Treatment Option Overview
Role of Observation
Iris melanomas have relatively good outcomes with a 5-year survival rate of more than 95%. They are predominantly of the spindle-cell type and are usually smaller in size than posterior melanomas because of earlier detection. Conservative management is generally advocated whenever possible, but surgical intervention may be justified with unequivocal tumor growth or with extensive disease at initial examination.
The management of small choroidal melanomas is controversial, and it is not clear whether treatment of small tumors prevents metastasis. The natural history of small choroidal melanoma is poorly understood. Small, pigmented, choroidal lesions cannot always be differentiated reliably on examination. Growth is a presumed indicator of malignant potential. The likelihood of progression from the time of diagnosis to the time when tumor growth warrants treatment has not been well characterized. Some ophthalmologists advocate observation. This has been justified on several grounds, including the difficulty with establishing a correct diagnosis, the lack of any documented efficacy for globe-conserving treatments, and concerns for severe treatment-related morbidity. Others have advocated earlier therapeutic intervention.[1,3,4]
Although patients diagnosed with small choroidal tumors were not eligible for participation in the Collaborative Ocular Melanoma Study (COMS), these patients were offered participation in a prospective follow-up study to evaluate the natural history of small lesions. Two-year and 5-year tumor growth estimates of 21% and 31%, respectively, were reported. Clinical risk factors associated with tumor growth included:[3,5]
- Increased tumor thickness.
- Presence of subretinal fluid.
- Orange pigmentation.
- Absence of drusen.
- Absence of retinal pigment.
- Margin at the optic disc.
- Epithelial changes surrounding the tumor.
Role of Surgery
The selection of treatment depends on the following:
- Site of origin (choroid, ciliary body, or iris).
- Size and location of the lesion.
- Age of the patient.
- Occurrence of extraocular invasion, recurrence, or metastasis.
In the past, enucleation (eye removal) was the standard treatment for primary choroidal melanoma, and it is still used for large tumors. However, enucleation has been largely replaced by radiation therapy (i.e., brachytherapy with radioactive plaques; or external-beam, charged-particle radiation therapy) to spare the affected eye.[6,7]
Pre-enucleation external beam radiation therapy (EBRT)
In the case of large, choroidal tumors judged to require enucleation, the role of pre-enucleation EBRT was tested in a randomized trial and had no impact on overall survival (OS).[8,9][Level of evidence: 1iiA] In a COMS trial, 1,003 patients with large choroidal melanomas (≥2 mm in height and ≥16 mm in diameter, or ≥10 mm in height irrespective of diameter, or ≥8 mm in height and border <2 mm from the optic disc) with no known metastases were randomly assigned to receive enucleation alone or after preoperative external photon-beam radiation from cobalt 60 or accelerators (20 Gy in five daily fractions) to the orbit and globe.[8,9] Through 10 years of follow-up, the median survival in both arms was approximately 7 years, and the 10-year all-cause mortality was 61% in both arms (relative risk for death of 1.00; 95% CI, 0.85–1.18). Metastasis-free survival was also virtually identical in both arms.
Transscleral local resection
Eye-sparing transscleral local resection plays a very limited role in the management of uveal melanoma. It is used in patients with large choroidal and ciliary body tumors who are not candidates for radiation therapy but are highly motivated to retain their eye.[10-12] The procedure is technically demanding and is generally performed only in centers with specialized expertise in this surgery. There is a substantial risk of retinal detachment, intraocular bleeding, and complications associated with the anesthesia-induced hypotension used to decrease the risk of bleeding. Adjuvant brachytherapy or neoadjuvant proton-beam therapy is often administered. Experience is limited to retrospective, single-center, case series.[10-12][Level of evidence: 3iiiDiv]
Surgical resection of metastases
Surgical resection of metastases from ocular melanoma has been reported in case series of highly selected patients with occasional favorable outcomes.[13,14] However, the favorable outcomes may be the result of strong patient-selection factors, and the role of resection in this setting is unclear.[13,14][Level of evidence: 3iiiDiv]
Role of Radiation Therapy
Episcleral brachytherapy using plaques containing small radioactive “seeds” is the most common form of radiation used in the management of intraocular melanoma. Iodine-125 (125I), cobalt-60 (60Co), palladium-103 (103Pd), iridium-192 (192Ir) and ruthenium-106 (106Ru) are examples of radioactive isotopes used in the brachytherapy plaques. Isotopes with relatively low photon and electron emissions (125I, 103Pd, and 106Ru) are more easily shielded to reduce the exposure to adjacent normal tissues, and 125I is probably the most commonly used radioisotope. Although plaque radiation therapy allows preservation of the eye, visual acuity is frequently lost over time.
In a case series of 1,106 patients who were treated with plaque radiation therapy for uveal melanoma and who had an initial acuity of at least 20/100, 68% developed poor acuity (i.e., 20/200 or worse) within 10 years.
Factors associated with worse acuity outcomes included the following:
- Age older than 60 years.
- Diminished baseline acuity.
- Increased tumor size and thickness.
- Location near the fovea or optic disc.
- isotope (106Ru, 60Co, or 192Ir vs. 125I).
125I brachytherapy yields equivalent overall and melanoma metastasis-specific survival rates to enucleation for medium-sized melanomas.[Level of evidence: 1iiA] The randomized COMS Medium Tumor Trial compared 125I episcleral-plaque brachytherapy (85 Gy at 0.42–1.06 Gy/hr) to enucleation in 1,317 patients with medium-sized choroidal tumors (tumor height 2.5 mm–10.0 mm and tumor diameter ≤16.0 mm that were not contiguous with the optic disc). Eighty-five percent of the patients treated with 125I brachytherapy retained their eye for 5 years or more, and 37% of them had visual acuity better than 20/200 in the irradiated eye 5 years after treatment. No statistically significant differences in mortality were observed between the two study arms after 12 years of follow-up, whether considering death from all causes or death with histopathologically confirmed melanoma metastasis. Five- and 10-year all-cause mortality rates were 19% and 35% in both study arms; cumulative all-cause mortality at 12 years was 43% in the 125I arm versus 41% in the enucleation arm (RR, 1.04; 95% CI, 0.86–1.24). Five-year metastasis-specific mortality rates were 13% in both arms; at 10 years, the rates were 21% and 22% (RR for metastasis-specific mortality, 1.07; 95% CI, 0.81–1.41 through 12 years).
In a companion study within the COMS, 209 patients were prospectively assessed for quality of life during the first 5 years of follow-up. Both study groups reported increasing difficulty with vision-oriented daily activities and ocular pain as time elapsed. Most measures of visual function were similar between the two groups, but there were statistically significant differences favoring the brachytherapy group in comfort with driving for the first year after therapy and in reported peripheral vision for the first two years after therapy. These differences disappeared by year 5 of follow-up.[Level of evidence: 1iiC]
Charged-particle EBRT (using protons, carbon ions, or helium ions) is the other major form of radiation therapy used in the management of ocular melanomas.[20-23] This form of radiation therapy requires sophisticated equipment available only at selected centers, and charged-particle EBRT involves patient cooperation during treatment (e.g., voluntarily fixating the eye on a particular point so the tumor is positioned properly in the radiation beam). A lower risk of early and late local radiation failures has been reported after charged-particle EBRT than after brachytherapy, possibly resulting from differences in dose distribution of the two techniques.[Levels of evidence: 1iiDiv and 3iiiDiv]
In a single-center, single-surgeon study 184 patients with uveal melanomas smaller than 15 mm in diameter and smaller than 10 mm in thickness were randomly assigned to receive 125I brachytherapy versus helium ion radiation (to an estimated dose of 70 Gy equivalents in five fractions over 7 to 11 days in each arm). The local tumor regrowth rate by 4 years was 13.3% in the brachytherapy arm versus 0% in the helium ion arm (P < .001). However, the rates of metastasis, death from metastasis, and overall mortality was very similar in both arms.[Level of evidence: 1iiDiv]
Because of its dose distribution, charged-particle irradiation can be used to treat larger tumors and tumors closer to the fovea or optic disc than plaque brachytherapy. A large, single-center, single-surgeon series of 2,069 patients treated with proton-beam therapy had an actuarial local control rate of 95% (95% CI, 93%–96%) at 15 years. The cumulative rate of enucleation was 16% (95% CI, 13%–20%), most frequently as a result of neovascular glaucoma, blind uncomfortable eyes, or local recurrence (46%, 31%, and 23% of enucleations). As with plaque radiation, risk factors for deterioration in visual acuity after charged-particle radiation were tumor size, location near the fovea or optic disc, baseline acuity, and underlying diabetes.
Similarly, another large, single-center, single-surgeon, consecutive series of 886 patients treated with proton-beam irradiation reported a local control rate of 92.1% (95% CI, 89.8%–94.6%) and ocular conservation rate of 87.3% (95% CI, 83.9%–90.9%) at 10 years.][Level of evidence: 3iiDiv] The actuarial OS at 10 years was 64.1% (95% CI, 59.5%–69.0%).
In a single-center, phase I/II study of 57 evaluable patients treated with carbon ion-beam irradiation and followed for a median of 26 months, 26 patients developed neovascular glaucoma or severe eye pain from increased intraocular pressure, and 3 patients had enucleation. One patient had a local tumor recurrence.
In an attempt to lower the complication rate and improve functional outcome, a decreased dose of 50 cobalt Gy equivalents (CGE) has been compared to 70 CGE proton beam (each delivered in 5 fractions, usually within a 7-day period). Patients (n = 188) with tumors smaller than 15 mm in diameter and smaller than 5 mm in height that were located near the optic disc or macula were randomly assigned to the two doses in a double-masked study design. At 5 years, there were no statistically significant differences in local tumor control, rate of metastasis, visual acuity, or complication rates. However, the visual fields were better in the 50 CGE group.[Level of evidence: 1iDiv]
As noted above in the section on the Role of Surgery in the Treatment Option Overview section of this summary, the role of pre-enucleation external photon-beam radiation therapy has been tested in a randomized trial and has shown no impact on OS for large choroidal tumors treated with enucleation.[8,9]
External-beam–photon-beam (gamma-ray) radiation therapy with gamma-knife stereotactic radiation surgery as a single-fraction  or fractionated stereotactic radiation [27,28] is being investigated as an alternative to brachytherapy or charged-beam radiation for posterior uveal melanomas, particularly for tumors too large or too close to the optic disc or macula to treat with brachytherapy. Because the dose rate of radiation delivery is slower than is the case with charged particles, specialized techniques are used to immobilize the eye  or to avoid delivery of the photons while the eye is moving or closed. Experience is more limited with external-beam–photon therapy than for either brachytherapy or charged-particle EBRT, and there are no controlled comparisons to either of the other techniques. Early results from single-center series suggest similar levels of local tumor control and eye retention rates, but patient-selection factors may play a role.[Level of evidence: 3iiiDiv]
Role of Transpupillary Thermotherapy
Transpupillary thermotherapy (TTT) directs an infrared laser, usually at a wavelength of 810 nm, through a dilated pupil in one or more sessions to induce heat necrosis of uveal melanomas. This method carries the theoretical advantage of high-precision destruction of tumor tissue under direct visualization. However, TTT has important limitations that confine its use to very restricted circumstances.[1,29] The limited ability of TTT to penetrate thick tumors with sufficient energy restricts its use to small melanomas, or tumors of a size that some ophthalmologists recommend for follow-up without any initial therapy. (Refer to the Role of Observation section in the Treatment Option Overview section of this summary for more information.) When used as the primary therapy, there are relatively high rates of local recurrence and retinal vascular damage. Recurrence rates are particularly high when the tumor abuts the optic nerve and overhangs the optic disc.[Level of evidence: 3iiiDiv]
In a single-center study, 95 patients with small choroidal melanomas (diameter <10 mm and thickness <3.5 mm) were randomly assigned to TTT versus 125I brachytherapy (100 Gy). The tumor regression rates in the TTT and 125I arms were 92% and 98%, respectively (P = .4). With a mean follow-up time of 56.2 months, there were four recurrences in the TTT arm and one in the 125I arm. However, the study is too small to provide clear information on efficacy differences.
TTT is also under evaluation as an adjunct to primary therapy with proton-beam radiation. In the setting of large uveal melanomas, proton-beam therapy is associated with exudative, inflammatory, and glaucomatous complications that may require enucleation. In a single-center trial, 151 patients with uveal melanomas at least 7 mm thick or at least 15 mm in diameter were randomly assigned to receive proton-beam radiation (60 CGEs over four daily fractions) with or without TTT (810 nm wavelength at 1, 6, and 12 months after therapy) and followed for a median of 38 months. There were no differences between the two groups in maculopathy, papillopathy, or glaucoma. The enucleation rate was lower in the TTT group (about 2% vs. 18% at 5 years, P = .02). However, the study was not masked, and replication would be important.
There are uncertainties regarding the optimal management of intraocular melanoma at all stages. Physicians should discuss with eligible patients opportunities for entry into ongoing clinical trials. Information about ongoing clinical trials is available from the NCI Web site.
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- Shields CL, Cater J, Shields JA, et al.: Combination of clinical factors predictive of growth of small choroidal melanocytic tumors. Arch Ophthalmol 118 (3): 360-4, 2000. [PUBMED Abstract]
- Robertson DM, Buettner H, Bennett SR: Transpupillary thermotherapy as primary treatment for small choroidal melanomas. Arch Ophthalmol 117 (11): 1512-9, 1999. [PUBMED Abstract]
- Factors predictive of growth and treatment of small choroidal melanoma: COMS Report No. 5. The Collaborative Ocular Melanoma Study Group. Arch Ophthalmol 115 (12): 1537-44, 1997. [PUBMED Abstract]
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- Hsueh EC, Essner R, Foshag LJ, et al.: Prolonged survival after complete resection of metastases from intraocular melanoma. Cancer 100 (1): 122-9, 2004. [PUBMED Abstract]
- Pawlik TM, Zorzi D, Abdalla EK, et al.: Hepatic resection for metastatic melanoma: distinct patterns of recurrence and prognosis for ocular versus cutaneous disease. Ann Surg Oncol 13 (5): 712-20, 2006. [PUBMED Abstract]
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- Shields CL, Shields JA, Cater J, et al.: Plaque radiotherapy for uveal melanoma: long-term visual outcome in 1106 consecutive patients. Arch Ophthalmol 118 (9): 1219-28, 2000. [PUBMED Abstract]
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