PEER REVIEWED

Radiotherapy in Ocular Oncology: Advances in Brachytherapy for Uveal Melanoma

AMY C. SCHEFLER, MD · TIMOTHY G. MURRAY, MD, MBA · ARNOLD MARKOE, MD, DSC

Uveal melanoma, though the most common primary intraocular malignancy, is a rare disease, with approximately 1200 to 1500 cases reported per year in the United States. Long-term survival rates at major ocular oncology centers have improved over the past 20 years. Predominantly focused on early detection and treatment, local tumor control at major centers is currently in the 90% to 98% range using either radioactive plaque therapy (brachytherapy) or proton-beam radiotherapy. Both therapies have proved to be extremely effective in achieving local tumor control in published series. This article will review some major topics related to radioactive plaque therapy for uveal melanoma.^1,2

HISTORY OF COMS TRIALS

In the 1970s through early 1990s, several nonrandomized clinical trials on patients with choroidal melanoma demonstrated mixed results regarding survival rates of patients after enucleation vs brachytherapy.^3-6 Many investigators also felt that they had observed a peak in mortality after enucleation and attributed this to surgical manipulation, calling into question the role of enucleation.⁷

The Collaborative Ocular Melanoma Study (COMS) trials were created to answer these unresolved treatment controversies. The COMS investigators divided all choroidal melanoma patients into 3 groups based on published data from the early 1980s, which indicated that greater tumor base diameter and apical height were risk factors for metastatic disease and failure after brachytherapy.⁸ Based on the size classification of the patient's lesion, he/she was eligible for enrollment into 1 of the 3 major COMS studies (Table 1).^9-11 At the time of the study planning, the investigators felt that the tumors designated as medium-sized in the COMS classification were large enough to justify treatment (rather than observation) and small enough to be hopeful about success with brachytherapy.¹² Most peripapillary tumors were excluded from this trial because of the investigators' concern that dosimetry calculations would be imprecise and inconsistent among centers (Figure 1). Eligible patients were enrolled in the medium-sized trial, which was a prospective, multicenter study in which patients were randomized to iodine 125 brachytherapy or enucleation.¹⁰ Further discussion follows.

Figure 1. Juxtapapillary/macular uveal melanoma after treatment with iodine 125 brachytherapy. Notice early radiation changes in the form of hard exudates overlying the tumor. Tumors such as this were excluded from the COMS.

ISOTOPES

Iodine 125 for choroidal melanoma was first described by Sealy in 1976.¹³ The major advantages of this design over the previously described technique with cobalt 60 were the ability to protect the surrounding ocular structures, including the eyelids and lacrimal system, and the decrease in radiation exposure to the surgical staff.¹⁴ The isotope was chosen for the COMS trials because of its availability in the United States in a wide range of seed strengths and relative safety due to ease of shielding.^15,16 It also has a favorable half-life, allowing multiple uses prior to disposal.¹⁷

Other isotopes that have been used in the treatment of uveal melanoma include strontium 90, iridium 192, ruthenium 106, and palladium 103 (Table 2). Palladium 103 is also a low gamma emitter and presents a lesser exposure hazard to surgical personnel than cobalt 60. Compared with iodine 125, palladium 103 has a lower energy and a more rapid dose fall-off and thus has been proposed as an alternative to decrease the incidence of complications.¹⁸ Beta emitters such as ruthenium 106 have an even more rapid dose fall-off than palladium 103.¹⁹ Ruthenium 106 minimizes the dose to contralateral structures but delivers a very high dose to the sclera and cannot be used for the treatment of tumors with an apical height greater than 3 to 5 mm. Ruthenium 106 has been the preferred isotope in many centers in Europe.¹⁴ A discussion of the outcomes in patients treated with ruthenium 106 and palladium 103 follows.

PLAQUE CONFIGURATIONS

Radioactive plaques are designed by the radiation physicist prior to surgery based on the ophthalmologist's specifications of tumor configuration and size. The radioactive seeds are housed within a carrier plaque with a thin gold sheet for radiation shielding. Standard plaque diameters are 10, 12, 15, 18, 20, or 22 mm, and they have suture holes that are used to facilitate fixation to the sclera.²⁰ Most ophthalmologists choose to add an extra 1 mm to the tumor height when designing the plaque in order to account for scleral thickness.

Plaques are now manufactured in various shapes, including round, notched, deep notched, rectangular, curvilinear, and doughnut-shaped. Some clinicians use notched plaques for peripapillary tumors to minimize radiation exposure to the optic nerve. Application of the notched plaques requires 3 components: a standard 20 mm notched gold plaque with anteriorly placed eyelets for ease of suturing; a standardized silicone seed carrier, which is available in 10, 12, 15, 18, and 20 mm sizes; and a set of open gold rings available in 10 mm to 18 mm sizes that serve as radiation barriers and echographic localization indicators.²¹

INTRAOPERATIVE TUMOR LOCALIZATION

Tumors that are located posterior to the vascular arcades make plaque placement particularly difficult. Assurance of accurate localization of the radioactive plaque can be achieved with intraoperative ultrasound (Figure 2).²² Localization with ultrasonography may be easier with the radioactive plaque than with a template because the active plaque gives a better acoustic image to the ultrasonographer and delineates the seeds and the insert. The borders of the plaque can be easily visualized by ultrasound enabling an immediate opportunity for repositioning if necessary.

Figure 2. Intraoperative ultrasound localization of iodine 125 plaque to verify adequate treatment of tumor margins. Reprinted with permission.²¹

IODINE 125: TUMOR CONTROL AND PATIENT SURVIVAL

The COMS and others have reported on local control rates and patient survival after brachytherapy with iodine 125 plaques. In the COMS medium-sized tumor trial, the Kaplan-Meier estimate of the 5-year rate of treatment failure was 10.3% and the enucleation rate was 12.5%.²³ Treatment failure was the most common reason for enucleation within 3 years of treatment. After 3 years of follow-up, ocular pain was the most common indication. Risk factors for enucleation were greater tumor thickness, closer proximity of the posterior tumor border to the foveal avascular zone, and poorer baseline visual acuity in the affected eye. Local treatment failure was weakly associated (adjusted risk ratio, 1.5), with reduced survival after controlling for baseline tumor and patient characteristics. This finding was particularly notable since it indicated that there was a beneficial life-saving effect of local treatment when successful, albeit small. This finding was further supported by the natural history study arm of the COMS, an observational report on patients who refused treatment, in which there was a mildly elevated 5-year risk of death for natural history study patients (adjusted risk ratio, 1.54) vs COMS trial patients.²⁴

Mortality rates following iodine 125 brachytherapy in the COMS trial were no different following brachytherapy (81% 5-year survival) than following enucleation (82% 5-year survival) up to 12 years after treatment.¹² The study's power was sufficient to indicate that neither treatment was likely to change mortality rates by as much as 25% relative to the other. Given these findings, clinicians have been able to confidently recommend brachytherapy to patients with appropriate medium-sized melanomas and the use of eyesparing brachytherapy has become more widespread than it was prior to COMS (Figure 3a and 3b).

Figure 3a. A medium-sized melanoma as classified by the COMS criteria prior to treatment.	Figure 3b. Lesion in 3A at 6 months after brachytherapy. Note the early radiation retinopathy.

PALLADIUM 103 VS IODINE 125

Finger et al. have reported on the use of palladium 103 in the United States to treat choroidal melanomas.¹⁸ The seeds are the same size and thus can be used in the same carrier plaque as iodine 125. Compared with iodine 125, palladium 103 has a lower energy and a more rapid dose fall-off,¹⁹ and for this reason, palladium has been proposed as an alternative to iodine 125 in order decrease the incidence of radiation complications.^18,19 Clinical experience with this radioisotope is limited, but small studies indicate low incidence rates of radiation retinopathy.²⁵ More extensive trials using this isotope are required to determine if tumor control rates are comparable to iodine 125. The potential disadvantage of this isotope is that the more rapid fall-off dose could result in a higher tumor recurrence rate.

RUTHENIUM 106 VS IODINE 125

Ruthenium 106 has been used in Europe for several decades. It is a beta emitter that has an even more rapid dose fall-off than palladium 103.¹⁹ Ruthenium 106 minimizes the dose to surrounding and contralateral ocular structures but delivers a very high dose to the sclera if used at a total dose of 120 to 160 Gy to maximize radiation delivery to the tumor. Ruthenium 106 is typically not used for the treatment of tumors with an apical height >3 mm to 5 mm because of an inadequate dose to the tumor apex.

Excellent long-term follow-up studies regarding outcomes in these patients have been published.^26-30 Several authors have reported that local tumor control rates and need for enucleation appear to be inferior with ruthenium 106 compared to iodine 125 (COMS data), especially when apical tumor height is considered.^26-28,30 These failure rates are likely higher because the tumor apex can fall outside of ideal dosimetry (beyond the radiation dose fall-off ).

Five-year all-cause mortality rates appear approximately equal when comparing tumors of equivalent apical height treated with iodine 125 in COMS vs with ruthenium 106. Furthermore, at 10 years of follow-up, Lommatzsch et al. also reported the Kaplan-Meier estimate of melanoma-specific mortality rate for patients treated with ruthenium 106 to be 19% and the equivalent statistic for brachytherapy patients in the COMS medium tumor trial was 18%.^27,31 Again, it must be noted that the mean tumor height in the ruthenium study was 2.7 mm (vs 4.8 mm in the COMS). Given this data, investigators with access to multiple isotopes often report a varied approach in which iodine 125 is used for patients with thicker tumors and ruthenium 106 is favored for thinner, smaller lesions in the hope of achieving better visual acuity outcomes.²⁶

CONCLUSION

Excellent overall 5- and 10-year local control rates in the United States and other developed nations exceed 95% for uveal melanoma treated with modern brachytherapy. Looking forward, clinical controversies that remain unresolved after the COMS include: efficacy/necessity of brachytherapy in patients with small melanomas and best treatment of large melanomas (enucleation or brachytherapy). Furthermore, despite excellent local control rates, visual outcomes in at least half of patients treated with iodine 125 are poor by 5 years after treatment.³² Emerging research on alternative adjunctive therapies for saving vision such as antivascular endothelial growth factor compounds are currently being explored. Finally, effective methods for early detection and treatment of metastatic uveal mela-noma disease are also being pursued since plaque therapy has no impact on preexisting micrometastatic disease.^24,33 RP

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