plaque should be placed on the sclera, covering the scleral marks that identify the tumor perimeter as well as a tumor-free perimeter of 2 mm or more. If the therapeutic plaque is the same size as or smaller than the boundary of the tumor base as marked on the sclera, the procedure should be halted, and a larger plaque is prepared for a future procedure. If the dummy plaque is large enough to cover the tumor area plus 2 mm of tumor-free area, a surgical marking pencil should be used to mark the perimeter of the dummy plaque in the appropriate treatment position on the sclera. After the perimeter of the dummy is removed, the radioactive plaque is placed within the dummy plaque scleral mark and anchored with two or three scleral sutures.

The location of the radioactive plaque can be confirmed by transillumination examination. Examination with indirect ophthalmoscopy can be performed while transscleral transillumination is performed using a fiberoptic light source to visualize the boundary of the plaque relative to the tumor. After confirming proper plaque positioning the conjunctiva is sutured over the plaque.

After surgery, confirmation of the plaque position relative to the tumor can be performed by B-scan ultrasonography or magnetic resonance imaging.

Typically, treatment duration is about 3–6 days. After completion of the treatment period the plaque is surgically removed.

EPIMACULAR BRACHYTHERAPY FOR AGE-RELATED MACULAR DEGENERATION

SURGICAL TECHNIQUE

The subject is prepared as per standard eye surgery and the procedure is accomplished through a standard vitrectomy procedure.

Surgery begins with a standard vitrectomy procedure. An infusion cannula is inserted and secured in the sclera about 3–4 mm from the surgical limbus, usually in the inferotemporal quadrant (Figure 49.4A).

An appropriate lens for vitreoretinal surgery is placed and a limited vitrectomy performed. After vitrectomy, the treatment probe is placed in the vitreous cavity and under microscopic visualization, the surgeon places the tip of the probe directly above the macula to evaluate hand positioning better during treatment (Figure 49.4B). Once the proper probe positioning is determined by the surgeon, the probe is positioned back in the mid vitreous position and the radiation source is then advanced by pushing the sliding mechanism towards the tip of the probe (Figure 49.4C). The probe is then positioned back to the proper treatment location (Figure 49.4D) just above the neovascular membrane, with the center marker directly above the center of the choroidal neovascular complex (Figure 49.4E).

The appropriate treatment time is previously determined by the radiation source activity in order to deliver 24 Gy to the target area. Typically, treatment time varies between 2 and 5 minutes. After treatment time is reached, the surgeon pulls the sliding mechanism back to the storage position and locks it in place. After the slider mechanism is in the storage and locked position, the delivery probe will be removed from the eye and the sclerotomies closed. A radiation survey is performed to ensure that the source has been fully retracted to its storage position.

OUTCOMES

CHOROIDAL MELANOMA

Typically, choroidal melanomas treated with brachytherapy are expected to reduce in size to approximately 50% of their pretreatment thickness over a period of approximately 2 years.22,31 Only a small percentage of medium-sized and large-sized melanomas become relatively

flat scars. As the tumor contracts, increased internal ultrasonographic reflectivity and decreased vascularity are observed.

The maximum tumor size that can be effectively treated with radiation without causing severe radiation complications is still uncertain. The COMS guidelines recommend that the radioactive plaque should extend beyond the recognized tumor base by a 2-mm margin. Following these guidelines, a maximum basal dimension of a tumor treatable with brachytherapy is approximately 21 mm. The COMS reported that enucleations were more common for tumors with greater thicknesses and greater base dimensions, although percentages were not given.31

The COMS medium-size tumor trial enrolled 1317 patients and randomized between enucleation and iodine-125 brachytherapy.22 The mortality rate was not statistically different 12 years after treatment. The all-cause 5-year mortality rates were reported to be approximately 20% and the estimated tumor-specific mortality was 10%.22

Between 5% and 10% of patients treated with radiotherapy ultimately require enucleation because of tumor recurrence or radiation complications. In the COMS, 10% of eyes were enucleated because of suspected or documented tumor recurrence. Importantly, tumor recurrences have consistently been reported to be associated with an increased rate of metastases, even when subsequently treated with enucleation. The COMS calculated a metastasis risk ratio of 1.5% when there was a local recurrence.31 Although eyes with recurrences are often managed with enucleation, local edge recurrences may sometimes be controlled with photocoagulation or transpupillary thermotherapy.

Eyes with juxtapapillary tumors comprise a distinct group with poorer prognosis. The recurrence rate is significantly higher (15%), resulting in a greater incidence of enucleation.32

The visual outcome in eyes treated with iodine-125 is similar to that reported for other forms of radiation therapy (helium ion, 53% 20/200 or less; proton beam, 42% 20/200 or less) and suggests that research efforts should continue to be directed toward ways to reduce the complications of radiation.

BRACHYTHERAPY FOR AGE-RELATED MACULAR DEGENERATION

Reports in the more recent published literature describe mixed results. In a pooled analysis of eight phase I studies, results indicated that radiotherapy may only act to slow or delay the progress of the disease. A dose–response relationship was noted in at least one observational study, and better vision outcomes were reported with higher radiation doses in three recently published randomized clinical trials. External photon beam radiation was used in all of these studies.

In 1998, Bergink et al.33 reported that, 1 year following treatment with four fractions of 6 Gy, 52% of observed eyes versus 32% of treated eyes experienced a 3-line loss of vision. In 1999, Char et al.34, in a small clinical trial involving 27 patients with varying lengths of follow-up, reported fewer incidences of vision loss among patients treated with one fraction of 7.5-Gy photon beam irradiation than among observed patients. In 2000, Kobayashi and Kobayashi reported successful treatment of patients with smaller neovascularized regions with 20-Gy photon beam divided in 10 fractions of 2 Gy over 14 days in a randomized prospective double-blind study.35 A total of 101 eyes were randomized to radiation treatment versus observation. Patients with classic CNV were also included. A statistically significant difference in change of logMAR visual acuity was found for follow-up of 6, 12, and 24 months (P < 0.0001; P < 0.0001; P < 0.0001, respectively). The increase in CNV size for 1 and 2 years in the treatment group was significantly smaller than that in the control group (P = 0.0147; P = 0.0008), showing that radiation was effective in reducing CNV leakage and size. No CNV regression was noted in the control group. No serious treatment sideeffects were reported in any of the studies.

In contrast, the Radiation Therapy for Age-related Macular Dege­ neration study group trial used eight fractions of 2 Gy; Marcus and colleagues used seven fractions of 2 Gy; and Hart et al. used six fractions of 2 Gy but none of these studies demonstrated a clear clinical benefit.36–38 Although the cumulative doses (16, 14, and 12 Gy) of radiation in the trials showing no effect do not seem appreciably less than those in the

Surgery and Pharmacotherapy • 5 section

Radiotherapy External and chapteEpimacular• 49

A

C

E

Bergink et al.33 and Kobayashi and Kobayashi35 studies (24 and 20 Gy, respectively), the differences in biological effect could be appreciable. With radiation therapy, the biological effect depends on the dose per fraction, the number of fractions, and the time between fractions. For example, the biological effect of the dose used in the study by Bergink et al. may be as much as three times the biological effect of the dose used in the study by the RAD research group.

B

D

Figure 49.4  (A) Overview of the standard vitrectomy procedure performed during the epimacular radiation delivery using the Neovista VIDION brachytherapy system. (B) Insertion of the probe in the mid vitreous cavity after vitrectomy. (C) Activation of the radiation sliding mechanism. At this time, the radiation source is internally moved towards the tip of the probe for treatment. (D) After activation of the sliding mechanism, the probe is positioned back to the macular region. (E) It is important to ensure that the center marker is directly above the center of the choroidal neovascular complex, with the probe tip lightly touching the retina.

A study by Flaxel et al. has shown the development of radiation retinopathy in 11 of 27 eyes receiving proton beam 14 cobalt gray equivalent within a year.39 This study demonstrated efficacy in terms of neovascular closure in eyes with age-related macular degeneration but was limited by radiation retinopathy at 1 year.

Jaakkola et al. evaluated Sr-90 plaque brachytherapy in a prospective, nonrandomized clinical trial.40 A single dose of 15 Gy at a depth of