Intraocular (Eye) Melanoma Treatment (PDQ®): Treatment - Health Professional Information [NCI]

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Intraocular (Eye) Melanoma Treatment

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of intraocular (eye) melanoma. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.

Information about the following is included in this summary:

  • Prognostic factors.
  • Cellular classification.
  • Staging.
  • Treatment options by cancer stage.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version, written in less technical language, and in Spanish.

General Information

Melanoma of the uveal tract (iris, ciliary body, and choroid), though rare, is the most common primary intraocular malignancy in adults. The mean age-adjusted incidence of uveal melanoma in the United States is approximately 4.3 new cases per million population.[1] The age-adjusted incidence of this cancer has remained stable for the past 50 years.

Uveal melanoma is diagnosed mostly at older ages, with a progressively rising age-specific incidence rate that peaks near the age of 70.[1] Host susceptibility factors associated with the development of this cancer include Caucasian race, light eye color, fair skin color, and the ability to tan.[1,2] In view of these susceptibility factors, numerous observational studies have attempted to explore the relationship between sunlight exposure and risk of uveal melanoma. To date, these studies have found only weak associations or yielded contradictory results.[1] Similarly, there is no consistent evidence that occupational exposure to UV light or other agents is a risk factor for uveal melanoma.[1]

Uveal melanomas can arise in the anterior (iris) or the posterior (ciliary body or choroid) uveal tract. Iris melanomas have the best prognosis, whereas melanomas of the ciliary body have the worst. Most uveal tract melanomas originate in the choroid. The ciliary body is less commonly a site of origin, and the iris is the least common. The comparatively low incidence of iris melanomas has been attributed to the characteristic features of these tumors, i.e., they tend to be small, slow growing, and relatively dormant in comparison with their posterior counterparts. Iris melanomas rarely metastasize.[3] Melanomas of the posterior uveal tract are cytologically more malignant, detected later, and metastasize more frequently than iris melanomas. The typical choroidal melanoma is a brown, elevated, dome-shaped subretinal mass. The degree of pigmentation ranges from dark brown to totally amelanotic.

Most uveal melanomas are initially completely asymptomatic. As the tumor enlarges, it may cause distortion of the pupil (iris melanoma), blurred vision (ciliary body melanoma), or markedly decreased visual acuity caused by secondary retinal detachment (choroidal melanoma). Serous detachment of the retina frequently complicates tumor growth. If extensive retinal detachment occurs, secondary angle-closure glaucoma occasionally develops. Clinically, several lesions simulate uveal melanoma, including metastatic carcinoma, posterior scleritis, and benign tumors, such as nevi and hemangiomas.[4]

Careful examination by an experienced clinician remains the most important test to establish the presence of intraocular melanoma. Ancillary diagnostic testing, including fluorescein angiography and ultrasonography, can be extremely valuable in establishing and/or confirming the diagnosis.[5]

A number of factors influence prognosis. The most important are cell type, tumor size, location of the anterior margin of the tumor, the degree of ciliary body involvement, and extraocular extension. Cell type, however, remains the most often used predictor of outcome.[6] The selection of treatment depends on the site of origin (choroid, ciliary body, or iris), the size and location of the lesion, the age of the patient, and whether extraocular invasion, recurrence, or metastasis has occurred. Extraocular extension, recurrence, and metastasis are associated with an extremely poor prognosis, and long-term survival cannot be expected.[7] The 5-year mortality rate caused by metastasis from ciliary body or choroidal melanoma is approximately 30%, compared with a rate of 2% to 3% for iris melanomas.[8] In a group of patients with large tumors of the choroid or choroid and ciliary body, the concurrent presence of abnormalities in chromosomes 3 and 8 was also associated with a poor outcome.[9]

In the past, enucleation (eye removal) was the accepted standard treatment for primary choroidal melanoma, and it remains the most commonly used treatment for large tumors. Because of the effect of enucleation on the appearance of the patient, the diagnostic uncertainty encountered by the ophthalmologist (particularly in the case of smaller tumors), and the potential for tumor spread, alternative treatments, such as radiation therapy (i.e., brachytherapy or external-beam, charged-particle radiation therapy), transpupillary thermotherapy, photocoagulation, and cryotherapy have been developed in an attempt to spare the affected eye and possibly retain useful vision.[10,11] One of the clinical trials of the randomized Collaborative Ocular Melanoma Study compared iodine 125 (125 I) episcleral-plaque brachytherapy to enucleation in treating patients with medium-sized choroidal tumors.[12] Eighty-five percent of the patients treated with 125 I brachytherapy retained their eye for 5 years or more, and 37% had visual acuity better than 20/200 in the irradiated eye 5 years after treatment.[12] No 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.[13]

References:

1. Singh AD, Bergman L, Seregard S: Uveal melanoma: epidemiologic aspects. Ophthalmol Clin North Am 18 (1): 75-84, viii, 2005.
2. Weis E, Shah CP, Lajous M, et al.: The association between host susceptibility factors and uveal melanoma: a meta-analysis. Arch Ophthalmol 124 (1): 54-60, 2006.
3. Yap-Veloso MI, Simmons RB, Simmons RJ: Iris melanomas: diagnosis and management. Int Ophthalmol Clin 37 (4): 87-100, 1997 Fall.
4. Eye and ocular adnexa. In: Rosai J: Ackerman's Surgical Pathology. 8th ed. St. Louis, Mo: Mosby, 1996, pp 2449-2508.
5. Avery RB, Mehta MP, Auchter RM, et al.: Intraocular melanoma. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 1800-24.
6. McLean IW: Prognostic features of uveal melanoma. Ophthalmol Clin North Am 8 (1): 143-53, 1995.
7. Gragoudas ES, Egan KM, Seddon JM, et al.: Survival of patients with metastases from uveal melanoma. Ophthalmology 98 (3): 383-9; discussion 390, 1991.
8. Introduction to melanocytic tumors of the uvea. In: Shields JA, Shields CL: Intraocular Tumors: A Text and Atlas. Philadelphia, Pa: Saunders, 1992, pp 45-59.
9. White VA, Chambers JD, Courtright PD, et al.: Correlation of cytogenetic abnormalities with the outcome of patients with uveal melanoma. Cancer 83 (2): 354-9, 1998.
10. Zimmerman LE, McLean IW, Foster WD: Statistical analysis of follow-up data concerning uveal melanomas, and the influence of enucleation. Ophthalmology 87 (6): 557-64, 1980.
11. De Potter P, Shields CL, Shields JA: New treatment modalities for uveal melanoma. Curr Opin Ophthalmol 7 (3): 27-32, 1996.
12. Diener-West M, Earle JD, Fine SL, et al.: The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma, III: initial mortality findings. COMS Report No. 18. Arch Ophthalmol 119 (7): 969-82, 2001.
13. Collaborative Ocular Melanoma Study Group.: The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: V. Twelve-year mortality rates and prognostic factors: COMS report No. 28. Arch Ophthalmol 124 (12): 1684-93, 2006.

Cellular Classification

Primary intraocular melanomas originate from melanocytes in the uveal tract.[1] Four distinct cellular types are recognized in intraocular melanoma (revised Callendar classification):[2]

1. SPINDLE A CELLS (spindle-shaped cells with slender nuclei and lacking visible nucleoli).
2. SPINDLE B CELLS (spindle-shaped cells with larger nuclei and distinct nucleoli).
3. EPITHELIOID CELLS (larger polygonal cells with one or more prominent nucleoli).
4. INTERMEDIATE CELLS (similar to but smaller than epithelioid cells).

Most primary intraocular melanomas contain variable numbers of epithelioid, spindle A, and spindle B cells (mixed-cell melanomas). Pure epithelioid-cell primary melanomas are infrequent (approximately 3% of cases).[1] In the Collaborative Ocular Melanoma Study, mixed-cell type melanomas predominated (86% of cases).[3]

Several microscopic features can affect the prognosis of intraocular melanoma, including cell type, mitotic activity, lymphocytic infiltration, and, possibly, fibrovascular loops.[1] Cell type remains the most often used predictor of outcome following enucleation, with spindle A cell melanomas carrying the best prognosis and epithelioid cell melanomas carrying the worst.[1,4]

References:

1. Klintworth GK, Scroggs MW: The eye and ocular adnexa. In: Sternberg SS, ed.: Diagnostic Surgical Pathology. Philadelphia, Pa: Lippincott Williams & Wilkins, 1999, pp 994-6.
2. Grossniklaus HE, Green WR: Uveal tumors. In: Garner A, Klintworth GK, eds.: Pathobiology of Occular Disease: A Dynamic Approach. 2nd ed. New York, NY: M. Dekker, 1994, pp 1423-77.
3. Histopathologic characteristics of uveal melanomas in eyes enucleated from the Collaborative Ocular Melanoma Study. COMS report no. 6. Am J Ophthalmol 125 (6): 745-66, 1998.
4. McLean IW: Prognostic features of uveal melanoma. Ophthalmol Clin North Am 8 (1): 143-53, 1995.

Classification and Stage Information

Tumor Size

Uveal melanoma most often assumes a nodular or dome-shaped configuration, but occasionally tumors can be flat or diffuse and involve extensive areas of the uvea with little elevation.

Tumor size classifications according to boundary lines are as follows:

1. SMALL: Range from 1 mm to 3 mm in apical height and have a basal diameter of at least 5 mm.[1]
2. MEDIUM: Range from 2 mm to 3 mm up to 10 mm in apical height and have a basal diameter of less than 16 mm.[2]
3. LARGE: Greater than 10 mm in apical height or have a basal diameter of at least 16 mm.[3]
4. DIFFUSE: Horizontal, flat growth pattern, with the thickness of the tumor measuring approximately 20% or less than the greatest basal dimension; this uncommon variant of uveal melanoma seems to have a poorer prognosis.[4]

In clinical practice, the tumor base may be estimated in average optic disc diameters (1 dd = 1.5 mm). The average elevation may be estimated in diopters (3 diopters = 1 mm). Other techniques, such as ultrasonography, should be used to provide more accurate measurements.

An important function of ophthalmic ultrasonography is the detection of extrascleral extension.[5,6] Extrascleral extension measuring 2 mm or more in thickness can invariably be demonstrated provided it is located behind the equator where the intraocular tumor, sclera, and adjacent orbital fat are readily imaged.[7] Orbital extraocular extension of choroidal melanoma may be found in eyes with medium and large tumors, but it is very rare in eyes with small melanomas.

Metastatic Disease

Because the uveal tract is a vascular structure without lymphatic channels, tumor spread occurs principally by local extension and by dissemination through the blood stream. If regional preauricular, submandibular, or cervical lymph node involvement is seen, subconjunctival extension of the primary tumor has occurred.[8]

Systemic metastases are generally hematogenous in origin, and the first site identified is usually the liver.[9] Lung, bone, and subcutaneous sites are also common.[9] In the Collaborative Ocular Melanoma Study trials, the liver was the only site of detectable metastasis in 46% of patients with metastases reported during follow-up or at the time of death; 43% had metastases diagnosed in the liver and other sites.[9] In patients with a history of ocular melanoma who present with hepatic metastases of unknown origin, metastatic melanoma should be considered in the differential diagnosis.

It is particularly unusual for choroidal melanomas of any size to invade the optic nerve or its meninges.[10] Metastasis of choroidal melanoma to the contralateral choroid is also rare.[9,11]

Other Classification and Staging

An American Joint Committee on Cancer staging system has been developed for melanoma of the uveal tract,[12] and its widespread utilization has been advocated.[13]

References:

1. 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.
2. Diener-West M, Earle JD, Fine SL, et al.: The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma, II: characteristics of patients enrolled and not enrolled. COMS Report No. 17. Arch Ophthalmol 119 (7): 951-65, 2001.
3. The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma I: characteristics of patients enrolled and not enrolled. COMS report no. 9. Am J Ophthalmol 125 (6): 767-78, 1998.
4. Shields CL, Shields JA, De Potter P, et al.: Diffuse choroidal melanoma. Clinical features predictive of metastasis. Arch Ophthalmol 114 (8): 956-63, 1996.
5. Scott IU, Murray TG, Hughes JR: Evaluation of imaging techniques for detection of extraocular extension of choroidal melanoma. Arch Ophthalmol 116 (7): 897-9, 1998.
6. Romero JM, Finger PT, Iezzi R, et al.: Three-dimensional ultrasonography of choroidal melanoma: extrascleral extension. Am J Ophthalmol 126 (6): 842-4, 1998.
7. Echography (ultrasound) procedures for the Collaborative Ocular Melanoma Study (COMS), Report no. 12, Part I. J Ophthalmic Nurs Technol 18 (4): 143-9, 1999 Jul-Aug.
8. Dithmar S, Diaz CE, Grossniklaus HE: Intraocular melanoma spread to regional lymph nodes: report of two cases. Retina 20 (1): 76-9, 2000.
9. Diener-West M, Reynolds SM, Agugliaro DJ, et al.: Development of metastatic disease after enrollment in the COMS trials for treatment of choroidal melanoma: Collaborative Ocular Melanoma Study Group Report No. 26. Arch Ophthalmol 123 (12): 1639-43, 2005.
10. Shields CL, Santos MC, Shields JA, et al.: Extraocular extension of unrecognized choroidal melanoma simulating a primary optic nerve tumor: report of two cases. Ophthalmology 106 (7): 1349-52, 1999.
11. Singh AD, Shields JA, Shields CL, et al.: Choroidal melanoma metastatic to the contralateral choroid. Am J Ophthalmol 132 (6): 941-3, 2001.
12. Malignant melanoma of the uvea. In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 365-70.
13. Finger PT: Do you speak ocular tumor? Ophthalmology 110 (1): 13-4, 2003.

Iris Melanoma

Melanocytic stromal proliferations of the iris are the most common tumors of the iris. Clinical differentiation between an iris nevus and a melanoma might sometimes be difficult and at times impossible. Melanomas of the iris are usually small discrete lesions, though occasionally, they may be diffuse, infiltrative, multiple, and they may result in heterochromia, chronic uveitis, or spontaneous hyphema. Iris melanomas that involve more than 66% of the angle circumference are associated with secondary glaucoma.[1]

Routine evaluation of iris melanomas includes gonioscopy, transillumination of the globe, and indirect ophthalmoscopy with 360° of scleral depression. Photographic documentation is essential to document progression in size or growth of the tumor.[2] Anterior segment fluorescein angiography may be helpful to demonstrate the vascularity of the lesion but is not diagnostic. High-resolution ultrasound biomicroscopy can be used to measure small lesions (basal dimensions and thickness) and to assess tumor involvement of the anterior ciliary body, angle, and overlying sclera.[3] The main disadvantage with this technology is its limited penetration of large lesions. In these cases, conventional ultrasonography is more accurate.

In general, iris melanomas have relatively good outcomes, with a 5-year survival rate of more than 95%. Iris melanomas are predominantly of the spindle cell type and are usually smaller in size than posterior melanomas because of earlier detection. Clinical features, including prominent tumor vascularity, rapid growth, and heterogeneous pigmentation, are associated with an epithelioid cell component.[4] Involvement of the iridocorneal angles is frequently associated with ciliary body invasion.[4]

Conservative management is generally advocated whenever possible, but surgical intervention may be justified with unequivocal tumor growth and with extensive disease at initial examination.

STANDARD TREATMENT OPTIONS:

1. OBSERVATION WITH CAREFUL FOLLOW-UP: In asymptomatic patients with stable lesions; follow-up includes serial photography.[1]
2. LOCAL RESECTION: When progressive and pronounced growth is documented.
3. ENUCLEATION: If the tumor is not amenable to local resection (diffuse involvement of the iris, involvement of more than 50% of the iris and anterior chamber angle, intractable glaucoma, and extraocular extension).[5]
4. PLAQUE RADIOTHERAPY: Offered as an alternative for large, diffuse, surgically nonresectable lesions of the iris.[6]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with iris melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Marcus DM, Sahel JA, Jakobiec FA, et al.: Pigmented tumors of the iris. In: Albert DM, Jakobiec FA, eds.: Principles and Practice of Ophthalmology. Philadelphia, Pa: WB Saunders Co., 1994, pp 3198-3208.
2. Yap-Veloso MI, Simmons RB, Simmons RJ: Iris melanomas: diagnosis and management. Int Ophthalmol Clin 37 (4): 87-100, 1997 Fall.
3. Pavlin CJ, McWhae JA, McGowan HD, et al.: Ultrasound biomicroscopy of anterior segment tumors. Ophthalmology 99 (8): 1220-8, 1992.
4. Conway RM, Chua WC, Qureshi C, et al.: Primary iris melanoma: diagnostic features and outcome of conservative surgical treatment. Br J Ophthalmol 85 (7): 848-54, 2001.
5. Melanocytic tumors of the iris stroma. In: Shields JA: Diagnosis and Management of Intraocular Tumors. Saint Louis, Mo: C.V. Mosby Company, 1983, pp 83-121.
6. Shields CL, Shields JA, De Potter P, et al.: Treatment of non-resectable malignant iris tumours with custom designed plaque radiotherapy. Br J Ophthalmol 79 (4): 306-12, 1995.

Ciliary Body Melanoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Melanoma involving the ciliary body is a rare tumor that carries a poor prognosis. This malignancy is often diagnosed late, and in some cases, diagnosis may be difficult because of similarity to other eye diseases. The differential diagnosis of ciliary body melanoma should be considered in cases of unilateral pigmentary glaucoma and chronic uveitis.[1]

Ultrasound biomicroscopy can be used to evaluate tumor shape, thickness, margins, reflectivity, and local invasion.[2,3] Patients with tumors greater than 7 mm in thickness are at increased risk for metastatic disease and melanoma-related death than patients with thinner tumors.[4]

STANDARD TREATMENT OPTIONS:

There are several options for management of ciliary body melanoma. The choice of therapy, however, depends on many factors.

1. PLAQUE RADIATION THERAPY: A 5-year local control rate of greater than 90% has been reported but is associated with a high incidence of secondary cataract.[4,5][Level of evidence: 3iiiDiv]
2. EXTERNAL-BEAM, CHARGED-PARTICLE RADIATION THERAPY: Provides precisely focused radiation with a homogenous dose distribution pattern; requires sophisticated equipment available only at selected centers; involves patient cooperation during treatment (voluntarily fixating the eye on a particular point so the tumor is positioned properly in the radiation beam);[6,7] appears that the tumor control rate is similar to that obtained with plaque radiation therapy, but charged-particle radiation therapy may produce worse anterior-segment complications.[8]
3. LOCAL TUMOR RESECTION: Mainly suitable for selected ciliary body or anterior choroidal tumors with smaller basal dimension and greater thickness.[9,10]
4. ENUCLEATION: Performed for large melanomas when there is no hope of regaining useful vision; also indicated in the presence of intractable secondary glaucoma and extraocular extension.[5,8]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with ciliary body and choroid melanoma, small size. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Nguyen QD, Foster CS: Ciliary body melanoma masquerading as chronic uveitis. Ocul Immunol Inflamm 6 (4): 253-6, 1998.
2. Marigo FA, Finger PT, McCormick SA, et al.: Iris and ciliary body melanomas: ultrasound biomicroscopy with histopathologic correlation. Arch Ophthalmol 118 (11): 1515-21, 2000.
3. Daftari I, Barash D, Lin S, et al.: Use of high-frequency ultrasound imaging to improve delineation of anterior uveal melanoma for proton irradiation. Phys Med Biol 46 (2): 579-90, 2001.
4. Gündüz K, Shields CL, Shields JA, et al.: Plaque radiotherapy of uveal melanoma with predominant ciliary body involvement. Arch Ophthalmol 117 (2): 170-7, 1999.
5. Finger PT: Plaque radiation therapy for malignant melanoma of the iris and ciliary body. Am J Ophthalmol 132 (3): 328-35, 2001.
6. Munzenrider JE: Uveal melanomas. Conservation treatment. Hematol Oncol Clin North Am 15 (2): 389-402, 2001.
7. Char DH, Kroll SM, Castro J: Ten-year follow-up of helium ion therapy for uveal melanoma. Am J Ophthalmol 125 (1): 81-9, 1998.
8. De Potter P: [Choroidal melanoma: current therapeutic approaches] J Fr Ophtalmol 25 (2): 203-11, 2002.
9. De Potter P, Shields CL, Shields JA: New treatment modalities for uveal melanoma. Curr Opin Ophthalmol 7 (3): 27-32, 1996.
10. Char DH, Miller T, Crawford JB: Uveal tumour resection. Br J Ophthalmol 85 (10): 1213-9, 2001.

Small Choroidal Melanoma

The natural history of small choroidal melanoma remains poorly understood. Small, pigmented choroidal lesions cannot always be differentiated reliably on examination. Growth is a presumed indicator of malignant potential.[1]

Although patients diagnosed with small choroidal tumors were not eligible for participation in the Collaborative Ocular Melanoma Study, 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.[2] Clinical risk factors associated with tumor growth included increased tumor thickness, presence of subretinal fluid, orange pigmentation, absence of drusen, absence of retinal pigment, margin at the optic disc, and epithelial changes surrounding the tumor.[2,3]

The 5-year melanoma-related mortality rate in patients treated for small choroidal melanomas has been reported as high as 12%.[4,5] Several studies indicate that the two most important clinical factors predictive of mortality are larger tumor size (at the time of treatment) and documentation of tumor growth.[6]

Typical features of the tumor on ophthalmoscopy, fluorescein angiography, and ultrasound examination of the eye contribute to the clinical diagnosis. Accuracy of the tumor thickness measurement by echography is an important issue with very small tumors. Wide-field photography is helpful to detect the rate of choroidal tumor growth.[7] Although these techniques have improved the diagnostic differentiation of larger size melanomas, the accuracy of diagnosis for small melanomas is more uncertain. Furthermore, smaller tumors may not produce symptoms, depending on their location with respect to the macula, and may go undetected unless discovered during the course of a routine eye examination.

The management of small choroidal melanomas is controversial. The likelihood of progression from the time of diagnosis to growth warranting treatment has not been well characterized. In the past, many ophthalmologists advocated observation. This was justified on several grounds, including the difficulty in establishing a correct diagnosis, the lack of any documented efficacy for globe-conserving treatments, and concerns for severe treatment-related morbidity. Some investigators have advocated earlier therapeutic intervention, since smaller tumor size at the time of treatment appears to be associated with lower mortality rates.[3,8,9]

The management of choroidal melanomas depends on many factors; most important are tumor size and location.[10] In otherwise healthy patients, a small choroidal melanoma in the posterior fundus is amenable to several treatment options, including radiation therapy, laser photocoagulation, transpupillary thermotherapy, a combination of these methods, or even enucleation.[10,11,12,13]

STANDARD TREATMENT OPTIONS:

1. OBSERVATION: Is important in patients for whom the diagnosis is uncertain or in whom tumor growth is not documented; also is prudent in asymptomatic patients with stable lesions, particularly in elderly or debilitated patients, or in patients with tumor growth in their only useful eye.[5]
2. PLAQUE RADIATION THERAPY: Used for small- or medium-sized uveal melanomas, amelanotic tumors, or tumors that touch the optic disc for greater than 3 clock-hours of optic disk circumference.[12,13]
3. EXTERNAL-BEAM, CHARGED-PARTICLE RADIATION THERAPY: Provides precisely focused radiation with a homogeneous dose distribution pattern and little lateral spread; requires sophisticated equipment available only at selected centers; involves patient cooperation during treatment (voluntarily fixating the eye on a particular point so the tumor is positioned properly in the radiation beam); in eyes with tumors less than 6 mm in thickness and located more than 3 mm distant from the optic disc or fovea, clinically significant visual loss can usually be avoided.[10,12,13,14]
4. GAMMA KNIFE RADIATION SURGERY: Is a newer method of radiation therapy; preliminary experience suggests this treatment may be a feasible option for small-sized to medium-sized melanomas.[15]
5. LASER PHOTOCOAGULATION: Can be used in very selected cases of small posterior choroidal melanoma; indirect ophthalmoscope laser therapy may be combined with plaque radiation therapy.[12]
6. TRANSPUPILLARY THERMOTHERAPY: Causes substantial tumor necrosis in choroidal melanomas up to 3.5 mm in thickness; currently used in selected cases with deeply pigmented small choroidal melanomas in the posterior pole with minimal or no contact with the optic nerve; can be used as a primary treatment or as an adjunctive method to plaque radiation therapy.[8,9,16,17,18]
7. LOCAL TUMOR RESECTION: Used mainly for selected ciliary body or anterior choroidal tumors with smaller basal dimension and greater thickness.[19]
8. ENUCLEATION: Is favored when severe intraocular pressure elevation is a factor; may also be considered in small- and medium-sized melanomas that are invading the tissues of the optic nerve; an eye-sparing procedure rather than enucleation should be considered if there is hope for useful vision.[11]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with ciliary body and choroid melanoma, small size. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Augsburger JJ: Is observation really appropriate for small choroidal melanomas. Trans Am Ophthalmol Soc 91: 147-68; discussion 169-75, 1993.
2. 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.
3. 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.
4. Diener-West M, Hawkins BS, Markowitz JA, et al.: A review of mortality from choroidal melanoma. II. A meta-analysis of 5-year mortality rates following enucleation, 1966 through 1988. Arch Ophthalmol 110 (2): 245-50, 1992.
5. Mortality in patients with small choroidal melanoma. COMS report no. 4. The Collaborative Ocular Melanoma Study Group. Arch Ophthalmol 115 (7): 886-93, 1997.
6. Shields CL, Shields JA, Kiratli H, et al.: Risk factors for growth and metastasis of small choroidal melanocytic lesions. Ophthalmology 102 (9): 1351-61, 1995.
7. Murray TG: Small choroidal melanoma. Arch Ophthalmol 115 (12): 1577-8, 1997.
8. Shields CL, Shields JA, Perez N, et al.: Primary transpupillary thermotherapy for small choroidal melanoma in 256 consecutive cases: outcomes and limitations. Ophthalmology 109 (2): 225-34, 2002.
9. Robertson DM, Buettner H, Bennett SR: Transpupillary thermotherapy as primary treatment for small choroidal melanomas. Arch Ophthalmol 117 (11): 1512-9, 1999.
10. Munzenrider JE: Uveal melanomas. Conservation treatment. Hematol Oncol Clin North Am 15 (2): 389-402, 2001.
11. Shields JA, Shields CL: Atlas of Intraocular Tumors. Philadelphia, Pa: Lippincott Williams & Wilkins, 1999.
12. Shields CL, Shields JA, Gündüz K, et al.: Radiation therapy for uveal malignant melanoma. Ophthalmic Surg Lasers 29 (5): 397-409, 1998.
13. Finger PT: Radiation therapy for choroidal melanoma. Surv Ophthalmol 42 (3): 215-32, 1997 Nov-Dec.
14. Char DH, Kroll SM, Castro J: Ten-year follow-up of helium ion therapy for uveal melanoma. Am J Ophthalmol 125 (1): 81-9, 1998.
15. Woodburn R, Danis R, Timmerman R, et al.: Preliminary experience in the treatment of choroidal melanoma with gamma knife radiosurgery. J Neurosurg 93 (Suppl 3): 177-9, 2000.
16. Shields CL, Shields JA: Transpupillary thermotherapy for choroidal melanoma. Curr Opin Ophthalmol 10 (3): 197-203, 1999.
17. Godfrey DG, Waldron RG, Capone A Jr: Transpupillary thermotherapy for small choroidal melanoma. Am J Ophthalmol 128 (1): 88-93, 1999.
18. Bartlema YM, Oosterhuis JA, Journée-De Korver JG, et al.: Combined plaque radiotherapy and transpupillary thermotherapy in choroidal melanoma: 5 years' experience. Br J Ophthalmol 87 (11): 1370-3, 2003.
19. Char DH, Miller T, Crawford JB: Uveal tumour resection. Br J Ophthalmol 85 (10): 1213-9, 2001.

Medium and Large Choroidal Melanoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Enucleation remains the standard therapy for most large choroidal melanomas and melanomas that cause severe glaucoma or invade the optic nerve. One of the two clinical trials of the Collaborative Ocular Melanoma Study (COMS) compared preoperative external-beam radiation therapy plus enucleation to enucleation alone in patients with large choroidal tumors to address the concern that enucleation might precipitate tumor metastasis and shorten survival.[1] After 10 years of follow-up, the cumulative all-cause mortality rate for each treatment arm was 61%. In addition, the 10-year rates of death with histopathologically confirmed melanoma metastasis were not significantly different (45% in the pre-enucleation radiation arm and 40% in the enucleation-alone arm, P = .40).[1][Level of evidence: 1iiA]

Episcleral radionuclide plaque brachytherapy and external-beam, charged-particle radiation therapy offer patients eye-sparing and vision-sparing alternatives to enucleation.[2,3] Both treatment approaches result in relatively slow regression of uveal melanoma during a period of 6 months to 2 years. Most tumors regress to approximately 50% of their original thickness; only occasionally does a tumor regress to a completely flat scar.[2] Local control is achieved in a large proportion of treated eyes with either technique. The probability of visual preservation and of eye retention with either method is related to tumor size and location.

Plaque brachytherapy is the most frequently used eye-sparing treatment for choroidal melanoma. Iodine 125 (125 I), gold 198 (198 Au), palladium 103 (103 Pd), and other ophthalmic plaques can be effective in the treatment of medium-sized melanomas.[4,5,6,7]125 I is the most commonly used isotope because of its good tissue penetration, accessibility, adequate shielding of the source, and lesser risk to other ocular structures and medical personnel. Methods to ensure proper plaque placement are critical to successful radiation therapy.[8,9,10,11,12]

Results from the second COMS clinical trial, which compared 125 I plaque brachytherapy to enucleation in patients with medium-sized choroidal tumors, revealed no significant difference in cumulative all-cause mortality between the two study arms at 12 years of follow-up (43% for 125 I plaque brachytherapy vs. 41% for enucleation; risk ratio = 1.04; 95% CI, 0.86–1.24).[13][Level of evidence: 1iiA] In addition, the 12-year rates of death with histopathologically confirmed melanoma metastasis did not differ significantly between the 2 study arms (21% in the 125 I brachytherapy arm and 17% in the enucleation arm, P = .62). Among the patients treated with 125 I brachytherapy, 85% retained their eye for 5 years or more, and 37% had visual acuity better than 20/200 in the irradiated eye 5 years after treatment.[14]

Charged-particle radiation therapy can be performed with a proton beam or helium ions.[15,16] Some investigators report better tumor control with helium ion irradiation than with 125 I episcleral plaque treatment in terms of local tumor control and eye retention; however, more anterior segment complications are found.[15,17]

Another radiation therapy technique occasionally employed but not as extensively studied is Gamma Knife surgery. Preliminary evidence suggests that Gamma Knife surgery may be a feasible treatment option for medium-sized choroidal melanomas.[18]

STANDARD TREATMENT OPTIONS:

Tumor growth pattern is a factor in the therapeutic decision. If there is a diffuse melanoma or if there is extraocular extension, enucleation should be considered, but radiation therapy can be employed for less extensive disease.

Medium-sized choroidal melanomas

1. PLAQUE RADIATION THERAPY: Allows eye preservation in most patients, but vision is generally reduced; probability of vision preservation after treatment is related to tumor size and location.[2,3,4,5,6,7,8,9,10,11,12,14,15,19]
2. EXTERNAL-BEAM, CHARGED-PARTICLE RADIATION THERAPY: Provides precisely focused radiation with a homogeneous dose distribution pattern and little lateral spread; requires sophisticated equipment available only at selected centers; involves patient cooperation during treatment (voluntarily fixating the eye on a particular point so the tumor is positioned properly in the radiation beam); allows for good local tumor control and reasonable retention of the treated eye for periods of as long as 10 years after treatment, according to reports.[15,16,17]
3. LOCAL EYE-WALL RESECTION: Allows for good ocular retention rates and visual results; survival does not appear to be compromised.[20,21]
4. COMBINED THERAPY, WITH ABLATIVE LASER COAGULATION OR TRANSPUPILLARY THERMOTHERAPY TO SUPPLEMENT PLAQUE TREATMENT: Can be used to minimize recurrence; transpupillary thermotherapy can be used in conjunction with plaque radiation therapy for medium-sized and larger melanomas as an adjuvant treatment to enhance the effects of radiation therapy and to minimize damage to normal ocular tissue;[22] the addition of laser photocoagulation to plaque radiation therapy for juxtapapillary choroidal melanoma has been reported to increase tumor control substantially;[23] ocular side effects do occur but are usually not clinically significant.
5. ENUCLEATION: Is considered primarily if there is a diffuse melanoma or if there is extraocular extension; radiation complications or tumor recurrence may eventually make enucleation necessary.[22]

Large choroidal melanomas

1. RADIATION THERAPY PLUS ENUCLEATION.[24]
2. ENUCLEATION.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with ciliary body and choroid melanoma, medium/large size. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Hawkins BS; Collaborative Ocular Melanoma Study Group.: The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma: IV. Ten-year mortality findings and prognostic factors. COMS report number 24. Am J Ophthalmol 138 (6): 936-51, 2004.
2. Shields CL, Shields JA, Gündüz K, et al.: Radiation therapy for uveal malignant melanoma. Ophthalmic Surg Lasers 29 (5): 397-409, 1998.
3. Finger PT: Radiation therapy for choroidal melanoma. Surv Ophthalmol 42 (3): 215-32, 1997 Nov-Dec.
4. Earle J, Kline RW, Robertson DM: Selection of iodine 125 for the Collaborative Ocular Melanoma Study. Arch Ophthalmol 105 (6): 763-4, 1987.
5. Packer S, Stoller S, Lesser ML, et al.: Long-term results of iodine 125 irradiation of uveal melanoma. Ophthalmology 99 (5): 767-73; discussion 774, 1992.
6. Finger PT, Berson A, Szechter A: Palladium-103 plaque radiotherapy for choroidal melanoma: results of a 7-year study. Ophthalmology 106 (3): 606-13, 1999.
7. Karvat A, Duzenli C, Ma R, et al.: The treatment of choroidal melanoma with 198 Au plaque brachytherapy. Radiother Oncol 59 (2): 153-6, 2001.
8. Finger PT, Romero JM, Rosen RB, et al.: Three-dimensional ultrasonography of choroidal melanoma: localization of radioactive eye plaques. Arch Ophthalmol 116 (3): 305-12, 1998.
9. Hanna SL, Lemmi MA, Langston JW, et al.: Treatment of choroidal melanoma: MR imaging in the assessment of radioactive plaque position. Radiology 176 (3): 851-3, 1990.
10. Harbour JW, Murray TG, Byrne SF, et al.: Intraoperative echographic localization of iodine 125 episcleral radioactive plaques for posterior uveal melanoma. Retina 16 (2): 129-34, 1996.
11. Tabandeh H, Chaudhry NA, Murray TG, et al.: Intraoperative echographic localization of iodine-125 episcleral plaque for brachytherapy of choroidal melanoma. Am J Ophthalmol 129 (2): 199-204, 2000.
12. Finger PT, Iezzi R, Romero JM, et al.: Plaque-mounted diode-light transillumination for localization around intraocular tumors. Arch Ophthalmol 117 (2): 179-83, 1999.
13. Collaborative Ocular Melanoma Study Group.: The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma: V. Twelve-year mortality rates and prognostic factors: COMS report No. 28. Arch Ophthalmol 124 (12): 1684-93, 2006.
14. Diener-West M, Earle JD, Fine SL, et al.: The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma, III: initial mortality findings. COMS Report No. 18. Arch Ophthalmol 119 (7): 969-82, 2001.
15. Char DH, Quivey JM, Castro JR, et al.: Helium ions versus iodine 125 brachytherapy in the management of uveal melanoma. A prospective, randomized, dynamically balanced trial. Ophthalmology 100 (10): 1547-54, 1993.
16. Fuss M, Loredo LN, Blacharski PA, et al.: Proton radiation therapy for medium and large choroidal melanoma: preservation of the eye and its functionality. Int J Radiat Oncol Biol Phys 49 (4): 1053-9, 2001.
17. Char DH, Kroll SM, Castro J: Ten-year follow-up of helium ion therapy for uveal melanoma. Am J Ophthalmol 125 (1): 81-9, 1998.
18. Woodburn R, Danis R, Timmerman R, et al.: Preliminary experience in the treatment of choroidal melanoma with gamma knife radiosurgery. J Neurosurg 93 (Suppl 3): 177-9, 2000.
19. Melia BM, Abramson DH, Albert DM, et al.: Collaborative ocular melanoma study (COMS) randomized trial of I-125 brachytherapy for medium choroidal melanoma. I. Visual acuity after 3 years COMS report no. 16. Ophthalmology 108 (2): 348-66, 2001.
20. Char DH, Miller T, Crawford JB: Uveal tumour resection. Br J Ophthalmol 85 (10): 1213-9, 2001.
21. Peyman GA, Juarez CP, Diamond JG, et al.: Ten years experience with eye wall resection for uveal malignant melanomas. Ophthalmology 91 (12): 1720-5, 1984.
22. Seregard S, Landau I: Transpupillary thermotherapy as an adjunct to ruthenium plaque radiotherapy for choroidal melanoma. Acta Ophthalmol Scand 79 (1): 19-22, 2001.
23. Shields JA: The expanding role of laser photocoagulation for intraocular tumors. The 1993 H. Christian Zweng Memorial Lecture. Retina 14 (4): 310-22, 1994.
24. The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma II: initial mortality findings. COMS report no. 10. Am J Ophthalmol 125 (6): 779-96, 1998.

Extraocular Extension and Metastatic Intraocular Melanoma

Extrascleral extension usually confers a poor prognosis. For patients with gross tumor involvement of the orbit, treatment requires orbital exenteration often combined with preoperative or postoperative radiation therapy; however, there is no evidence that this radical surgery will prolong life. Most patients with localized or encapsulated extraocular extension are not exenterated. This subject is controversial.[1,2,3,4,5]

No effective method of systemic treatment has been identified for patients with metastatic ocular melanoma.[6]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with extraocular extension melanoma and metastatic intraocular melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

1. Shammas HF, Blodi FC: Prognostic factors in choroidal and ciliary body melanomas. Arch Ophthalmol 95 (1): 63-9, 1977.
2. Pach JM, Robertson DM, Taney BS, et al.: Prognostic factors in choroidal and ciliary body melanomas with extrascleral extension. Am J Ophthalmol 101 (3): 325-31, 1986.
3. Kersten RC, Tse DT, Anderson RL, et al.: The role of orbital exenteration in choroidal melanoma with extrascleral extension. Ophthalmology 92 (3): 436-43, 1985.
4. Hykin PG, McCartney AC, Plowman PN, et al.: Postenucleation orbital radiotherapy for the treatment of malignant melanoma of the choroid with extrascleral extension. Br J Ophthalmol 74 (1): 36-9, 1990.
5. Gündüz K, Shields CL, Shields JA, et al.: Plaque radiotherapy for management of ciliary body and choroidal melanoma with extraocular extension. Am J Ophthalmol 130 (1): 97-102, 2000.
6. Wöll E, Bedikian A, Legha SS: Uveal melanoma: natural history and treatment options for metastatic disease. Melanoma Res 9 (6): 575-81, 1999.

Recurrent Intraocular Melanoma

The prognosis for any patient with recurring or relapsing disease is poor, regardless of cell type or stage. The question and selection of further treatment depends on many factors, including the extent of the lesion, age and health of the patient, prior treatment, and site of recurrence, as well as individual patient considerations. Clinical trials are appropriate and should be considered whenever possible.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent intraocular melanoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

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Changes to This Summary (12 / 05 / 2007)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Added Purpose of This PDQ Summary as a new section.

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Date Last Modified: 2007-12-05

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