1.75 mm was used, with the plaque placed using an applicator with an 8-mm diameter and 12-mm radius curvature. The disc was attached to a handle via a steel shaft. The applicator was surgically introduced in the episcleral surface, under the macula, and held in place manually for the treatment period of 54 minutes. Twenty patients with recently diagnosed CNV received plaque brachytherapy treatment and 12 patients were followed as controls. At 12-month follow-up, 3 (15%) of the 20 brachytherapy-treated eyes experienced a decrease of 6 or more lines of visual acuity, as compared to 6 (50%) of the 12 nontreated eyes (P = 0.057). The mean number of lines lost was 2.6 (sd 3.7) for treated eyes and 5.3 (sd 3.2) for nontreated eyes (P = 0.024). No radiationrelated adverse effects were noted.

In the radiation treatments to date, namely photon and proton external beam and plaque brachytherapy, most of the critical ocular tissues received doses similar to that intended for the target area. Therefore, there was a small window between toxicity and effectiveness. Although there were several attempts to mitigate the side-effects by fractionating the total dosage in multiple applications over a period of time, the ideal and effective therapeutic window was not established. In several reports either the dosage was too small to provide therapeutic benefit, or the side-effects relating to neighboring structures exceeded the limited benefits.

Recently, a new form of localized epimacular delivery of radiation directly to the site of the neovascular tissue combined with anti-VEGF agents is being evaluated. This new epimacular brachytherapy strategy is being evaluated in eyes with exudative age-related macular degeneration. This technique has a shielded and directional applicator that limits the radiation dose to critical ocular tissues, i.e., retina outside the macular region, optic nerve, and lens. Initial studies have shown promising results with the use of a single treatment using the localized epimacular brachytherapy associated with anti-VEGF therapy (two injections of bevacizumab) to treat exudative age-related macular degeneration. After 12 months of follow-up the mean change in best corrected visual acuity was a gain of 8.9 letters.7 This new regimen is being evaluated in a large multicenter phase III study.

COMPLICATIONS

Preservation of good vision following brachytherapy is inversely related to the occurrence of complications. Complications associated with brachytherapy include radiation retinopathy, optic neuropathy, and cataracts. Other long-term side-effects reported include neovascular glaucoma, vitreous hemorrhage, radiation choroidopathy, scleral necrosis, retinal detachment, keratitis, conjunctivitis, ptosis, enophthalmos, wound-healing abnormalities, bone necrosis, soft-tissue necrosis, cellulitis, and dry eye.

The incidence of radiation-induced complications is clearly dependent on the total amount of radiation delivered to the eye and the proximity of the tumor relative to macula and optic nerve. Importantly, radiation retinopathy and optic neuropathy are dose-related, fractionrelated, and time-related. Importantly, the dose required is directly related to the size and location of the tumor.

RADIATION RETINoPATHY

The effect of radiation on the retina is well known and numerous reports have shown that radiation retinopathy can occur with radiation doses of 20 Gy or higher. In general, visual prognosis is less favorable when foveal or optic nerve radiation is in excess of 50 Gy.41 Most studies also show that the higher the dosage, the higher the incidence of radiation retinopathy. In a study by Takeda et al., the retina in 21 eyes was exposed to a dose of 50 Gy or more.42 Eight of the 21 eyes (38%) developed severe retinal complications. In contrast, none of the 22 eyes that received less than 50 Gy developed retinal complications through at least 2 years of follow-up (range, 2–11 years). More recent data indicate that 45–50 Gy delivered to half or more of the retina results in clinically apparent retinopathy.

There are isolated reports of radiation-induced radiation retinopathy at lower radiation doses. However, it is believed that some predisposing factors lower the threshold for radiation retinopathy development. These factors included chemotherapy and diabetes. It is believed that radiation should be used with caution in individuals with these conditions.

In general, radiation dose and area irradiated are the most important factors in the development of severe complications. In two reports by Finger, plaque radiation of anterior melanomas was more likely to cause reversible vision loss secondary to cataract while treatment of posterior tumors is more likely to be associated with irreversible visual losssecondarytoradiationretinopathy.43,44 AnotherstudybySummanen et al. indicated that the risk for maculopathy and optic neuropathy was greater with increased proximity of the posterior tumor margin to the fovea and the optic disc.45 In a multivariate analysis, the strongest risk indicator for radiation retinopathy was location of posterior tumor margin within 2 mm of the fovea (relative risk (RR) 3.4, 95% confidence interval (CI) 2.0–6.0) and for radiation optic neuropathy was location of tumor within 1 DD of the optic disc (RR 6.1, 95% CI 3.0–12.4). The area of retina receiving radiation is also a risk factor for retinopathy. In a report by Midena et al., patients with orbital tumors had a higher incidence of radiation retinopathy compared to patients with periorbital tumors treated with external beam radiotherapy (63.6% versus 36.3%).46

We have conducted a preclinical study with 160 pigmented rabbits (160 eyes) with the objective of evaluating and quantifying the effects of various dosages of beta-radiation in the retina and underlying tissues. All rabbits underwent pars plana vitrectomy and received focal epimacular radiation with the following dosages: 0, 13, 19, 26, 32, 38, 41, 51, 62, 77, 82, 103, 123, 164, and 246 Gy. All rabbits underwent the following preand postoperative exams: color fundus photography, fluorescein angiography, and electroretinography. After the pre-established follow-up all rabbits were sacrificed and underwent light and electron microscopy. The acute effects of selective focal radiation in the retinal and subretinal tissues were determined. Significant acute changes were observed in eyes that received dosages ≥ 51Gy. These results show that retinal and subretinal tissues, including retinal pigment epithelium, Bruch’s membrane, choriocapillaries, and choroid, are relatively resistant to high dosages of radiation for a period of at least 6 months.

OPTIC NEUROPATHY

As for all other radiation-related complications, the incidence of radiation neuropathy also increased with increased exposure to radiation. In a prospective study by Kellner et al. to evaluate the incidence of optic neuropathy following Ru106/Rh106 brachytherapy, no patient with peripheral tumor (peripheral melanomas with a central tumor margin of more than 60° to the optic disc) had clinical signs of optic neuropathy or pathological pattern visual evoked potential.47 In contrast, 18% of patients with central melanoma (tumor within 15° of the optic disc) had clinical signs of optic neuropathy and 50% developed pathological pattern visual evoked potential. Most reports indicated that the threshold for radiation optic neuropathy is above 50 Gy. Jiang et al. evaluated a series of 219 patients that received radiation therapy for tumors of the nasal cavity and paranasal sinuses.48 They found that the total radiation dose was the predominant determinant for optic toxicity. While no patient receiving a dose of less than 50 Gy developed radiation optic neuropathy or chiasm injury, the 10-year actuarial incidence of optic nerve chiasm injury was approximately 5% and 30% for patients receiving 50–60 Gy and 61–78 Gy, respectively. A study by Lommatzsch et al. has evaluated 93 patients with juxtapapillary choroidal melanomas that were treated with plaque brachytherapy.49 In this study, the probability of developing complete radiation optic neuropathy after a median dose of 51.2 Gy was 23% and 53% at 5 and 10 years, respectively. In another study by Parsons et al., evaluating the risk of radia- tion-induced optic neuropathy, none of the 106 patients receiving a total dose to the optic nerve less than 59 Gy developed optic neuropathy after a minimum of 3 years of follow-up (range, 3–21 years). In contrast,

Surgery and Pharmacotherapy • 5 section