Brachytherapy for Uveal Melanoma: New Developments and Controversies

AMY C. SCHEFLER, MD ∙ TIMOTHY G. MURRAY, MD, MBA • JERRY A. SHIELDS, MD

The Collaborative Ocular Melanoma Study (COMS) trials, a series of multicenter, randomized clinical studies examining the use of brachytherapy for uveal melanoma, were begun in the US in the late 1980s. Favorable results for cosmesis, short-term preservation of vision, and survival were published in the 1990s for patients treated with brachytherapy. Since then, the use of enucleation has declined and eye-preserving therapies such as brachytherapy and proton-beam radiotherapy have been more widely employed. Nonetheless, many management issues remain unresolved, including indications for brachytherapy in patients with small and large melanomas, indications for adjunctive laser or transpupillary thermotherapy and other new modalities, such as stereotactic radiosurgery, and treatment of radiation-induced side effects. Herein we will highlight several of the aforementioned controversies and questions for future clinical research.

NEW MODALITIES FOR DIAGNOSTIC IMAGING IN CHOROIDAL MELANOMA

One of the clinical challenges in caring for patients with small choroidal melanomas is predicting which lesions will demonstrate growth. Reports have shown that the clinical features associated with tumor growth in small melanocytic lesions include: greater thickness (≥2.0 mm), location closer to the foveola (<3.0 mm), subretinal fluid, and presence of symptoms and orange pigment.¹ Some recent work has focused on the use of OCT to detect small amounts of subretinal fluid adjacent to small lesions. Since subretinal fluid is a known risk factor for growth, OCT may become a more integral modality in follow-up of these patients.

Autofluorescence patterns of small melanomas have also been described recently. Most choroidal melanomas appear to have a pattern of confluent hyperfluoresence, whereas most nevi do not.² Autofluorescence may be a noninvasive tool to assess lipofuscin in these lesions, another risk factor for growth and malignant transformation.³

DIAGNOSTIC APPROACHES

Almost two decades ago, chromosomal abnormalities, including gain or loss of chromosomal material in chromosomes 3, 6, and 8, were detected in primary uveal mela noma tissue and found to be associated with metastasis.⁴ Monosomy 3 in uveal melanoma was subsequently shown to be a statistically significant predictor of both relapse-free and overall survival.⁵ It is associated with metastatic disease, with one study demonstrating that 57% of patients with monosomy 3 developed metastases within three years, while no patients with disomy 3 developed metastatic disease⁵ (Figures 1A and 1B).

Onken et al. examined global gene expression patterns of 3,075 genes in 25 enucleated eyes.⁶ The authors identified two tumor groups: class 1 (low grade) and class 2 (high grade). Class 2 tumors demonstrated downregulated gene clusters on chromosome 3 and upregulated clusters on chromosome 8q. These classifications strongly predict metastatic death with a 95% Kaplan-Meier–based survival prediction at 92 months of 95% in class 1 and 31% in class 2. Onken et al. demonstrated that these classifications outperformed other prognostic indicators. Other groups have observed a strong association between monosomy 3 and expression of various proteins such as HSP-27.⁷

Over the past five years, the number of clinical centers performing karyotyping, single nucleotide polymorphism analysis, fluorescent in situ hybridization (FISH) analysis, and/or comparative genomic hybridization on fine needle aspiration and enucleation specimens has increased dramatically. Some groups have also begun to perform FISH or microsatellite array on fine needle aspiration biopsy specimens as well.^8,9 Biopsies have been attempted via pars plana and trans-scleral approaches. Some authors have reported that heterogeneity of gene expression patterns in different tumor areas may cause inconsistent results.¹⁰ Nonetheless, in recent series, sufficient tissue material for diagnosis was obtained for FISH in 98% of cases and for microsatellite assay in 86% of cases.^8,9

Figure 1A. A 55-year-old female at presentation with medium sized nasal melanoma. The lesion measured 2.9 mm in apical thickness and 14.5 by 12.5 mm in basal dimensions. She underwent iodine 125 brachytherapy and retained 20/20 vision for more than two years.

Figure 1B. After two years of follow-up, the patient developed an acute central retinal artery occlusion. On presentation to the emergency room, her vision had dropped to hand motion. The patient's presumed tumor-related hypercoagulable state led to an embolic event. CRAO is an uncommon event after brachytherapy, but this patient's case underscores the need for better systemic therapy for patients given the fact that many of them, like this patient, likely have systemic micrometastases at the time of diagnosis. One month after the CRAO, her vision was 5/200 E. The patient now takes systemic anti-coagulation medication.

As new treatments or prophylactic drugs for metastatic melanoma are developed and available for clinical trials, it will be important to identify which patients are appropriate for entry into such studies. Furthermore, recent studies have indicated that patients report a desire for prognostic information even in the absence of the availability of definitive treatments for metastatic disease.¹¹

CHANGING INDICATIONS FOR TREATMENT

• Treatment of small melanomas. COMS medium tumor trial was published in the early 2000s. The initial trial results demonstrated that five-year mortality rates after brachytherapy were statistically equivalent to those after enucleation. The tumor size requirements for his trial were 2.5 to 10 mm in apical height and >16 mm in largest basal diameter. However, since the completion of the COMS, many investigators have raised the question of whether melanomas smaller than these should also be treated with brachytherapy. Although the COMS observational study of small melanomas indicated that the long-term mortality rate for these patients is low (eight-year all-cause mortality of 14.9%),¹² many feel it may be significant enough to justify the consideration of brachytherapy in these patients, particularly in patients with high-risk clinical features.¹³

Sobrin et al. reported a 3.9% (95% confidence interval, 0-11.2%) melanoma-specific five-year mortality rate in patients with small melanomas who were observed and then treated with iodine 125 brachytherapy at the time of either observed growth or development of orange pigment.¹⁴ The only other study examining this group of patients reported a five-year melanoma-specific mortality rate of 5.8%.¹⁵ The melanoma-specific five-year mortality rate for the tumors in the COMS small tumor study was 1%,¹² but calculation of this rate included a large number of patients whose suspected tumors did not grow, were never treated, and are therefore at lower metastatic risk than the patients in the other studies. Moreover, there were no defined criteria or threshold for treatment in the COMS small-tumor trial and this group may have included patients whose lesions demonstrated no growth or high-risk features. The treated group in the COMS thus must have had a higher death rate, but this was not calculated in the report.

Shields et al. reported on the use of transpupillary ther-motherapy as monotherapy for small choroidal melanomas.¹⁶ After a mean of three treatment sessions, complete tumor control without recurrence was found in 232 cases (91%) and recurrence in 24 cases (9%). Patients with tumors abutting or overhanging the optic disc or those requiring more than three sessions for tumor control were more likely to develop ultimate tumor recurrence.

A randomized, prospective trial of visual and survival outcomes in patients managed by observation vs prompt treatment is needed to answer this critical question.¹⁴ Singh et al. have proposed such a multicenter clinical trial.¹⁷

• Treatment of large melanomas. Investigators are also experimenting with the use of plaques for patients with large tumors^19,20 (Figure 2). Many authors have argued that micrometastases are thought to develop before the diagnosis of the primary tumor in patients with large sized tumors, so enucleation may offer limited or no survival benefit, making a vision-sparing treatment worthwhile.¹⁸ Available data are limited and comparisons are difficult based on the collection of different outcome variables.

Shields et al.¹⁹ have reported on the largest series of large melanoma patients. Three hundred fifty-four patients with tumors larger than 8 mm in apical height who underwent iodine 125 brachytherapy had a 10-year Kaplan-Meier estimated metastasis rate of 55% vs the COMS equivalent large-tumor trial statistic of 46%. Puusari et al.¹⁸ treated 97 patients with large tumors (based on COMS criteria) with iodine 125 brachytherapy. They found a Kaplan-Meier estimated eight-year melanoma-specific mortality rate of 46% vs the COMS equivalent statistic of 40% at 10 years in the enucleation arm of the large-tumor trial.²⁰

These results indicate that brachytherapy may carry a greater risk of mortality by 10 years post-treatment, but a large, randomized study with extended follow-up examining this controversy would be necessary to resolve this question.

• Treatment of peripapillary melanomas. In the COMS medium-tumor trial, patients with peripapillary/juxta-papillary choroidal melanomas were excluded based on the fact that they were considered to have higher than average risk for tumor recurrence and distant metastases. Recently, several groups have explored the use of several treatment modalities for these patients. Shields et al. treated 141 consecutive patients with juxtapapillary melanomas overhanging the optic disc head with iodine 125 and cobalt 60 plaques that were notched or round.²¹ Complications included nonproliferative retinopathy in 61 eyes (51%), proliferative retinopathy in 26 (22%), maculopathy in 44 (37%), papillopathy in 57 (48%), neovascular glaucoma in 23 (19%), and vitreous hemorrhage in 48 (40%). Enucleation was necessary in 27 eyes (23%), and tumor recurrence was found in 12 eyes (10%), with metastases in 15 patients (13%) and death in four cases (3%).

Recently, Krema et al. reported the use of stereotactic radiotherapy for 64 patients with juxtapapillary melanomas.²² At 37 months of follow-up, the local tumor control rate was 94%, the rate of metastatic disease was 15%, and the survival rate was 90%. Radiation-induced complications were: neovascular glaucoma (42%), cataract (53%), retinopathy (81%), and optic neuropathy (64%). Secondary enucleation was necessary for 10 patients (16%), in four patients for tumor recurrence and in six for painful neovascular glaucoma. These two retrospective studies indicate that current management of juxtapapillary tumors can be successful with multiple modalities, but not without significant ocular and visual side effects. Experimental modalities to treat these lesions in a manner that results in more preservation of vision is needed.

ADJUNCTIVE THERAPIES

Several investigators have reported the use of argon laser or transpupillary thermotherapy in combination with plaque radiotherapy with the goal of ensuring better local tumor control, especially for tumors located near the optic nerve and fovea.^23-27 The largest of these studies, by Shields et al., examined the local tumor control rates in 270 patients treated with iodine 125 plaque therapy, followed by three sessions of transpupillary thermotherapy administered at plaque removal and at four-month intervals.²⁶ The tumors were medium sized on average, based on COMS size criteria. Kaplan-Meier estimates of tumor recurrence were 2% at two years and 3% at five years. These local control rates appear to be higher than those observed in the COMS (10.3% failure at five years) but cannot be compared easily due to short follow-up time in the Shields et al. study.

When compared with patients treated with radioactive plaque therapy alone, tumors treated with radioactive plaques and argon laser appear to regress faster but result in more short-term visual acuity loss.²⁷ Larger randomized prospective trials are needed comparing radioactive plaque therapy alone to plaque therapy with adjunctive laser and/or transpupillary thermotherapy.

NEW TREATMENTS FOR RADIATION RETINOPATHY

The most visually significant and common late postoperative complication of brachytherapy in choroidal melanoma patients is radiation retinopathy. Radiation retinopathy is a slowly progressive, occlusive vasculopathy characterized by radiation-induced endothelial damage. Gunduz et al. reported, by Kaplan-Meier analysis, rates of nonproliferative and proliferative radiation retinopathy at five years of 42% and 8%, respectively²⁸ Risk factors for the development of nonproliferative radiation retinopathy include tumor margin of less than 4 mm from the fovea and radiation dose rate of greater than 260 cGy/hour to the tumor base.²⁸ Risk factors for the development of proliferative radiation retinopathy include diabetes and tumor base greater than 10 mm.²⁸

Figure 2. Large inferior uveal melanoma with associated serous retinal detachment. Many clinicians are currently treating these patients with plaque therapy to improve their quality of life since their long-term survival is likely not affected by the local therapy they receive.

Panretinal photocoagulation (PRP) can be used for radiation retinopathy when proliferative disease is present.²⁹ A small study reviewed the effect of performing prophylactic PRP prior to the development of clinically evident radiation retinopathy. None of the patients lost more than three lines of vision.³⁰ Macular edema can be managed with focal grid laser and intravitreal triamcinolone, although the effect of these treatments is often temporary.³¹

Recently investigators have begun experimenting with intravitreal injections of anti-vascular endothelial growth factor compounds such as bevacizumab (Avastin, Genentech, Inc.) to treat radiation retinopathy in patients treated with iodine 125,^32,33 palladium 103,³⁴ and ruthenium 106.³⁵ These studies contained very few patients and short follow-up. Our unpublished experience with over 100 patients indicates that bevacizumab is very effective in achieving short-term resolution of macular edema due to radiation retinopathy, but long-term data on this treatment are not yet available.

CONCLUSION

Many controversies remain unsolved in the treatment of uveal melanoma. Patients who present the greatest challenge to the ocular oncologist include those with: juxtapapillary tumors, tumors too small or large to meet traditional COMS size criteria, and tumors associated with severe radiation-related complications after treatment. Some new pharmaco therapies such as bevacizumab and expanding indications for brachytherapy are extending our ability to care for these patients, but more collaborative clinical trials are needed. RP

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