receptor function by SU5416 and SU6668 can enhance the efficacy of irradiation.16

By examining the anti-VEGF strategy combined with radiotherapy for tumors, several general conclusions can be drawn. The first is that combination therapy with VEGF inhibitors is probably more effective than radiotherapy alone in many types of tumors. The second is that the effect appears to be at least partly due to an elevation in po2, which may be mediated through a change in microvessel density and/or interstitial fluid pressure. As VEGF is a growth factor that is up-regu- lated by radiotherapy and acts as a survival factor for endothelial cells, it is plausible that VEGF inhibition results in blockade of this survival signal, leading to a greater radiation therapeutic effect.

Extrapolating this analysis for the treatment of eyes with exudative age-related macular degeneration, it is conceivable that the combined treatment strategy using focal brachytherapy and anti-VEGF therapy has more than an additive effect, in part due to the same mechanisms observed in the combined treatment for tumors.

INDICATIONS

CHOROIDAL MELANOMA

Radiation is the most widely used method to treat posterior uveal melanoma; brachytherapy and external beam irradiation are the two most common methods of radiotherapy employed.

The most commonly used form of radiotherapy has been the use of radioactive plaques. Treatment of a malignant tumor of the uvea by brachytherapy was first reported in 1930.2 The preferred isotope has changed over the years and iodine-125 and ruthenium-106 plaques have largely replaced cobalt-60 at most institutions. Radioactive plaques were originally conceived to be used for the treatment of small and medium-sized melanomas that were outside the retinal vascular arcade and posterior to the ora serrata. More recently, studies have presented a rationale for using plaque radiotherapy for macular melanoma,17 ciliary body melanoma,18 large melanoma,19 and melanoma with extrascleral extension.20

Another method of radiotherapy is external beam radiation (chargedparticle irradiation).21 This technique was originally believed to provide a collimated beam that would limit the radiotherapy selectively to the area of the tumor. However, this theory has not been substantiated by clinical experience. Radiation complications in the eye and adnexa have been described at a rate comparable to those reported using radioactive plaques.

Current data show that patients treated with radiotherapy have a survival rate similar to those treated by enucleation.22 Mortality rates following brachytherapy have not differed from mortality rates following enucleation for up to 12 years after treatment.22 The power of the Collaborative Ocular Melanoma Study (COMS) randomized study has allowed clinicians confidently to recommend radiation for appropriate medium-size melanomas, recognizing that enucleation does not offer a greater chance of survival with follow-up to 12 years.

The optimal radiation dosage for the treatment of uveal melanoma remains controversial, but doses between 50 and 100 Gy have been accepted as appropriate. The American Brachytherapy Society has currently presented the COMS dose recommendation as the guideline for the treatment of choroidal melanoma.23 Considerations regarding properties of half-life, shielding, tissue penetration, and physical form have made iodine-125 a preferred choice of isotope for brachytherapy in many institutions.

EXUDATIVE AGE-RELATED

MACULAR DEGENERATION

Ocular radiation therapy has been explored as a treatment modality for exudative age-related macular degeneration for many years. Since proliferative tissue is more susceptible to the effects of ionizing radiation

than nonproliferative tissue, choroidal neovascular membranes, which are composed of endothelial cells and proliferate more rapidly than the endothelial cells of the retina, are more sensitive to radiation treatment than the retinal vasculature and nonproliferating capillary endothelial cells and larger vessels. Early reports on the treatment of CNV with brachytherapy describe resolution of subretinal fluid, hemorrhages, and exudates after radiation therapy.

Currently, the use of radiation for the treatment of subfoveal CNV remains controversial.

The scientific rationale for using radiation therapy for a nonmalignant disease characterized by neovascular growth is based on experimental and clinical evidence. Reports in peer-reviewed publications indicate that localized radiation treatment has the ability to prevent proliferation of vascular tissue. More specifically, low-dose radiation has been shown to inhibit neovascularization. After low-dose radiation, vascular endothelium demonstrates morphologic and DNA changes, inhibition of replication, increased cell permeability, and apoptosis. Fibroblast proliferation and subsequent scar formation, a hallmark of end-stage neovascular age-related macular degeneration, are also inhibited.

Choroidal neovascular membranes, which are composed of endothelial cells and proliferate more rapidly than the endothelial cells of the retina, are more sensitive to radiation treatment than the retinal vasculature and nonproliferating capillary endothelial cells and larger vessels. Early studies examining the effect of radiation in the eye have demonstrated that low-dose radiation, while altering the biology of choroidal neovascular membranes, may affect the natural history of eyes with exudative age-related macular degeneration.

Recently, a new form of localized epimacular delivery of radiation directly to the site of the proliferative, neovascular tissue could theorectically minimize the well-established side-effects of treatment with both ionizing and nonionizing radiation. This technique has a shielded and directional applicator which will be placed just over the retina to give a dose to the CNV believed to have therapeutic benefit, while limiting the dose to the critical ocular tissues, i.e., retina outside the macular region, optic nerve, and lens.

The radiation source in the Neovista VIDION brachytherapy system is based on an Sr-90/yttrium-90 (Y-90) beta-irradiating isotope (Figure 49.1). The Sr-90/Y-90 isotope has a 28-year half-life and a relatively limited depth of effective penetration. This provides the ability to deliver the therapeutic dose to the treatment area, while limiting the exposure to nontarget tissues (Figure 49.2). With a source activity of approximately 11 mCi the treatment duration will be relatively short, approximately 2–4 minutes.

The source consists of a cylindrical aluminum insert that is doped with the Sr-90/Y-90 isotope and resides inside a stainless-steel canister. Initial studies have indicated promising results with the use of localized epimacular Sr-90 brachytherapy delivered concomitantly with intravitreal bevacizumab to treat exudative age-related macular degeneration.7

OTHER OCULAR TUMORS

Although radiotherapy is mostly used to treat choroidal melanomas, it has also been used to treat various ocular tumors.

Figure 49.1  Neovista VIDION brachytherapy system based on a strontium/yttrium-90 beta-irradiating isotope for focal epimacular delivery of beta-radiation.

Surgery and Pharmacotherapy • 5 section