Management of Choroidal Melanoma and Ciliary Body Melanoma
Uveal melanoma is a malignant tumor arising from melanocytes in the uveal tract (iris, ciliary body, or choroid). It is the most common primary intraocular tumor in adults and is most frequently derived from the choroid. There is a strong tendency for metastasis, particularly to the liver, and prognosis is poor when the tumor has disseminated. This article focuses on the treatment of posterior (ciliary body and choroidal) uveal melanoma. The treatment of anterior (iris) melanoma or conjunctival melanoma is discussed elsewhere.
Depending upon several clinical factors, management options today include observation, radiation, laser, surgery, medical management, or a combination of these approaches. The selected management depends on size, thickness, location, and activity of the tumor, the status of the opposite eye, and the age, general health, and psychological status of the patient. Each patient should have a detailed ophthalmic evaluation and the size and extent of the tumor carefully documented with drawings, color fundus photography, and ultrasonography. The known risk factors for growth and metastasis should be considered and therapeutic options should be discussed. The potential effects of the treatment on a patient’s life prognosis, quality of life, tolerance to the proposed treatment, and expected visual outcome are important considerations.
For centuries, immediate enucleation was believed to be the best treatment for an eye with uveal melanoma. However, despite high rates of enucleation, mortality remained high due to metastases to the liver and other sites. In the late 1970s, some authorities challenged the efficacy of enucleation for preventing metastatic disease and even proposed that enucleation may promote or accelerate metastasis. The validity of these arguments was challenged by others, who believed that early enucleation offered the patient the best chance of cure. This controversy was responsible for initiating a trend away from enucleation and increasing the use of more conservative, eye-sparing approaches. In 1985, the landmark Collaborative Ocular Melanoma Study (COMS) was organized to address issues regarding the treatment of uveal melanoma. The COMS answered many questions about the demographics, natural history, pathophysiology, and treatment of choroidal melanoma. More recently, key prognostic risk factors have been identified, with tumor thickness being one of the most important. As metastatic risk has been observed with increasing millimeter tumor thickness, early intervention is advised for posterior uveal melanomas.
The goals of treating uveal melanoma is to achieve the following:
- Preservation of useful vision in the affected eye
- Tumor destruction
- Prevention of metastasis and recurrence
A choroidal nevus is a well-circumscribed, benign melanocytic tumor that is managed by periodic observation. They typically appear as small (less than 2 mm thick, asymptomatic, and with overlying retinal pigment epithelial atrophy and drusen, signifying a chronic condition. Approximately 6% of the Caucasian population manifests a choroidal nevus. About 1 in 5000 to 1 in 8800 choroidal nevi evolve into choroidal melanoma. Generally, some choroidal nevi are difficult to distinguish from small choroidal melanomas. Recent studies have identified high risk features predictive of growth in concerning choroidal nevi that can be remembered using the mnemonic TFSOM-UHHD: “To Find Small Ocular Melanoma-Using Helpful Hints Daily”:
- Thickness > 2 mm
- Fluid subretinal
- Symptoms of flashes or floaters
- Orange pigment
- Margin within 3mm on the optic nerve head
- Ultrasound Hollow
- Halo absent
- Drusen absent
Choroidal melanocytic tumors that display no factors have a 3% chance for growth at 5 years and most likely represent choroidal nevi. Tumors that display one factor have a 38% chance for growth, and those with two or more factors show growth in over 50% of cases at 5 years.
Patients with suspicious nevi should be reexamined and imaged in 3 months and monitored for changes in size. If no growth is observed, then reexamination can occur every 6 months thereafter.
Documented growth of a melanocytic choroidal tumor is suggestive that the lesion is a choroidal melanoma. Growth over a short time (<2 years) is strongly suggestive of melanoma whereas growth over a long period (>10 years) could suggest a nevus. Since documented growth may be associated with worse systemic prognosis, some patients with small tumors that show three or more risk factors are treated promptly, without waiting for documentation of growth. Increasing tumor size both in base and thickness leads to increased risk for metastasis. Based on the few patients with medium size choroidal melanoma who refuse treatment and are followed, natural history studies have found that there is greater mortality and higher risk of death.
Local Therapy to the Eye
There are several methods for surgical management of posterior uveal melanoma including enucleation, exenteration, and local resection.
Removal of the eye was the gold standard for uveal melanoma for centuries until the late 1970s due to concern that enucleation could facilitate metastasis. This inspired the use of eye-sparing strategies and the utility of these treatments were confirmed in the landmark Collaborative Ocular Melanoma Study (COMS) in the 1980s. In the COMS medium sized tumor trial, there was no survival difference between patients who underwent enucleation and those who were treated with iodine-125 plaque brachytherapy. The large sized tumor trial indicated that external beam radiotherapy prior to enucleation did not provide a survival benefit compared to enucleation alone.
Enucleation is generally indicated for advanced melanomas that occupy most of the intraocular structures, have caused severe secondary glaucoma or total retinal detachment that is not reversible to alternative treatments, or tumors invading the optic nerve. Enucleation with a long section of the optic nerve is appropriate in such cases. However, many juxtapapillary melanomas that abut the optic nerve and show no evidence of invasion can be managed by custom-designed notched radioactive plaques rather than enucleation.
The "no touch enucleation" was introduced to minimize the amount of surgical trauma and theoretically to lessen the chance of tumor dissemination at the time of surgery. An essential aspect of this technique was to freeze the venous drainage from the tumor prior to cutting the optic nerve. The "no touch" technique has recently fallen into disuse at most centers because it is cumbersome and its benefits are only theoretical. However a gentle standard technique of enucleation should be employed, without clamping the optic nerve prior to cutting it.
After removal of the eye, fine needle aspiration biopsy can be performed for genetic testing purposes.
There have been advances in the types of orbital implants used following enucleation. The hydroxyapatite implant, designed to improve the ocular motility in patients undergoing enucleation, is used widely. Other implants include polyethylene and polymer coated hydroxyapatite.
The subject of orbital exenteration for uveal melanomas with extrascleral extension is controversial. It seems that complete orbital exenteration should not be done in cases of mild degrees of extrascleral extension. However, in the rare instance of massive orbital extension in a blind, uncomfortable eye, primary orbital exenteration is probably justified. In most instances of orbital extension for uveal melanoma, it is not necessary to sacrifice the skin of the eyelid. The eyelid-sparing exenteration provides a better cosmetic appearance.
Local resection of melanomas involving the ciliary body and choroid can be performed using a partial lamellar sclerouvectomy technique. This surgical technique is a modification of the one popularized by Foulds, and later Shields and Damato, in which the tumor is removed with the aim of leaving the retina and vitreous intact. It is best performed in growing small or medium size ciliary body melanomas or choroidal melanomas near the equator. It should be noted that alternative, less invasive treatments, such as plaque brachytherapy, can also be used to treat ciliary body melanomas and choroidal melanomas at the equator.
Local resection of a posterior uveal melanoma offers several theoretical advantages over enucleation and radiotherapy. In contrast to enucleation, it is designed to preserve vision and to maintain a cosmetically normal eye. Compared to radiotherapy, there are fewer long-term complications if the initial surgery is successful. However, there is a higher risk for immediate complications, such as vitreous hemorrhage, retinal detachment and cataract, while radiotherapy is uncommonly associated with these immediate complications. However, radiotherapy carries the risk for long-term complications of radiation retinopathy, papillopathy, glaucoma, and cataract. There is no current evidence that local resection of posterior uveal melanoma is different from enucleation or radiotherapy with regard to patient survival. There are fewer complications and better visual results for smaller, more anteriorly located tumors. More complications can be expected when larger post-equatorial tumors are managed in this manner. In addition, incomplete resection of posterior melanomas is a concern.
Presently, radiotherapy is the most widely employed intervention for posterior uveal melanoma. However, between 5% and 10% of patients treated with radiotherapy ultimately require enucleation of the affected eye because of tumor recurrence or radiation complications (e.g. neovascular glaucoma, radiation retinopathy, radiation optic neuropathy). Radiation tumor vasculopathy is also common as the irradiated tumor can become ischemic, resulting in macular edema, serous retinal detachment, retinal ischemia, and neovascular glaucoma.
At some centers, transpupillary thermotherapy, photocoagulation, and intravitreal anti-vascular endothelial growth factor or periocular triamcinolone injections are used after radiotherapy to reduce the risk of vascular complications.
Treatment of ciliary body melanomas with radiation may result in cataracts, punctal occlusion, keratoconjunctivitis, radiation anterior uveitis, or scleral necrosis.
The most commonly employed form of radiotherapy is brachytherapy using a episcleral radioactive plaque that is temporarily sutured to the scleral surface. Iodine-125, Ruthenium-106, and Palladium-103 plaques have largely replaced Cobalt-60 at most institutions.
Following the COMS medium size tumor trial, plaque brachytherapy became the standard of care for small and medium-sized melanomas located outside the macular region and posterior to the ora serrata. Shields and associates found that plaque brachytherapy can also be custom fit to treat small, medium, and even large uveal melanoma up to approximately 12 mm in thickness (Table 1). Although treating large melanoma was effective with satisfactory tumor control, complications of radiation maculopathy and papillopathy were higher and often led to poor long term vision.
Innovations in radiotherapeutic planning have allowed plaque brachytherapy to be custom designed to treat uveal melanoma at any site within the eye including the macula using a round or notched plaque, juxtapapillary region using a notched plaque, ciliary body using a round or curvilinear plaque, iris using a curvilinear plaque, and extrascleral extension.
Plaque brachytherapy combined with thermotherapy has provided tumor control in 97% with only 3% recurrence at 5 years in choroidal melanomas. The high control rate was maintained for eyes with juxtapapillary choroidal melanoma, despite the fact that this location is difficult for plaque placement. In primary ciliary body melanoma, plaque brachytherapy achieved a 92% 5-year local control rate.
Fine needle aspiration biopsy is usually performed prior to implantation of the radioactive plaque.
External Beam Radiotherapy
In uveal melanoma, external beam radiotherapy in the form of charged particle therapy and stereotactic radiosurgery, have been used.
Charged particle therapy
First used in 1975, charged particle therapy applies a focused beam of collimated protons or helium ions to deliver a high dose of radiation to a targeted area. Damage to surrounding tissues is limited due to the Bragg peak effect, where the most destructive ionizing radiation occurs immediately before the location that the particles stop traveling. It is used in medium- to large-sized tumors or for tumors in regions inaccessible to plaque brachytherapy such as the optic disc and fovea. Proton beam therapy is a well-established treatment option but is cost prohibitive and limited to only a few dozen centers around the world. Similar to plaque brachytherapy, radiation complications in the eye and adnexa can occur. Tumor control with charged particle and plaque radiotherapy are similar.
Stereotactic radiosurgery is a non-invasive form of therapeutic radiation that is delivered over a small, well-defined 3-dimensional area. GammaKnife and CyberKnife, are examples of stereotactic radiosurgery that have been used against choroidal melanomas unsuited for plaque brachytherapy. As with plaque brachytherapy, radiation injuries are common.
Laser therapies include photocoagulation, transpupillary thermotherapy, and photodynamic therapy. They are rarely used as primary intervention and are usually used as adjunctive therapy or for residual disease.
Photocoagulation is an acceptable method for treating selected small choroidal melanomas. It was originally performed with xenon photocoagulation and later with argon laser photocoagulation. Studies have shown that xenon achieved better tumor control but argon was associated with fewer complications. Low energy long-exposure laser therapy has been advocated by some authorities.
Recently, transpupillary thermotherapy has largely replaced argon laser for treating selected small choroidal melanomas, particularly those that are less than 3 mm in thickness and located more than 3 mm from the foveola.
Photocoagulation is not used in ciliary body melanomas.
Complications of photocoagulation include branch retinal vein occlusion, cystoid macular edema, epiretinal membrane formation, choroidal neovascularization, vitreous hemorrhage, and retinal detachment.
In transpupillary thermotherapy (TTT), focused heat via a modified infrared diode laser system, is delivered to the tumor causing tumor necrosis. It is typically delivered in 3 sessions and, at completion, leaves an atrophic chorioretinal scar at the site of the previous tumor.
The ideal tumor characteristics for primary TTT include small (thickness < 3.0 mm), deeply pigmented extramacular tumors with minimal subretinal fluid or no contact with the optic disc as heat absorption lessens at the disc. Tumor control is found in over 90% of properly selected cases. Currently, TTT is used most frequently as a supplement to plaque radiotherapy. An alternative technique using a TTT probe has been found effective for choroidal melanoma and intrascleral tumor.
The greatest advantage of TTT over plaque radiotherapy is the preservation of vision, and this treatment is particularly beneficial for tumors near, but not under, the fovea. However, when the tumor is subfoveal or immediately adjacent to the fovea, plaque radiotherapy combined with 3 sessions of extrafoveal TTT is used in order to adequately treat the tumor and retain useful vision as long as possible. Primary TTT can also be useful for elderly patients, particularly those with diabetes mellitus, to potentially avoid macular edema.
The most common side effects of TTT for small melanoma include branch retinal vein occlusion, retinal traction, and retinal hemorrhage. Tumors at the optic disc absorb less light and recur more frequently. Patients undergoing TTT should be amenable to long-term follow-up to monitor for recurrences.
Photodynamic therapy (PDT) involves intravenous administration of a photosensitizer that, when activated by a specific wavelength of light, releases reactive oxidative species within tumor vasculature and induces endothelial changes and thrombosis. PDT with verteporfin for uveal melanoma is infrequently used and very little is reported in the literature. Published studies have shown short-term tumor control while circumventing the risks of radiation retinopathy in small melanomas, but long-term tumor control rates are lower. One report on 4 patients showed tumor regression for 18 months in one patient, but lack of response or continued growth in 3 patients. Others have emphasized that this is best used with amelanotic choroidal melanoma.
Treatment of Metastatic Disease
Ideally, the best management of uveal melanoma would be to use methods of preventing metastasis in the early stages of the intraocular disease. Unfortunately, there is no current method of achieving this. Nearly half of all patients with uveal melanoma will develop metastatic disease. Uveal melanoma spreads exclusively hematogenously, unless it becomes large enough to infiltrate the conjunctival lymphatics. In the Collaborative Ocular Melanoma Study (COMS), the most frequent sites of metastases at time of death were the liver (93%), lung (24%), and bone (16%). More than 80% had multiple sites of metastasis. The 5 and 10-year cumulative metastasis rates are 25% and 34%, respectively. Prognosis is very poor after metastasis has occurred.
Locoregional Treatment of liver metastasis
The liver is the most frequent site of metastasis. About 90% of patients with large choroidal melanomas in the COMS had liver metastases at the time of death, and 57% had exclusive liver metastases. Treating hepatic metastases from uveal melanoma requires a multidisciplinary approach. Treatment choice depends on the number of hepatic metastases, tumor size/volume, and time to systemic metastasis.
Direct surgical procedures on the liver can be used to manage metastatic liver nodules. Other locoregional therapies involve the hepatic artery, which predominantly supplies metastatic tissue.
Surgical resection of metastatic nodules
While good outcomes have been reported in patients with uveal melanoma with metastasis to the liver, surgical intervention is rarely indicated as most patients present with multiple liver metastases involving both liver lobes.
Transcatheter intraarterial therapies
Surgical or local ablative therapies are rarely used because hepatic metastases usually involve multiple regions of the liver. Transcatheter intra-arterial therapies that target the entire liver are more commonly used. These treatments may prolong survival for a few months. However, it is unlikely that it will be curative as most patients will develop progression of liver metastases despite these treatments.
Hepatic intra-arterial chemotherapy
Liver metastases are perfused by the hepatic arteries whereas normal hepatic tissue is primarily supplied by the portal vein. Direct delivery of chemotherapy to the hepatic artery via an indwelling catheter allows maximal exposure of hepatic metastases to cytotoxic chemotherapy while minimizing systemic toxicity. Hepatic intra-arterial chemotherapy with fotemustine, melphalan, cisplatin, vinblastine, and dacarbazine on patients with metastatic uveal melanoma have been performed but no significant increase in overall survival has been observed.
In hepatic transarterial chemoembolization (TACE), chemotherapy is infused through the hepatic artery followed by selective obstruction of a distal hepatic artery branch to “starve” a metastatic tumor and induce tumor necrosis. Conventional TACE involves the infusion of chemotherapy mixed with lipiodol (ethiodized oil) followed by occlusion of a prespecified hepatic artery branch that feeds the tumor with an embolic agent (e.g. polyvinyl sponge). The use of conventional TACE using a wide variety of chemotherapeutic medications and protocols have been used, but the best chemotherapy choice or embolic therapy remains unknown. Different embolization procedures have emerged. More recently, drug-eluting beads have been used as embolic materials that are infused with anti-cancer medications, such as doxorubicin, irinotecan, and epirubicin.
Patients undergoing TACE must have disease limited to the liver or liver-dominant disease without signs of hepatic failure, such as encephalopathy, or decreased portal vein blood flow (e.g. acute or chronic portal vein thrombosis).
Postembolization syndrome, characterized by fever, right upper quadrant abdominal pain, elevated liver enzymes, nausea, and/or vomiting, is a common complication. Other important but rare complications include cholecystitis, pulmonary embolism, hepatic abscess, bile duct injury, gastric mucosal injury, and acute pancreatitis. Hematologic or vascular complications have also been reported.
Transarterial hepatic immunoembolization
Immunoembolization involves hepatic artery embolization using granulocyte-macrophage colony-stimulating factor with lipiodol (instead of chemotherapy as in TACE) to induce tumor ischemia and stimulate antigen presenting cells to facilitate antigen uptake and enhance systemic immunity against tumor cells. One study with 34 participants with metastatic uveal melanoma showed positive outcomes, with an overall survival of 14.4 months. Common complications include transaminitis, abdominal pain, and nausea/vomiting.
Selective Internal Radiation Therapy
Selective internal radiation therapy, also referred to as transarterial radioembolization (TARE), involves inserting radioactive yttrium-90 microspheres into the hepatic artery that occlude the tumor microvasculature and deliver localized radiation to hepatic tumors. Studies have shown variable results with overall survival ranging from 9 to 24 months in patients with unresectable liver metastases from uveal melanoma.
Isolated hepatic perfusion
Isolated hepatic perfusion (IHP) is a complex open surgical procedure where hepatic blood flow is segregated from the systemic vasculature through cannulation and clamping of the hepatic artery and inferior vena cava and joining this circulation to an extracorporeal circuit. This distinct circulation allows administration of highly potent chemotherapies to the entire liver while bypassing systemic circulation and reducing undesirable systemic effects. Melphalan is the most commonly used chemotherapy agent. However, this surgical procedure is complex and extensive, limiting its availability. IHP is also associated with considerable morbidity and mortality due to veno-occlusive disease and hepatotoxicity. In addition, because of the open surgical nature of this procedure, IHP generally is not repeated.
Percutaneous isolated hepatic perfusion (PHP) is a minimally invasive alternative to IHP. A major advantage of PHP compared to IHP is the potential for multiple perfusion treatments. As with IHP, melphalan is the most commonly investigated chemotherapy agent in metastatic uveal melanoma. A recent meta-analysis has shown no difference in outcomes between IHP and PHP.
Chemotherapy is reserved for metastatic uveal melanoma. However, effective chemotherapy agents used against metastatic cutaneous melanoma are generally ineffective in metastatic uveal melanoma. Various antineoplastic agents, including standard chemotherapeutic agents, targeted cancer therapy, and immunotherapy have been investigated, but no significant improvement in overall survival or progression free survival has been observed. However, some recent studies have shown encouraging results.
Chemotherapeutic agents have been evaluated as monotherapy or combination therapy, including dacarbazine, temozolomide, treosulfan, and fotemustine, with response rates of <10%.
Uveal melanoma and cutaneous melanoma are clinically and biologically distinct. In uveal melanoma, mutations in GNAQ and GNA11 are the most common along with mutations to SF3B1, EIF1AX, and BAP1. In contrast, cutaneous melanoma most often involves mutations in BRAF, NRAS, and KIT. While effective immune checkpoint inhibitors have been identified in the treatment against metastatic cutaneous melanoma, these medications have not demonstrated the same effect in metastatic uveal melanoma. However, novel and promising treatments are under investigation.
One promising treatment option is tebentafusp, a bispecific fusion protein that is composed of a monoclonal high-affinity T cell receptor, which presents uveal melanoma antigens, fused to an anti-CD3 single-chain antibody fragment that activates cytotoxic T cells. A phase 3 trial of tebentafusp was the first to show reduced risk of death from metastatic uveal melanoma compared to investigator’s choice (dacarbazine, pembrolizumab, or ipilimumab) in treatment-naive HLAA*02:01-positive patients with metastatic uveal melanoma.
As radiotherapy is the most commonly used treatment option, the main ocular complication following radiotherapy is retinopathy with resultant decreased visual acuity. Gunduz and associates studied retinopathy following plaque radiotherapy and noted nonproliferative retinopathy in 42% at 5 years and proliferative retinopathy in 8% at 5 years. Other radiation complications included cataract (39%), papillopathy (8%), vitreous hemorrhage (7%), neovascular glaucoma (1%), and scleral necrosis (1%). The treatment of these complications involves laser photocoagulation, anti-vascular endothelial growth factor medications, and anti-inflammatory medications.
The prognosis for uveal melanoma should be considered in terms of life, the globe, and visual acuity. With regards to life prognosis, uveal melanoma prognosis has been shown to be dependent on several clinical factors including tumor location in the ciliary body, large tumor size, diffuse (flat) configuration, and extraocular extension as well as histopathologic and cytogenetic factors including epithelioid cell type, increased mitotic activity, infiltrating lymphocytes, tumor vascular networks, and chromosomal mutations including monosomy 3 and 8q addition. In several articles, tumor size has been identified as one of the key clinical features predictive of metastasis. One large analysis on 8033 eyes with uveal melanoma found that increasing millimeter thickness of uveal melanoma was associated with increasing risk for metastasis (Table 1). These findings highlight the importance of close monitoring and early intervention.
Table 1. Probability for systemic metastasis from posterior uveal melanoma based on millimeter increments in tumor thickness at 3, 5, and 10 years after diagnosis
|Tumor thickness, mm||Probability for Systemic Metastasis, %|
|3 years||5 years||10 years||20 years|
|Using 1-mm increments|
|Using small, medium, and large COMS classifications|
|Large (> 8.0)||22.3||35.0||49.2||66.9|
Fine needle aspiration biopsy of uveal melanoma is used for prognostication and is performed immediately prior to radioactive plaque placement or in eyes undergoing brachytherapy or after enucleation. Chromosomal and genetic analysis, gene-expression-profile testing, and cytogenetic prognostic testing can aid in treatment decisions. A clinically validated gene expression profile (GEP) test for uveal melanoma prognostication (DecisionDx-UM) is currently the standard of care in most ocular oncology centers in the United States (Table 2). This test was validated by the Collaborative Ocular Oncology Group after it successfully classified 97.2% of cases.
Table 2. Prognostication with gene expression profiling
|RNA GEP Class||Metastatic Risk||5-year metastatic risk||Associated genetic mutation|
|Class 1A||Low||2%||SF3B1, EIF1AX|
|Class 1B||Intermediate||21%||SF3B1, EIF1AX|
With regards to the globe, nearly 95% of patients treated with conservative measures such as radiotherapy or resection, maintain their globe on follow up. The greater the tumor thickness, the greater the risk for enucleation.
With regards to visual acuity, a study on 1106 consecutive plaque-irradiated patients with uveal melanoma found poor visual acuity (20/200 or worse) in 34% at 5 years and 68% at 10 years of follow-up. Factors related to poor visual acuity included increasing tumor thickness, proximity of tumor to foveola of less than 5 mm, evidence of tumor recurrence, patient age 60 years or older, subretinal fluid, cobalt isotope, tumor posterior to equator, and worse initial visual acuity.
Patients with uveal melanoma should have regular systemic follow up examinations by both an ocular oncologist and a medical oncologist. The ocular oncologist should monitor the uveal scar for tumor regression and complications of therapy. The medical oncologist should survey for metastatic disease. Particular evaluation of the liver, lung, and skin should be made as this malignancy most often metastasizes to these sites. Physical examination and liver function testing is recommended twice yearly, as well as annual liver magnetic resonance imaging and chest radiography for monitoring. Following radiotherapy there are complications of radiation retinopathy, papillopathy, cataract, glaucoma, scleral necrosis, and pain.
In 1809, the first known complete natural history of uveal melanoma was documented by Scottish surgeons Allan Burns and James Wardrop. In 1882, Ernst Fuchs was the first to describe sarcom des uvealtractus (“uveal sarcoma,” now known as uveal melanoma) as “one of the most malignant of diseases” and recommended enucleation as the treatment of choice to prevent metastasis and death.
The Zimmerman-McLean-Foster Hypothesis
Following enucleation, metastatic disease and mortality remained high. In the 1970s, a landmark paper by a group of expert ophthalmic pathologists proposed that an elevated intraocular pressure while cutting the optic nerve at the time of enucleation could facilitate the passage of tumor cells through the vortex veins into systemic circulation thereby resulting in liver metastases. This became known as the “Zimmerman-McLean-Foster Hypothesis.” Although this hypothesis sparked controversy regarding the safety of enucleation, it also inspired new surgical techniques, such as the “no touch enucleation,” and encouraged the use of globe-salvaging therapies such as radiation and laser therapies. Further studies have refuted this hypothesis, and have attributed high frequencies of liver metastases to micrometastases that occur years prior to the initial clinical diagnosis of uveal melanoma.
The Collaborative Ocular Melanoma Study
The Collaborative Ocular Melanoma Study (COMS) is a prospective multicenter trial that was funded and organized by the National Eye Institute in 1985 to evaluate the role of different interventions for patients with uveal melanoma. The first patient was enrolled in 1987 and accrual was completed in 1998. To date, the COMS is the largest study performed in ocular oncology. There were three major prospective multicenter COMS trials (Table 3). The results of the COMS confirmed numerous previous publications regarding management of choroidal melanoma.
Large-size tumor trial
The “Zimmerman-McLean-Foster Hypothesis” inspired the use of additional treatments with enucleation, such as pre- or post-enucleation radiation, particularly in large choroidal melanomas. This trial sought to evaluate if pre-enucleation radiotherapy offered a survival benefit compared to enucleation alone.
Large choroidal melanomas were defined as 2.0 mm or more in apical height and greater than 16.0 mm in longest basal diameter, or more than 10.0 mm apical height regardless of basal diameter, or greater than 8.0 mm apical height regardless of basal diameter if less than 2.0 mm to the optic disc.
The randomized controlled prospective large-sized tumor trial involved 1003 treatment-naive patients with large choroidal melanomas who were treated with enucleation alone (n=506) or pretreatment external beam radiotherapy (20 Gy) followed by enucleation (n=497). In the pretreatment group, radiotherapy was delivered as five daily fractions of 4.0 Gy and eyes were enucleated within 80 hours after the final fraction. All eyes were enucleated within 4 weeks after randomization in both groups. Patients were monitored 6 and 12 months after enrollment, then annually. The primary outcome was survival rates in each treatment group. The 5-year survival rates were 57% in the enucleation alone group and 62% with pre-enucleation radiation. The authors concluded that there were no survival differences between pre-enucleation radiotherapy and enucleation alone in patients with large choroidal melanomas.
The 10-year survival rates were 40% in the enucleation alone group and 45% in the pretreatment radiation group. The authors concluded that no survival differences were observed.
Following these trials, pre-enucleation radiotherapy was abandoned.
Medium-size tumor trial
Following the concerns of the “Zimmermann-McLean-Foster Hypothesis,” radiotherapy was considered the best alternative to enucleation for medium-sized choroidal melanomas. This trial aimed to evaluate differences in survival rates in patients treated with iodine-125 plaque brachytherapy alone compared to treatment with enucleation alone.
Medium-sized choroidal melanomas were defined as 2.5 to 10.0 mm in apical height and no more than 16.0 mm in longest basal diameter.
The randomized controlled prospective medium-sized tumor trial involved 1317 treatment-naive patients with choroidal melanomas who were treated with enucleation (n=660) or iodine-125 plaque brachytherapy (n=657). Plaque brachytherapy treatment or enucleation was performed within 4 weeks after enrollment. The primary outcome was survival rates in each treatment group. The 5-year survival rates were 81% for the enucleation group and 82% for the iodine 125-plaque brachytherapy group (p=0.48). The authors concluded that there were no survival differences in patients treated with enucleation and patients treated with iodine-125 plaque brachytherapy.
The 12-year survival rates were 41% in the enucleation group and 43% in the iodine-125 plaque brachytherapy group.
The results of these trials encouraged the use of iodine-125 plaque brachytherapy for medium-sized choroidal melanomas.
Small-size tumor trial
The treatment of small melanomas has been controversial and many were managed with only observation. Treatment was often deferred in small melanomas because of the potential for severe visual impairment after radiation.
Small choroidal melanomas were defined as 1.0 to 3.0 mm in apical height and 5.0 to 16.0 mm in largest basal diameter.
The prospective observational small-size tumor trial involved 188 patients who were managed by observation. The primary outcome was tumor growth, which was defined as an increase to a medium-size or large-size choroidal melanoma based on COMS tumor classification criteria. In untreated small choroidal melanomas, 11% grew by 1 year, 21% by 2 years, and 31% by 5 years.
Table 3. Brief summary of three major prospective trials in the Collaborative Ocular Melanoma Study
|Large-size* tumor trial||Randomized controlled||Enucleation alone vs external beam radiotherapy followed by enucleation||No difference between 5-year survival rates between enucleation alone (57%) and enucleation with pretreatment external beam radiotherapy (62%) in large choroidal melanomas.|
|Medium-size** tumor trial||Randomized controlled||Enucleation vs iodine-125 plaque brachytherapy||No difference in 5-year survival rates between enucleation (81%) and iodine-125 plaque brachytherapy (82%) in medium-size choroidal melanomas.|
|Small-size*** tumor trial||Observational||Observation||Tumor growth in untreated small choroidal melanomas were 11% by 1 year, 21% by 2 years, and 31% by 5 years.|
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