumorsthat have metastasized to orbital structures. Table 1 illustratesthe 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 ofcellular composition);
• the injured tissue's functional reserve to withstand the evolutionof a clinically apparent complication; and
• other factors, such as the vascular nutritional integrityof the organ.

General Schema of Ocular Complications

These three factors underlie a general schema that can be appliedto the eye and orbital contents. Acute lesions represent primaryfunctional cell necroses affecting rapidly proliferating cells.Acute radiation-induced lesions may be defined as effects thatoccur either during the course of fractionated radiation therapyor within several weeks following its completion. Such lesionstypically occur in the eyelid skin (blepharitis), conjunctiva(conjunctivitis), and corneal epithelium (keratitis). With propermedical management, recovery from these mild forms of radiationinjury generally occurs within several weeks after the completionof the treatment.

Subsequent cellular recovery may be followed by delayed lesions,which are predominantly stromal in pathogenesis. These lesionsmay consist of edema followed by interstitial fibrosis. Pathogenicmechanisms include endothelial damage in the microcirculationwith passage of proteinaceous fluid into the interstitial spacesthrough the damaged vascular barrier.

Late effects may also occur coincidentally with permanent changesin arterioles and small arteries. Late tissue complications, particularlywhere there are few rapidly proliferating cells, are thought tobe due to the nutritional consequences of ischemic vascular damage.Typical delayed radiation-induced effects on the eye include cataractformation and radiation retinopathy. Such lesions commonly developafter a latent interval of at least several months. However, thelatent period can vary widely--from a few months to many years--dependingon individual biologic factors and radiation dose. In general,the higher the dose employed, the earlier the particular responsewill be observed.

Factors Influencing the Development of Radiation Injury

Factors that influence the probability of radiation injury maybe categorized as technical and nontechnical. Technical factorsinclude human mistakes in the delivery of radiation therapy andsystematic errors, such as those due to inaccurate initial adjustmentof equipment, incorrect procedures, or unrecognized deviationof a particular parameter over time. Estimates of the incidenceand significance of mistakes in the delivery of the radiationtherapy program range from 1% to 40%. The incidence varies accordingto the type of treatment and the complexity of the treatment technique.

Strict attention to detail is mandatory in radiation therapy programsfor tumors in or around the eye, since precise and proper controlof the technical components of treatment will significantly reducethe potential for radiation-induced complications.

The important technical factors are fraction size, protraction(or length) of the course of treatment, hyperfractionation, typeof radiation employed (eg, beta, photon, electrons, neutrons),the radiosensitivity of the tissues being irradiated, and thepatient's age.

Nontechnical factors that modify radiation tolerance include thepresence of a concurrent disease state that either compromisesthe tissue's arterial blood supply (such as diabetes mellitusand systemic hypertension) or increases the sensitivity of normaltissues to radiation damage (such as ataxia and telangiectasia)and simultaneous or sequential treatment with chemotherapeuticagents that may also modify radiation tolerance. Merriam, Merriamand Focht, and Merriam et al have summarized the reported clinicalcomplications according to the ocular tissue involved, the latentperiod, and the dose responsible for each effect [5-8]. Theseocular complications from radiation therapy have also been summarizedby my colleagues and myself [9].

Summary

The paper by Parsons et al summarizes in elegant detail basicdata on the risks involved when radiation therapy is used fortumors near the eye or optic nerves, whether these structuresare incidentally irradiated because of proximity of the tumor,or are clinically involved within the volume being reirradiatedbecause of tumor extension. The authors define the influence ofradiation treatment volumes and doses required, as well as thepotential 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 influenceof fractionation, fraction size, volume of tissue irradiated,and total dose to that volume on the incidence of severe dry eyesyndrome, retinopathy, and optic neuropathy. The most importantpoint is the fact that the incidence of these complications beginsto increase steeply after doses of 40, 50, and 60 Gy, respectively.

The paper clearly documents the risks involved when the eye isincluded in the radiation field. However, all efforts in the derivationof treatment programs of tumors in and near the eye should maintainthe basic premise of affording the maximum potential for curewith the minimum of complications. It is apparent that modern,innovative technologies with three-dimensional reconstructed treatmentprograms and treatment delivery will significantly reduce therisks involved in radiation therapy for tumors in and near theorbit; these new technologies allow for noncoplanar field set-upsto adequately encompass the tumor but decrease the orbital structuresirradiated to an absolute minimum. When a patient has a curabletumor, the treatment program should not be compromised to avoidcomplications. Active medical management during treatment, aswell as continued management in the follow-up period, with interventionwhen 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

References:

1. Chalupecky H: Über die wirkung der röntgenstrahlenauf das auge and die haut. Zentbl Augenheilk 21:234-368, 1897.

2. Birch-Hirschfeld GVA: Zur wirkung der röntgenstrahlenauf das menschliche auge. Klin Mbl Augenheilk 46:129, 1908.

3. Rohrschneider W: Experimentelle untersuchungen über dieveränderungen normaler augengewebe nach röntgenbestrahlung:III. Mitteilung: Veränderungen der linse der netzhaut unddes sehnerven nach röntgenbestrahlung. Graefes Arch Ophthal122:282, 1929.

4. Poppe E: Experimental investigation of the effects of roentgenrays on the eye. Oslo 1942.

5. Merriam GR Jr: Late effects of beta radiation on the eye. AMAArch Ophthalmol 53:708, 1955.

6. Merriam GR Jr, Focht EF: A clinical study of radiation cataractsand the relationship to dose. Am J Roentgenol 77:759, 1957.

7. Merriam GR Jr, Focht EF: A clinical and experimental studyof the effect of single and divided doses of radiation on cataractproduction. Trans Am Ophthamol Soc 60:35, 1962.

8. Merriam GR Jr, Biavati BJ, Bateman JL, et al: The dependenceof RBE on the energy of fast neutrons: IV. Indications of lensopacities in mice. Radiat Res 25:123, 1965.

9. Brady LW, Shields J, Augsburger J, et al: Complications fromradiation therapy to the eye, in Vaeth JM, Meyer JL (eds): Frontiersof Radiation Therapy in Oncology, vol 23, pp 238-250. Basel, Karger,1989.