Overview
Choroidal melanoma is the most common primary malignant intraocular tumor with an annual incidence in the USA of 0.8 cases per 100 000 population. Once metastasis becomes clinically apparent, the 1-year mortality rate approaches 80%. Given this poor prognosis, enucleation was historically considered the only appropriate management for choroidal melanoma. However, in recent decades there have been many new developments in management, with a trend toward more conservative therapeutic methods. The impetus for this shift in paradigm was the proposition by Zimmerman et al that enucleation may in fact promote metastasis by intraoperative dissemination of tumor emboli. The transient rise in post-therapeutic mortality that prompted this theory has been validated over the ensuing 25 years, but is now believed to be attributable to prediagnosis and treatment micrometastasis in uveal melanoma. Therapeutic options have since expanded to include transpupillary thermotherapy (TTT), plaque radiotherapy, charged-particle irradiation, local resection, and observation.
The Collaborative Ocular Melanoma Study (COMS) is the first set of randomized clinical trials designed with sufficient power to detect a difference in survival outcomes between treatment modalities. Between 1986 and 1994, investigators screened 6078 patients at 43 clinical centers, placing each eligible subject into one of three categories: small, medium, or large choroidal melanoma ( Figure 51.1 ). Specifically, small tumors were defined as less than 2.5 mm in apical height. Tumors between 2.5 and 10 mm in apical height and no more than 16 mm in basal diameter were classified as medium, and those greater than 16 mm in basal diameter were classified as large. Herein, we review management options for each of these size classifications, as evaluated by the COMS and other clinical studies.
Small choroidal melanoma
Of the three sizes of choroidal melanoma, treatment of small-sized tumors is most controversial. This is due in large part to the inability to differentiate reliably suspicious nevi from true cancers, with consequential limited understanding of the natural history and metastatic potential of such tumors.
Natural history
Five risk factors for growth were identified in a retrospective review of 1329 patients with choroidal tumors less than 3 mm in thickness. By multivariate analysis each of these clinical features (greater tumor thickness, orange pigment, symptoms of blurred vision or flashes/floaters, subretinal fluid, posterior margin touching the optic disc) was found independently to increase the relative risk of growth ( Box 51.2 ). Further, documented growth was predictive of metastasis. Another retrospective series found not only tumor thickness, orange pigment, and presence of symptoms but also hot spots on fluorescein angiogram and internal quiet zone on B-scan to be significant predictors of growth. Stratification of treatment based upon risk factors has been suggested to optimize management, but studies have failed to show a treatment benefit with respect to mortality.
Small choroidal melanocytic lesions will exhibit growth in 18–36% of cases and metastasis in 2–5% of cases when followed for at least 5 years. Given a lack of tumor-related mortality in cases that failed to exhibit growth, it has been argued that indeterminate lesions may be observed and treated only if growth is documented.
Transpupillary thermotherapy (TTT)
TTT is a technique by which a 3 mm diode laser beam introduced through the pupil heats the tumor to 60–65°F for 1 minute. In contrast to photocoagulation, which has been abandoned due to inadequate tumor control, TTT raises the tumor to a lower temperature but achieves a greater depth of tumor necrosis. Tumor necrosis is due primarily to the direct thermal effect of the laser, with secondary effect from ischemia due to vascular occlusion. TTT is contraindicated in patients with media opacity, peripheral tumor, significant subretinal fluid, and small pupil.
Originally introduced as monotherapy for choroidal melanoma in 1994, TTT was designed to spare patients the visual morbidity that plaque brachytherapy was known to impart. Early results were encouraging, with tumor control achieved in 91% of cases after a mean of three treatment sessions. However, Kaplan–Meier estimates revealed recurrence rates of 4% at 1 year, 12% at 2 years, and 22% at 3 years of follow-up. Further, a lack of benefit with respect to visual outcomes was demonstrated in a case-matched retrospective comparison of TTT monotherapy with plaque brachytherapy, which has more reliable tumor control rates. Clinicopathologic examination of eyes enucleated after failed TTT suggests high rates of extrascleral extension, in most cases undetectable on ultrasonography. Minor degrees of extraocular extension are expected to be locally controlled by brachytherapy. TTT is thus best employed as an adjunct to plaque brachytherapy, with TTT necrosing superficial tumor and plaque radiation necrosing tumor adjacent to and invading sclera. One study reported 93.8% local tumor control rate with combination therapy with brachytherapy and adjunctive TTT over a mean follow-up period of 5 years.
COMS small tumor trial
As part of the COMS, an observational study of small choroidal melanomas was undertaken with the goal of assessing tumor growth (defined as increase from small to either medium or large) and its impact on survival. Probability of growth by Kaplan–Meier analysis was 11%, 21%, and 31% at 1, 2, and 5 years following enrollment ( Figure 51.2A ; Box 51.1 ). Clinical features associated with tumor growth included prominent orange pigment, absence of drusen, absence of retinal pigment epithelium changes adjacent to the tumor, tumor thickness of at least 2 mm, and largest basal diameter of 12 mm or more ( Box 51.2 ). Though only 16 of the 204 patients received treatment, the risk of death was low, with the authors reporting a Kaplan–Meier melanoma-related mortality of 1% at 5 years ( Figure 51.2B ). All-cause mortality was higher, with patients are three to four times more likely to die of some competing cause than of their melanoma.
- •
< 2.5 mm in apical height
- •
At 5-year follow-up, probability 31% of growth is 18–36% and metastasis is 2–5%
- •
Decision to treat or observe is controversial
- •
Monotherapy with transpupillary thermotherapy (TTT) lacks benefit with respect to local tumor recurrence or visual outcomes
- •
Favorable local recurrence rates have been achieved with brachytherapy (±TTT)
- •
Greater tumor thickness, basal diameter
- •
Absence of drusen
- •
Orange pigment
- •
Symptoms of blurred vision or flashes/floaters
- •
Absence of RPE changes adjacent to the tumor
- •
Subretinal fluid
- •
Posterior margin touching the optic disc
Medium choroidal melanoma
A large body of literature attests to the efficacy of radiotherapy (either external-beam radiation therapy (EBRT) or episcleral plaque therapy) in the treatment of medium-sized choroidal melanoma. The COMS trial for medium-sized melanomas (discussed in detail below) concluded that sight-conserving brachytherapy does not adversely affect survival outcomes when compared with enucleation. Since the globe and some vision can usually be maintained, radiotherapy has become the mainstay for sight-preserving treatment of medium- and large-sized choroidal melanoma.
Plaque brachytherapy
Brachytherapy is the most commonly used radiation modality for the treatment of choroidal melanoma. A bowl-shaped heavy-metal plaque implanted with a radioactive isotope ( Figure 51.3 ), sized to exceed tumor margins by 2 mm, is sutured to episclera for a period of up to 1 week with the goal of delivering 80–100 Gy to the tumor apex. Plaques implanted with cobalt-60 were introduced in the 1960s; however, visual morbidity was high due to substantial radiation dosage to surrounding ocular structures by virtue of the high-energy emission properties of Co-60 which do not permit adequate shielding. Favorable long-term tumor control rates and improved visual outcomes have since been demonstrated with several other isotopes. Iodine-125 brachytherapy was evaluated by the COMS (discussed below) and as a result has become the most common isotope used in North America. One-half millimeter of gold can shield the I-125 source whereas equivalent shielding of Co-60 requires 2 meters or 6 foot of lead. Ruthenium-106, a beta-emitter, was concurrently popularized in Europe during the Cold War, and has since been adopted by some centers in the USA due to the theoretical decreased risk in visual morbidity suggested by dosimetry studies. A total of 579 patients in Sweden treated with ruthenium-106 for choroidal melanoma less than 7 mm in diameter (9.2% classified as “large” by COMS standard) enjoyed a 5-year tumor-specific survival rate of 94.9%. Other large studies have noted 82–84% overall (all-cause) 5-year survival rates with ruthenium-106. Strontium-90 and palladium-103 have been shown to produce local tumor control rates of 92% and 96% at 5-year follow-up. Due to the large sample size required to detect a difference between treatment outcomes with different isotopes, no randomized trials have been undertaken. Figure 51.4 shows a medium melanoma before and 1 year after treatment with iodine brachytherapy.
Brachytherapy versus enucleation
The COMS randomized 1317 patients with choroidal melanoma classified as medium-sized to receive either I-125 brachytherapy or enucleation ( Figure 51.1 and Box 51.3 ). Eligible patients were free of metastasis at enrollment. Follow-up is ongoing via periodic queries to the National Death Index, though formal clinical follow-up has ended. The 5-, 10-, and 12-year rates of death with histopathologically confirmed melanoma metastasis were similar for I-125 brachytherapy (10%, 18%, and 21%) and enucleation (11%, 17%, and 17%) ( Figure 51.5 ). Further, a trend towards increased 5-year risk of death for patients who were eligible for the COMS but deferred treatment when compared with COMS trial patients suggested a life-extending effect of treatment of medium- and large-sized melanomas.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
