Dosimetry

The optimal tumoricidal radiation dose for uveal melanoma remains unclear,^30,31 but doses range between 50 and 100 Gy, with doses less than 50 Gy being associated with significant treatment failures.³⁰ Kindy-Degnan et al.³² used helium ion radiation and reported on tumor apex dosages ranging between 50 and 80 Gy, showing that regardless of whether 50, 60, 70, or 80 Gy was used, there were no differences in tumor regression, survival, complications, or visual outcomes. Initially, the COMS decided to deliver 100 Gy to the tumor apex with a delivery rate of 50–125 cGy/h (tumors <5 mm in height are managed as if they were 5 mm thick).³³ However, in 1996, based on newer dosimetric measurements and the recommendations of the American Association of Physicists in Medicine (AAPM), the COMS modified the prescription dose to deliver 85 Gy to the tumor apex with a delivery rate of 43–105 cGy/hour.³⁴ Based on these modifications, with the AAPM-recommended calculation and revised prescription dose, the actual dose delivered to the tumor is the same. As a result, when analyzing studies prior to 1986 that utilized iodine-125, the actual dose to the tumor is 85% of the stated dose. Furthermore, the American Brachytherapy Society has presented the COMS dose recommendation as the guideline for the treatment of choroidal melanoma.³⁵ As more accurate estimates for some of the assumptions used and better calculation algorithms have become available, dosimetry has been further refined and recalculated incorporating anisotropy, line source approximation, and Silastic and gold shield attenuation. Tables of dose to the tumor apex and various other ocular structures have been presented for the various size plaques.³⁶ On average, the dose to the apex of the tumor appears to be 0.89 of the 85 Gy that has been assumed using the AAPM formalism.³⁶ The physics of brachytherapy has been reviewed in several publications.^36–38

Isotope selection

Brachytherapy is the application of radiation from isotopes over very short distances in contact with a surface. The radiation is distributed over a short distance from a surface or within the target tissue. Table 145.1 presents physical characteristics for the commonly used isotopes in brachytherapy. The table breaks isotopes into two broad categories: (1) those that emit γ-rays or X-rays; (2) those that emit β-particles (electrons). Table 145.1 footnotes explain some of the simplifications. The half-value (HVL) in water for a narrow beam is useful in comparing isotopes for the penetration of their radiations in tissue. The tenth-value layer (TVL) in lead for a broad beam is useful in evaluating penetration in shielding materials.

The most commonly used sources for brachytherapy are: iodine-125, palladium-103, and ruthenium-106, which have largely replaced iridium-192, cesium-137, radium-226, radon-222, and cobalt-60. Half-life will determine whether the isotope can be used practically, is feasible for commercial production, or can be reused. Isotopes such as gold-198 and radon-222 have very short half-lives, and are impractical for regular use.

The energy of γ-rays or X-rays relates to their penetration in matter in a complex way. The more energetic rays penetrate to a greater extent and are more difficult to shield; these two factors are dealt with in the last two columns of Table 145.1.

The HVL in water is an index of the extent to which the energy of the radiation is absorbed in water (or tissue). At short distances, important for application in localized tumors of the eye, the inverse-square law largely governs the radiation penetration in tissue. Figure 145.1 displays the depth–dose curves for iodine-125, iridium-192, and cobalt-60. Because of the small height (up to approximately 1 cm) of the tumors treated, this inverse-square law is far more important in determining scleral (or choroidal blood vessel) dose for a given dose to the tumor apex. The dose rate falls more rapidly near the source than further away. Thus, the scleral dose relative to the dose at the apex of the tumor may be reduced by simply introducing a space between the source and the sclera. In the orbit, only size constraints limit the magnitude of the space, with 1 mm being the maximum in plaques used for ocular brachytherapy. With greater distances and less energetic rays, tissue absorption begins to play a more important role. For the β-emitters, absorption in tissues, which is complex and related to the energy of the β-particle, must be measured.

Fig. 145.1 Computer-generated curves identifying depth–doses of radiation at varying distances in tissue from three different radiation sources. A single seed (1.0 mCi; 37 MBq) of each radioisotope was used.

(Reproduced with permission from Earle J, Kline RW, Robertson DM. Selection of iodine-125 for the Collaborative Ocular Melanoma Study. Arch Ophthalmol 1987;105:763–4. American Medical Association. All rights reserved.)

The TVL of lead is an index of the shielding that must be used around sources for the protection of personnel or the normal adjacent tissues. All the γ-ray or X-ray emitters except for iodine-125 and palladium-103 have values >1 cm.

The exposure rate constant is an expression of dose rate at a standard distance from a specified amount of isotope. More atoms of an isotope with a low constant can achieve the same dose rate as one with a higher constant, the other characteristics being equal. The curves of dose rate versus depth in tissue for different isotopes can nearly be superimposed by adjusting the amount of each isotope in inverse ratio to the ratio of the exposure rate constants (Fig. 145.2).⁴⁴

Fig. 145.2 Normalized curves (at 1 cm using a single seed of radioisotope) showing that depth–doses of radiation are nearly identical with the three radiation sources until beyond 15 mm, at which depth the radiation from iodine-125 begins to fall off.

(Reproduced with permission from Earle J, Kline RW, Robertson DM. Selection of iodine-125 for the Collaborative Ocular Melanoma Study. Arch Ophthalmol 1987;105:763–4. American Medical Association. All rights reserved.)

Beta-emitters, such as ruthenium-106, have been shown to be successful in tumor control for small to medium tumors, potentially up to 16 mm in diameter and up to 8 mm in thickness when used alone with calculated apex doses, or combined with transpupillary thermotherapy (TTT) when apex doses are insufficient.⁴⁵ The presumed advantages of these lower-dose radiation sources are a decrease in the potential risk to adjacent structures as well as decrease the risk of radiation retinopathy.⁴⁶ However, studies have not shown a reduction in treatment-related visual decline,⁴⁵ as doses are thought to still be above those maximally tolerated by the retina, vasculature, and optic nerve.

A final consideration is the ready commercial availability of well-packaged, calibrated, quality-controlled sources with a spectrum of activities. The COMS chose iodine-125 as a convenient, easily available isotope with favorable properties of half-life, shielding, tissue penetration, and physical form. As a result, iodine-125 is the most commonly used isotope in the USA. However, with high rates of radiation retinopathy and visual morbidity, other centers around the world are investigating the use of other isotopes, namely palladium-103 and ruthenium-106, in attempts to minimize the treatment-related side effects while still maintaining equivocal tumor control rates.

Plaque design

The iodine-125 plaque design used in the COMS evolved from that used by Rotman et al.⁴⁷ and Robertson et al.,¹⁸ and consists of a gold plaque that is approximately 0.4 mm thick with a lip around its perimeter that resembles a smooth bottle cap (Fig. 145.3).⁴⁴ The shielding device decreases lateral spread of radiation and results in a collimated beam of radiation. Plaques may be customized with notches or indentations of the gold rim to allow placement adjacent to the optic nerve sheath for juxtapapillary tumors. Notched plaques attempt to minimize the likelihood of plaque tilting secondary to placement next to the optic nerve sheath, as this tilt may result in excess radiation to the optic nerve, while decreasing the dose to the tumor apex. Other unique plaque designs and concepts include slotted plaques,⁴⁸ which may aid in the treatment of juxtapapillary tumors, including circumpapillary tumors, which prove difficult to treat. Within the gold plaque is a soft, pliable plastic (Silastic) seed carrier insert with evenly spaced troughs that accept the iodine-125 seeds. The carrier is designed so that the seeds are adjacent to the gold. The thickness of the seed carrier separates the seeds from the sclera surface by 1 mm. The prepared loops facilitate anchoring of the plaque to the sclera with sutures. Eyelet placement proves important to minimize the potential for plaque tilt, with those with circumferential eyelets posing decreased likelihood of tilting. The relative dose distribution associated with a particular radioactive plaque is basically determined by the arrangement (distribution) of the seeds in the plaque. The dose distribution from seeds within a plaque, such as shown in Figure 145.3, is demonstrated by the schematic in Figure 145.4. By distributing iodine seeds over the area of the plaque and having a 1 mm spacer between the seeds and the sclera, the scleral dose delivered by an iodine-125 plaque is approximately the same as that delivered by a cobalt-60 plaque. Monte Carlo calculations by Chiu-Tsao et al.⁴⁹ demonstrate a lower scleral dose for iodine-125 compared to cobalt-60, for a point source model.

Fig. 145.3 Iodine-125 plaque designed for the Collaborative Ocular Melanoma Study (COMS), consisting of gold housing and seed carrier insert.

Fig. 145.4 Schematic displaying isodose lines from iodine-125 (left) and cobalt-60 (right) therapeutic plaques, both delivering 100 Gy to the apex of a tumor 7 mm thick. A 1 mm spacer separates iodine-125 seeds from the sclera.

(Reproduced with permission from Earle J, Kline RW, Robertson DM. Selection of iodine-125 for the Collaborative Ocular Melanoma Study. Arch Ophthalmol 1987;105:763–4. American Medical Association. All rights reserved.)

Indications for treatment

Plaque placement technique

One of the first and most important steps in plaque placement is determining an accurate clinical estimate of the tumor base and height measurements prior to surgical placement. This allows for the correct sizing of the plaque containing the radiation seeds (i.e. iodine-125), which must be precisely communicated to the radiation oncologist. Estimates of tumor dimensions utilize a number of technologies, including photography, indirect ophthalmoscopy with and without measuring grids, and ultrasound. Intraoperative localization also utilizes ultrasound, with the added utility of fiberoptic light sources for transillumination.

With advancements in ophthalmic photography, including wide-angle photography and digital software measurements, tumors are more often captured in toto as montage images. Tumor dimensions can then be determined by approximating the basal tumor diameter with regards to disc diameters or use of calipers, with the horizontal diameter of the optic nerve approximated at 1.5 mm. Wide-angle photography has been shown to be more accurate than ultrasound in measuring the basal diameter, as it potentially captures those margins or pigmentation that are not determined on ultrasound secondary to lack of elevation.^90,91 Using this estimate, basal tumor diameter can be determined, with ultrasound (quantitative A-scan) aiding in the measurement of the tumor thickness and presence or absence of extraocular extension. For tumors that are unable to be captured completely by photographs, tumors can be measured using a technique first described by Hilton,⁹² where a grid is placed over the 20-D lens with each square representing 1 disc diameter. The tumor is viewed monocularly through the grid, allowing an approximate calculation of the basal diameter. The pre-surgical tumor estimates are important to pre-select plaque sizes to ensure that the plaque covers the entire tumor base along with 2 mm or more of tumor-free perimeter. For example, a tumor with a base diameter of 12 mm is treated with a 16 mm in diameter plaque.

Estimation of tumor size at or beyond the equator can be difficult, rendering it useful to know several distance approximations. The distance between the equator and the ora is ≅5 mm in the vertical meridians, 5.5 mm in the nasal meridian, and 6 mm in the temporal meridian. Also, with the COMS considering tumors >16 mm too large to be eligible for plaque brachytherapy, it is convenient to remember that 3 clock-hours at the equator and 4 clock-hours at the ora are each equivalent to a chord length of approximately 16 mm.

The choice of anesthesia is left to the discretion of the surgeon. After an adequate peritomy, the surface of the sclera corresponding to the tumor is exposed. If extraocular extension is observed within a pseudoencapsulated focus ≤2 mm in diameter, the plaque is placed over the tumor base and the extension. Because an extraocular extension of <2 mm may not worsen the prognosis for survival,⁹³ proceeding with brachytherapy as intended is reasonable. If extraocular extension is in excess of that noted, enucleation with tenonectomy must be considered. As an alternative, an iodine-125 plaque without a gold shield could be placed over the extension to allow radiation of orbital tissues adjacent to the visible extension. Ultrasound frequently detects extensions >2 mm,⁹⁴ with extensions of this size occurring infrequently.⁹³ As a result, discovery of large extraocular extensions (>2 mm) at surgery should rarely occur. For example, there have been virtually no such instances for globes enucleated in COMS.

At surgery, the tumor base is localized with standard techniques used for retinal breaks or transillumination (or both). Sometimes the shadow of the tumor can be clearly outlined on the sclera while the globe is transilluminated through the cornea (Fig. 145.5A). The perimeter of the tumor base should be verified with indirect ophthalmoscopy. The MIRA diathermy-transillumination unit may assist in outlining the tumor base (MIRA 1 electrode handle with fiberoptic bundle and coaxial cable with scleral transilluminator). The intense light of the angled fiberoptic transilluminator allows the operator to visualize the tumor with indirect ophthalmoscopy while simultaneously visualizing the transsclerochoroidal retinal illumination from the fiberoptic light tip as it is moved to localize the perimeter of the tumor. Indirect ophthalmoscopy with scleral depression can also aid in identifying tumor margins. With the fiberoptic light at the perimeter of the tumor, a low-intensity diathermy mark can be made on the sclera. This mark can be made darker with a surgical marking pen (Fig. 145.5B). The tumor diameter can be measured and recorded using calipers, followed by estimation of 2 mm perimeter beyond the tumor borders. A transparent acrylic dummy plaque with a diameter equal to that of the therapeutic plaque is used to facilitate localization and later placement of the opaque therapeutic plaque. The dummy plaque is placed on the sclera, covering the scleral marks that identify the tumor perimeter. The dummy plaque must completely cover the base of the tumor as well as a tumor-free perimeter of 2 mm or more (Fig. 145.5C). After the perimeter of the dummy plaque has been marked on the sclera with pencil or diathermy, it is removed, and the opaque therapeutic plaque is placed within this ring of scleral marks and anchored with two or three intrascleral sutures (Fig. 145.5D,E). If the therapeutic plaque is the same size or smaller than the boundary of the tumor base as marked on the sclera, the procedure is terminated, and a larger plaque is prepared and placed on the eye later. If the plaque diameter is 3 mm or more greater than the diameter of the tumor base, it is sutured in place.

Fig. 145.5 (A) Sketch showing a cross-section of an eye harboring a melanoma located in the mid peripheral fundus. (B) A fiberoptic light source has been placed over the cornea, and the shadow of the tumor is visible on the exposed sclera. A marking pencil has outlined the shadow of the tumor. (C) A transparent dummy plaque that is 4 mm greater in diameter than the estimated diameter of the tumor base has been centered over the area of the tumor base. A second row of marks has been made around the dummy plaque to facilitate placement of the opaque therapeutic plaque, which will overlap the boundary of the tumor by 2 mm on each side. (D) Gold-backed iodine-125 plaque being readied for placement. (E) When a rectus muscle must be detached because of an anteriorly located tumor, a double-armed mattress suture can be used to secure the end of the transected muscle and the muscle can then be allowed to retract. Each arm of the suture is passed intrasclerally 1.5 mm behind the insertion before exiting the sclera, 1 mm anterior to the insertion. Each arm is then passed through the undersurface of the conjunctiva into the cul-de-sac, where the ends can be tied so that they can be retrieved at the time of plaque removal. When the plaque is removed, the sutures are tightened and tied, thus drawing the muscle to a new point of attachment 1.5 mm behind the original insertion. (F) Therapeutic plaque anchored in position with three 5–0 nylon intrascleral mattress sutures.

The location of the radioactive plaque can be confirmed with a fiberoptic light source, using a technique similar to that described by Robertson et al.⁹⁵ The MIRA transillumination diathermy probe combined with indirect ophthalmoscopy can be used to provide transscleral transillumination around the boundary of the plaque. As the probe moves along the plaque, the light can be visualized in the choroid and its location relative to the tumor base can be readily seen. For anteriorly located tumors, transscleral illumination around the plaque boundary is ordinarily satisfactory, as standard B-scan ultrasonography proves difficult in discerning anterior segment structures. However, newer technologies such as ultrasound biomicroscopy (UBM) and anterior segment optical coherence tomography may open new avenues for anterior segment image acquisition.⁹⁶ Confirmation of the relationship of the tumor and plaque position can be obtained with B-scan ultrasonograpy.^97–99 Harbour et al.⁹⁷ showed that standard techniques for localizing plaque placement were suboptimal in 21% (14% posterior, 7% juxtapapillary) of patients, primarily in tumors located posteriorly and juxtapapillary. Intraoperative ultrasound allowed for identification of malpositioned plaques, affording the opportunity to reposition the plaque while still in the operating room. However, despite successful repositioning, Almony et al.¹⁰⁰ reported on plaque tilting at time of plaque removal. The authors found that whereas only 9% of patients had plaque tilt >1 mm at insertion, approximately 53% of plaques had tilt >1 mm at removal. Plaque tilt was also shown to be associated with a reduction in radiation doses to the tumor apex. Interestingly, three patients were found to have local tumor failure and were associated with plaque tilt of >2 mm at removal. As observed in prior studies, posteriorly located plaques, as well as juxtapapillary tumors necessitating notched plaques were more likely to have significant tilt at removal. Of note, episcleral hematoma was also identified as a risk factor for plaque tilt and often associated with disinsertions of rectus muscles. As a result, intraoperative ultrasound should be commonly used in combination with other localization techniques to ensure sufficient plaque placement and identify suboptimal or tilted plaques to allow for immediate repositioning. Although no long-term studies have been reported, intraoperative ultrasound may minimize the risk of local treatment failures.

A notable complication associated with plaque manipulation is hemorrhage in and around the tumor. Several investigators have reported on this complication,^2,17 along with the possibility of vitreous hemorrhage. These instances may be aided with the use of intraoperative ultrasound to assist plaque placement secondary to media opacities and inability to utilize standard techniques.

Tumors with margins close to the optic nerve present a unique situation regarding plaque placement. Although the diameter of the intrascleral portion of the optic nerve measures 1.5 mm, the diameter of the optic nerve sheath upon exiting the eye increases to 3–4 mm. As a result, for tumors that are within 2 mm from the optic nerve, applying a plaque with 2 mm tumor-free margins proves a difficult task. A standard round plaque may be situated with the posterior aspect placed against the optic nerve beyond the posterior edge of the tumor. However, plaques abutting the optic nerve have a high incidence of plaque tilt, resulting in decreased apical tumor dose with an associated risk of tumor failure, as well as an increased radiation dose to the optic nerve with risk of optic neuropathy.^97,100 These findings have been demonstrated by Williams et al.¹⁰¹ using MRI scans of plaques placed in a juxtapapillary position in cadavers. An alternative approach involves the design of plaques with an indentation to fit around the optic nerve. Additionally, the rim of the plaque may be removed to allow lateral radiation to provide treatment to those margins that are unable to be covered completely by the plaque. However, this latter option exposes the optic nerve to a higher dose of radiation with increased likelihood of significant visual morbidity.

Rectus muscles may be detached to facilitate plaque placement and minimize pressure on the globe, with understanding that these procedures pose the risk of hematomas and associated plaque tilt which may increase the likelihood of local failure. These findings suggest the use of intraoperative ultrasound following plaque placement and at removal to identify plaques that may have tilted significantly and placing the patient at risk for local tumor control failure.¹⁰⁰ After placement of the plaque, the rectus muscle may be sutured to the original insertion or anchored to the side of the plaque or anterior to the plaque. An adjustable suture placed at the time of plaque placement may be preferable if the muscle must remain detached during the brachytherapy period, as this will facilitate reattachment of the muscle at the time of plaque removal. Muscles are usually engaged with a double-armed absorbable suture if it must be detached at the time of plaque placement. The ends of the double-armed suture are passed intrasclerally 1.5 mm behind the insertion and then through the conjunctiva, where they are anchored in the cul-de-sac so that they can be retrieved at the time of plaque removal. Alternatively, the ends of the double-armed suture can be loosely tied and placed under the conjunctiva for later access when the plaque is removed. The muscle is allowed to retract and remain detached until the time of plaque removal (Fig. 145.5F).

Close evaluation of the tissue area of plaque placement must be emphasized, as any episcleral tissue around the optic nerve sheath, inferior oblique muscle, and posterior ciliary vessels and nerves may create added distance of the plaque away from the tumor.^102–106 These observations must be relayed to the radiation oncologist, as it may warrant recalculation of radiation doses or durations. On completion of plaque placement, the conjunctiva is closed over the plaque with sutures, although risk for complications is low for anteriorly located tumors where the conjunctiva is not able to be closed completely over the plaque or conjunctiva that retracts postoperatively.

Radiation plaques are kept in place for 4–5 days, with patients often staying as inpatients during the course of treatment. With conclusion of plaque treatment, plaque removal is usually performed with local anesthesia. There may be some utility to the use of ultrasound prior to plaque removal to identify those plaques that may have sustained significant tilt.¹⁰⁰ Once identified, discourse between the treating surgeon and the radiation oncologist is important to determine the possible need for a longer course of treatment or whether adjuvant TTT is warranted. Following the removal of the plaque, muscles that have been transected are reattached by approximating the sides of the muscle to near the original insertion, allowing the central portion to drape posteriorly (in general, a slight recession of the muscle approximately 1.5 mm may compensate for the tendency of the shortened reattached muscle to cause overaction). For preplaced sutures, the muscle is drawn up to the site of the intrascleral suture passage and secured.

Thermoluminescent ring dosimetry measurements were utilized early in the treatment of choroidal melanoma with plaque brachytherapy to determine the risk of radiation exposure to the surgeon’s hands during plaque placement. However, minimal radiation exposure was found, and the use of these radiation-detection devices was discontinued.

Postoperative observations

Serial follow-up examinations are conducted between 6 weeks and 3 months and usually at 6-month intervals thereafter. Documentation with wide-angle photography to measure tumor basal dimensions is necessary to enable early detection of tumor growth. Standardized A-scan and B-scan echography is obtained to determine tumor thickness. Occasionally, tumors exhibit swelling on the first postoperative visit following plaque removal, although tumor shrinkage may also be observed. In general, tumor shrinkage does not occur until 6–9 months after treatment, and some tumors may never demonstrate a decrease in size. Echographic changes following plaque brachytherapy include diminished tumor height and increased tissue reflectivity within the tumor. Additionally, a hypoechoic space corresponding to the site of prior plaque placement is frequently observed. This hypoechoic space may be exaggerated in cases of fungal granulomas, an unusual complication that has been reported following ruthenium-106 plaque treatment.¹⁰⁷

The ophthalmologist must also be vigilant during follow-up visits to identify early indicators of adverse effects of plaque brachytherapy, namely radiation retinopathy (maculopathy and optic neuropathy). These effects can present with subtle findings on optical coherence tomography (OCT) prior to clinical signs of radiation complications. Horgan et al.¹⁰⁸ report on the incidence of OCT changes in 70% of 135 patients with a mean time to onset of 12 months. Current treatment of radiation complications has not proven successful once an eye manifests with signs of radiation changes. Future treatment strategies will need to focus on early identification of the radiation effects, followed by targeted treatment in an effort to maintain visual acuity.

Local tumor response

Most choroidal melanomas treated with brachytherapy show evidence of shrinkage, with almost half of all tumors decreasing 50% from the pretreatment thickness. Despite the shrinkage seen in medium and large tumors, they will rarely regress to a flat scar. Shrinkage may not be observed at first, but usually progresses over 2 or more years, then remain stable thereafter. With tumor regression, echographic findings change concurrently, showing an increase in the internal reflectivity along with a decrease in tumor vascularity. Choroidal melanomas that have broken through Bruch’s membrane to form a collar-button configuration have a distinct regression pattern.¹⁰⁹ The body of these tumors tends to shrink while the collar-button portion becomes more prominent and darker, and may shed pigmented debris into the vitreous cavity. Histopathologically, this debris usually consists of pigment-laden macrophages, melanoma cells, or a combination of both.

With the exception of the first postoperative visit where tumors may swell and increase in size, choroidal melanomas following plaque brachytherapy should be observed at regular intervals for any signs of growth. If the tumor thickness increases by 300 µm, or if any of the tumor borders advance by 250 µm, the tumor is highly suspected of expansion. These tumors should be observed more frequently and if continued growth, 300 µm increase in thickness or 250 µm increase of any border, is observed, plaque brachytherapy is considered a failure and further treatment is recommended. Although several investigators have reported successful retreatment with brachytherapy leading to local tumor control,^8,12,110 definitive enucleation should be recommended. Tumors that recur following plaque brachytherapy may have a greater likelihood of metastasis; therefore, maximizing primary treatment response is imperative.

Recurrences

Failure to control tumor growth after plaque brachytherapy has been shown to vary from 1.7% to 16%,^{12,103,111–113} depending on the institution, isotope, and the length of follow-up. Wilson and Hungerford¹¹⁴ observed a recurrence rate of only 4% with iodine-125, compared to 5% with PBI and 11% with ruthenium-106. In addition, Fontanesi et al.¹¹⁵ reported a recurrence rate of 2.3% for 144 patients treated with iodine-125. The COMS enucleated 10% of eyes secondary to suspected or documented tumor recurrence.⁷¹ More recently, a recurrence rate of 1.7% was reported for 117 patients with choroidal melanoma treated with iodine-125 plaque brachytherapy.¹¹³ The study emphasized the importance of confirming proper plaque placement using intraoperative ultrasound at the time of surgery. Data from other plaques, ruthenium-106 and palladium-103, have also demonstrated low rates of local tumor failure at 3.9%⁴⁵ and 3%,⁵¹ respectively.

Efforts to reduce the rate of recurrences following plaque brachytherapy prove exceedingly important, as tumors with local recurrences, despite undergoing enucleation, have an increased risk of metastasis. Gragoudas et al.⁷² reported a risk ratio of 2.44 among patients treated with proton beam irradiation (PBI). Vrabec et al.¹¹² reported nearly three times greater estimated 5-year mortality (42% versus 13%) among patients treated with cobalt-60. Harbour et al.¹¹⁶ reported a 5-year actuarial rate of local recurrence of 10%, with metastasis occurring in 19% of patients with horizontal (marginal) recurrences (relative risk 2.2), and increasing to 49% if the recurrence was vertical and diffuse (relative risk of 5.1). In the COMS, tumors with local recurrence had a calculated risk ratio of 1.5% for metastasis.

Histopathologic findings in eyes treated with brachytherapy indicate that physical necrosis and tumor shrinkage are not uniformly observed. MacFaul and Morgan¹¹⁷ reviewed the histologic changes in 27 eyes treated with cobalt-60 and found clear evidence of radiation effect in all eyes, but tissue necrosis was not evident in 12 eyes. Necrosis was a predominant feature in only two eyes. Char et al.⁴ observed significant necrosis in only one of four eyes, whereas Rotman et al.⁴⁷ reported no recognizable viable tumor cells in two of three eyes enucleated after treatment. Saornil et al.¹¹⁸ reported on the histopathologic features of 22 eyes that underwent enucleation after treatment with iodine-125 plaque brachytherapy. The authors found that tumor necrosis was extremely variable with 50% of eyes not showing evidence of necrosis, and only 14% of eyes showing necrosis in 50% or more of the tumor. Additional findings within the tumors were varying degrees of inflammation, fibrosis, tumor blood vessel damage, and increased number of balloon cells. Changes in the surrounding retina were characterized by atrophy, hyperplasia, and fibrous metaplasia of the retinal pigment epithelium, retinal gliosis, protein, lipid and blood deposits within the retina, and retinal blood vessel abnormalities characterized by thickening, thrombosis, and neovascularizations. These changes are similar to those seen after proton beam irradiation.¹¹⁸ Finally, Avery et al.¹¹⁹ reported on the histopathologic findings in 75 eyes from the COMS that were enucleated after plaque brachytherapy and compared with eyes that received treatment with primary enucleation. Tumors treated with iodine-125 showed significantly less mitotic activity, marked inflammation, invasion of the retina and scleral extension, as well as vitreous hemorrhage. Additionally, 55% of eyes showed effects on the retinal vasculature consistent with changes seen with radiation retinopathy. Finally, only 60% of eyes showed evidence of tumor growth or extrascleral extension in tumors enucleated secondary to presumed failure of local control.

Visual results

Early reports by Stallard⁵ in 1968 appeared to indicate a satisfactory 5-year survival rate among 100 patients treated with cobalt-60; however, other early studies identified severe ocular complications that were disturbingly prevalent. MacFaul⁴⁰ reported that among 78 patients alive at 17 years post-radiation with cobalt-60, 35% of eyes treated required enucleation secondary to tumor growth or radiation complications. For those eyes that were not severe enough to necessitate enucleation, 35% had vision that was severely affected (hand movement or less), while only 39% had a visual acuity of 6/18 or better. These early studies also observed that exudative retinopathy sometimes did not appear until 7 years after treatment, and microvascular abnormalities were occasionally delayed 15 years.⁵ Additional studies with cobalt-60 showed evidence of radiation retinopathy, optic neuropathy, cataracts, and failure of local tumor control.^3,4,24,41 Complications following radiation were commonly seen after 2 years, but may present earlier.

The complications of radiation maculopathy and optic neuropathy are dependent on the total amount of radiation delivered to the macula and optic nerve, respectively. The resultant dose received by these structures depends on the tumor size and location, with increased risk in tumors with increased height and basal diameter, and located in close proximity to the fovea and optic nerve. In addition to dose-related effects, radiation complications are also associated with the size of the fractions for fractionated doses, increasing in severity for larger fractions. Other factors, such as concomitant use of chemotherapeutic agents and diabetes mellitus, may lower the threshold for developing radiation damage. Biologic variability also likely serves as another factor. Histopathologic studies have shown selective loss of endothelial cells that line blood vessels, resulting in capillary drop-out, microaneurysms, and other changes similar to those seen with diabetic retinopathy. Patients may present with macular edema, microaneurysms, telangiectatic vessels, capillary non-perfusion as seen on fluorescein angiography, neovascularization, or vitreous hemorrhages.^42,43

Visual prognosis has been shown to be less favorable when foveal or optic nerve radiation is in excess of 5000 Gy.²⁷ Brown et al.^24,25 indicated that the lowest doses of radiation generally causing macular retinopathy were 45 Gy from cobalt-60 plaques and 36 Gy from external beam radiation. Optic neuropathy was observed to occur from doses as low as 35 Gy from cobalt-60 and 36 Gy from external beam radiation. The same group²⁷ reported severe visual loss from radiation doses to the fovea as low as 21, 23, and 30 Gy. These cases showed visual loss from nonproliferative radiation retinopathy or exudative retinal detachments.

In 1976, Sealy et al.¹²⁰ first reported the use of iodine-125 in the management of melanoma. The isotope was chosen because of its advantageous physical characteristics, which allow the radiation to be almost completely shielded by a thin sheet (0.4 mm) of lead or gold. Packer et al.¹⁴ reported preliminary evidence on the use of iodine-125, followed by animal studies reported by Robertson et al.^17,18 Studies by Garretson et al.¹¹ found that visual acuity of 26 patients treated with iodine-125 remained within 2 Snellen lines in 54% of patients. Of those that developed radiation changes, mean duration to onset was approximately 32 months.

Although the proponents of iodine-125 had hoped that the lower energy emission, combined with greater space between source and sclera and lateral shielding, would delay or lower the incidence of radiation complications, long-term results have been disappointing, with almost 50% of eyes treated with brachytherapy being legally blind at 5 years. For patients treated with iodine-125 and with at least 3 years median follow-up, rates for radiation maculopathy range between 13–52%,^{106,121–125} while rates of optic neuropathy range between 0–46%.^{11,106,110,115,121–126} The upper range for radiation complications was shown in large tumors as based on COMS criteria.¹²⁵ Krohn et al.¹²¹ found that patients with radiation maculopathy had a median dose of 49 Gy to the macula, while Stack et al.¹²² found that patients who received >90 Gy to the macula had a 63% risk of maculopathy. Although radiation is known to significantly affect the retina, a recent report by Boldt et al.¹²⁷ reported that 49.2% of patients with choroidal melanomas had abnormalities in the posterior pole prior to plaque treatment, with rates increasing to >90% at 5 and 8 years post-treatment. Proliferative radiation retinopathy was found to occur in 5.2% of patients at 5 years, while optic neuropathy had an incidence of 27.4%. These observations suggest that the inflammatory and angiogenic factors of tumors may contribute to retinopathy prior to additive treatment effects of plaque brachytherapy. 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,¹²⁸ PBI 42% 20/200 or less¹²⁹) suggesting that research should continue to be directed toward ways to reduce or treat radiation complications. The COMS estimated that nearly 50% of patients treated with iodine-125 would lose substantial vision by 3 years (loss of ≥6 lines of vision), with 43% having visual acuity less than 20/200.²² Other recent studies with at least 3 years follow-up report between 42–74% of patients treated with plaque brachytherapy lose ≥2 lines of vision.^{121–123,130} The COMS presented quality of life data for 209 patients treated with either enucleation or brachytherapy.²⁹ At 2 years, patients treated with brachytherapy reported peripheral vision and vision for driving that was significantly better than patients who were treated with enucleation. However, following 3–5 years, these findings were not significantly different. This timing corresponds to the visual decline observed for brachytherapy-treated eyes secondary to complications of radiation retinopathy.

Studies with different isotopes are unlikely to be fruitful in decreasing radiation complications, but research continues in this field. Although the physical characteristics of certain isotopes may allow better shielding with a greater differential radiation dose between tumor apex and sclera, the γ-rays, X-rays, and β-particles must still obey physical laws. Besides iodine-125, two of the most commonly used isotopes for plaque brachytherapy are palladium-103 and ruthenium-106. Ruthenium-106 is a β-emitter and first reported to be efficacious in 11 melanomas by Lommatzsch in 1974.¹³¹ A later series of 309 patients treated with ruthenium-106 with a mean follow-up of 6.7 years, showed efficacy of treatment in 70% of eyes, with 23% retaining vision 6/12 or better.¹³² In a smaller subset of patients with juxtapapillary melanomas treated with ruthenium-106, Lommatzsch et al. showed that the probability of developing complete radiation optic neuropathy was 23% and 53% at 5 and 10 years, respectively. Additionally, the probability of retaining 20/40 vision was 38% and 26% at 5 and 10 years. Verschueren et al.⁴⁵ reported on 425 patients with small to medium-sized choroidal melanomas treated with ruthenium-106. The authors found that rates of radiation complications (maculopathy, retinopathy, and optic neuropathy) were 40% and 65% at 2 and 5 years, respectively. In addition, almost 38% had a decrease in vision to legal blindness, or <0.10.

For palladium-103, the Palladium-103 for Choroidal Melanoma Study Group⁵¹ reported on 400 patients treated with plaque brachytherapy. With regards to visual acuity, 79% and 69% of patients had vision 20/200 or better at 5 and 10 years, respectively. Finger et al.¹³³ also correlated the incidence of radiation maculopathy with tumor location, tumor height, and radiation doses in 384 patients treated with palladium-103. Tumors in an anterior location were much less likely to manifest with maculopathy versus tumors with a posterior location (7% compared with 41%). Additionally, with radiation doses to the fovea <35 Gy, doses between 35–70 Gy had a risk of 1.74, while those >70 Gy had a risk of 2.43. This study compares similarly with the incidence of maculopathy following iodine-125. Palladium-103 emits lower-energy photons than iodine-125, resulting in radiation that is more readily absorbed by the tumor and less absorbed by tissues in close proximity to the plaque.^134–136 Disadvantages of palladium-103 compared with iodine-125 include an increased scleral dose directly beneath the plaque (a disadvantage in treating tumors at or very near the fovea), a relatively short half-live (17 versus 60 days), and less available information on the dosimetry of palladium-103.

Despite use of lower-energy isotopes and modern plaque design with shielding to minimize radiation exposure to vital structures, radiation-related complications are commonly encountered, necessitating further research into their treatment and prevention. Although studies have shown that radiation retinopathy occurs over longer periods of time, 70% of patients treated with iodine-125 showed signs of retinopathy on OCT upon 2 years follow-up, with a mean onset of 12 months. Notably, only 38% of patients had clinical signs of radiation retinopathy and median visual acuity at onset of 20/40.¹⁰⁸ These earliest effects manifest as macular edema secondary to the leakage from capillaries with poor endothelial support. With the advent of optical coherence tomography, earlier identification of radiation complications can be attained.

Vascular endothelial growth factor (VEGF) has been shown to be elevated in eyes with choroidal melanoma, with the highest levels being found in those treated with radiation.^137,138 VEGF is a potent vascular permeability factor that may contribute to macular edema and has been suggested to play a role in radiation maculopathy.¹⁰⁸ Additional cytokines may also factor into the retinal response to radiation toxicity. Although current studies using bevacizumab, ranibizumab, and triamcinolone have not shown dramatic effects in the sustained treatment of radiation maculopathy,^139–143 there is some evidence that early identification followed by prompt treatment with anti-VEGF agents may decrease the progression of radiation retinopathy; therefore, stabilizing visual acuity. Horgan et al.¹⁴⁴ reported on the use of periocular triamcinolone in 108 patients at the time of plaque placement followed by repeat dosing at 4 and 8 months, finding that at 18 months, there was a significant decrease in the risk of macular edema and the risk of moderate to severe vision loss was decreased from 48% to 31%. Side-effects included increased intraocular pressure as well as progression of cataracts. Further studies with longer follow-up are needed to assess the effect of VEGF inhibitors, corticosteroids, or combination of the two on maculopathy, with focus on the early identification with OCT and early treatment prior to significant visual decline.

Laser photocoagulation has also been investigated in the treatment of radiation retinopathy. As with the treatment of clinically significant macular edema (CSME) from diabetes, focal laser therapy of 19 patients was shown to have an initial effect with improvement in vision and CME at 6 months; however, at 12 and 24 months, there was no significant difference between treated and untreated eyes.¹⁴⁵ In another study with a mean follow-up of 39 months, 12 patients treated with focal laser for CME resulted in 67% with improvement in visual acuity and 50% with resolution in CME.¹⁴⁶ With a mean follow-up of 109 months, 38 patients with CSME were treated with focal laser therapy, revealing that although both treated and untreated groups had a decrease in visual acuity post-plaque treatment, those treated with laser showed a better final vision.¹⁴⁷

In an alternative strategy using laser photocoagulation, Finger and Kurli treated 45 patients that developed radiation retinopathy following plaque brachytherapy with sector laser photocoagulation on the surface of the tumor and 2–3 mm of the margins.¹⁴⁸ With a mean follow-up of 48 months, approximately 65% had regression of radiation retinopathy and 47% had regression of maculopathy. However, almost 47% had loss of ≥3 lines of vision. Interestingly, when 16 tumors were treated prior to the development of radiation retinopathy or maculopathy, only three patients developed radiation complications which regressed with additional laser. Of note, compared with the group that received treatment after development of retinopathy, no (0) patients treated with prophylactic laser lost >3 lines of vision. Laser photocoagulation may have a role in the treatment and prevention of radiation retinopathy, and this study emphasizes the importance of early identification and treatment of radiation complications. Larger studies with additional patients are needed to determine the efficacy of laser treatment for radiation retinopathy.

A novel approach to the prevention of radiation complications has been investigated by Oliver et al.¹⁴⁹ on cadavers. The authors showed that using silicone oil, perfluorocarbons, and other vitreous substitutes, the effective radiation dose could be attenuated, potentially minimizing the effects to the vital eye structures. Although these are only proof of concept studies on cadavers, vitreous attenuators warrant further studies on the potential for protective effects.

Adjuvant therapy

To increase the number of neoplastic cells made nonviable within a choroidal melanoma during treatment and to reduce unwanted complications of radiation, some investigators have suggested the use of adjuvant therapies, including hyperthermia, chemotherapy, and antiangiogenic agents. Transpupillary thermotherapy (TTT) uses a diode laser and near-infrared irradiation. TTT may induce tumor cell necrosis up to 3 mm in depth, and has been investigated as primary treatment for small melanomas;⁶² however, 22% had failure of local tumor control at 3 years, with evidence of extraocular extension in some cases.¹⁵⁰ As a result, TTT has been used more frequently as an adjuvant therapy. Authors propose that adjuvant TTT may allow the use of lower radiation doses in order to decrease the risk for radiation complications, treat larger melanomas, as well as treat juxtapapillary tumors with margins close to the optic nerve precluding adequate plaque coverage of these margins. Additionally, TTT may be used for tumors that fail local control. Shields et al.¹⁵¹ reported on 270 patients with combined plaque brachytherapy and TTT, showing that failure of local control was estimated to be 2% and 3% at 2 and 5 years, respectively. TTT was applied at 4-month intervals in three sessions following treatment with plaque brachytherapy. Other authors have reported on the efficacy of combined treatment,^45,152,153 with a slight trend toward better visual acuity for those treated with adjuvant TTT.⁴⁵ Additionally, adjuvant TTT combined with plaque brachytherapy may be beneficial for juxtapapillary tumors as discussed above.⁸⁷

Choroidal melanoma has been shown to have a unique spatial distribution of vasculature with mature vessels found in the basal aspects of tumors, and immature neovessels radiating apically and peripherally. Vessel maturation was also shown to be associated with histopathologic predictors of poor prognosis. However, with the rich vasculature of these tumors, treatment with antiangiogenic agents has been proposed.¹⁵⁴ Additionally, cell lines of choroidal melanoma have been shown to secrete VEGF,¹⁵⁵ while others have shown increased concentrations of VEGF in the vitreous of eyes with choroidal melanoma.¹³⁸ Missotten et al.¹³⁷ reported increased concentrations of VEGF in choroidal melanomas compared to controls, with significant correlations with increasing tumor height and basal diameter. Interestingly, VEGF concentrations were found to be higher after treatment with plaque brachytherapy. As primary treatment for choroidal melanoma, a small case series reported that antiangiogenic agents when used alone were not effective at delaying tumor progression.¹⁵⁶ However, an interesting pilot study reported on the use of systemic administration of bevacizumab. The two patients treated had complete resolution of exudative retinal detachments, as well as significant decreases (>50%) in tumor height. Neither patient had local or systemic recurrence of choroidal melanoma at 40 and 35 months.¹⁵⁷ Adverse effects were mild, including hypertension, with no heart attacks, strokes, or deaths. Some investigators have proposed adjuvant treatment of choroidal melanoma with intravitreal bevacizumab combined with plaque brachytherapy. However, timing may prove to be an important factor for the efficacy of this treatment. Although treatment prior to plaque placement may result in tumor size reduction, this strategy may be associated with closure of tumor vasculature with resultant hypoxia of tumor cells. Hypoxic cells have been shown to be resistant to radiation therapy and chemotherapy. Other investigators have shown a reduction in tumor size and resolution of exudative retinal detachment when melanomas were treated with intravitreal bevacizumab upon plaque removal. Further studies with more patients and longer follow-up are needed to determine the efficacy and safety of antiangiogenic inhibitors in the treatment of choroidal melanoma.

Conclusion

The COMS Medium Tumor Trial established the use of iodine-125 plaque brachytherapy as a primary globe-salvaging treatment for choroidal melanoma. Plaque brachytherapy and enucleation were shown to have similar rates of melanoma-specific deaths. In addition, small, large, and juxtapapillary tumors have been successfully treated with plaque brachytherapy. Despite eye preservation, visual morbidity is high secondary to radiation-related complications, including radiation maculopathy and optic neuropathy. Alternative radioisotopes have been investigated to minimize treatment-related effects without significant reductions in visual loss. As a result, a better understanding of the mechanisms involved in radiation damage is needed, along with the development of treatment strategies for these visually devastating complications. Current studies emphasize the early identification and treatment of radiation retinopathy in hopes of maintaining useful vision. Radiation therapy, both plaque brachytherapy and proton beam irradiation, have been shown to have comparable results regarding local tumor control, survival/metastasis, and globe-salvage.^74,158–168 However, rates of radiation complications with resultant visual loss remain high regardless of treatment type. Previous studies^97,100 have shown that intraoperative ultrasound provides valuable information regarding plaque placement. Ultrasound may allow for the repositioning of plaques that have tilted, shifted, or inaccurately placed. There has been much debate about the learning curve for plaque placement, including whether ultrasound confirmation is needed in the hands of an experienced ocular oncologist. A study by Shah et al.¹⁶⁹ analyzed the learning curve associated with plaque placement for uveal melanoma over a 20-year period. The authors found that, initially, 21% of plaques required repositioning. This rate decreased to 12% after a period of 10 years, and further decreased to 4% after approximately 20 years. The study estimated that 1275 plaque cases were needed to obtain a precision rate of 90%. A study by Chang et al.¹⁷⁰ demonstrated this learning curve with a report that of 150 patients treated with plaque brachytherapy for uveal melanoma, 36% of patients required plaque repositioning secondary to inadequate placement. Intraoperative ultrasound provides a valuable tool to aid in plaque placement and maximizes the likelihood of local tumor control.