Melanoma is a type of tumor that arises from cells called melanocytes, which are responsible for making dark pigment. Most often, melanoma arises in the skin; however, melanocytes are found in many other places in the body where pigment is made. Ocular melanoma is a type of melanoma that arises in the eye. Ocular (or uveal) melanoma behaves differently than skin melanoma.
It isn’t – in fact, it is very rare. The annual incidence of ocular melanoma in the United States is 6 cases per 1 million persons, or about 1,500 new diagnoses per year. Ocular melanoma, and specifically melanoma of the uveal tract, not only poses a major threat to the function of the eye, but is a potentially fatal condition.
When they grow within the eye, these tumors can cause a variety of problems, including retinal detachment, astigmatism, cataracts, glaucoma, and inflammation. Like melanomas of the skin, they can spread to other sites in the body through the bloodstream (metastatic disease).
The different types of ocular melanoma correspond to the exact location in the eye where the tumor starts:
Relative to other solid tumors, ocular melanoma causes only a small number of cancer deaths annually in the United States. Having said that, and although it is potentially curable, approximately 25% of all affected patients eventually die from metastatic disease. The odds may be worse among patients who have certain tumor characteristics that are indicative of poor prognosis. Depending on the tumor size and location, therapies range from local ablative procedures to eye enucleation (removal of the entire eyeball and other structures in the eye socket). A major goal of clinical research has been to maximize cure rates while striving to preserve useful vision and avoid surgical removal of the eye.
Patients are often diagnosed during routine ophthalmologic exams. Patients must undergo a full work-up, including a full ophthalmologic exam, to establish the diagnosis and stage.
In the past, ocular melanoma has been successfully treated with surgery, namely enucleation (removal of the entire eye). In addition to taking away vision in the eye that is removed, enucleation also results in a cosmetic defect that can seriously impact a patient’s self-esteem. Therefore, “organ-preserving” treatments have been developed to preserve not only the eye, but also potentially vision.
Radiation is a major alternative to enucleation. Radiotherapy techniques include brachytherapy, stereotactic radiation (Dieckmann et al 2003), and proton radiotherapy. Other local treatments that do not involve ionizing radiation include trans-scleral local resection, transretinal resection and diode laser phototherapy. Proton radiotherapy is emerging as one of the most effective treatments of ocular melanoma, although its use has been confined to a few major centers in the world (see below).
One of the most commonly used treatments is brachytherapy. This involves temporarily attaching radioactive materials (called “plaques”) to the eye, usually with I-125 or Ruthenium-106. While left in place, the plaques emit radiation that penetrates a very short distance, allowing treatment of the tumor (and eye) without reaching other important tissues, like the brain or the other eye. This technique is limited to treating thin tumors (less than 8-10 mm thick) based on the penetration of the radioisotope.
When larger tumors need to be treated, external radiation can be used, ideally with very conformal radiation techniques. Stereotactic radiation uses photons (x-rays or gamma rays) that are highly concentrated on the tumor itself. Despite attempts to focus on the tumors, photons pass right through the body, radiating tissues as they exit. Protons, on the other hand, are heavy particles that deliver radiation dose to deep structures, but do not deposit any “exit dose,” meaning that they “stop on a dime”. This means that less radiation dose is delivered unnecessarily to healthy tissues.
Tumor Localization: The tumor must first be localized using transillumination and/or indirect ophthalmoscopy during surgery. Four markers (tantalum rings) are sewn to the outside of the eyeball (sclera) at the edges of the tumor. The measurements of the tumor are measured on the sclera, and drawings are made to document the shape of the tumor and the location of the tantalum rings. This information is put into a treatment-planning computer program. For tumors involving the front part of the eye (ciliary body and peripheral choroid), transillumination can be used to define the tumor in relation to the iris and cornea without the need for surgery.
Proton Radiation Planning: Simulation uses an interactive, three-dimensional treatment-planning program that helps determine all treatment parameters needed, including the position of the eye and all the settings for the proton radiation machine. These parameters are used to create a patient-specific treatment plan. During the simulation, x-rays are taken to determine the location of the tantalum rings in the treatment position. This information, along with the data from the drawings generated at the time of the surgery, and ultrasound measurements of the eye and tumor, are used to create a three-dimensional model of the tumor that is superimposed on a model of a normal eye, scaled to the patient’s eye. These parameters are defined to develop a treatment plan that will optimize the radiation dose to the tumor while minimizing irradiation of critical structures.
Proton Treatment of the Eye: A high-magnification closed-circuit television system is used to view the eye throughout the procedure. Patients are treated on a specialized chair positioned in the line of a fixed beam proton beam. Before irradiation, the patient’s head is immobilized, and the position of the eye is set. X-ray pictures used to position the tumor relative to the proton beam axis and to monitor immobilization of the eye during treatment. The treatment beam is checked with a beam-simulation field light, and treatment begins after confirming that the position and fixation are adequate.
The typical radiation dose is 70 cobalt Gy equivalents (CGE), delivered in five equal fractions of 14 CGE over 7 to 10 days. Alternate fractionation schemes include 60 CGE in 4 fractions.
Harvard has had a large experience treating uveal melanoma with proton radiotherapy. Between 1975-1986, 1006 adult patients were treated with protons at the Harvard Cyclotron, and excellent local control and probability of eye retention were achieved (Munzenrider et al, 1988 and 1989). Gragoudas et al. has updated this very extensive clinical experience with proton therapy, now with over 3000 patients treated during the past 30 years. This group has established strong evidence of the advantages of this modality for patients with uveal melanoma, particularly those with tumors that are large and/or are posteriorly located, for which other types of radiotherapy may be unsuitable or may produce more complications. Other centers have reported similar results with significant numbers of patients. The Hahn-Meitner Institute in Berlin reported on 245 patients with uveal melanoma treated with proton therapy (60 CGE in 4 fractions of 15 CGE) from 1998 to 2003 (Höcht et al 2004). The local control rate was 96.4% at 18.4 months (median) and 95.5% at 3 years of follow-up. The eye retention rate was 92.6% at 20 months (median) and 87.5% at 3 years. The Orsay Center similarly reported on 1,406 patients treated with 60 CGE in 4 fractions (Dendale et al 2006). The OS was 79% and the local control was 96% at 5 years with a 7.7% enucleation rate for complications. At the Biomedical Cyclotron Centre in Nice, France, 224 patients with uveal melanoma were treated with proton radiotherapy (Kodjikian et al 2004). They reported an OS of 78%, enucleation free survival rate of 70% at 5 year with only 10 patients having local recurrences (4.5%). Altogether, these data show that proton radiotherapy can provide excellent local control with good rates of eye preservation, suggesting that late side effects are minimal.
Brachytherapy. One study (Char et al 2002) compared outcomes in patients treated with brachytherapy with patients treated with proton radiotherapy. Compared with patients with uveal melanomas treated with I-125 brachytherapy, patients treated with proton radiotherapy had relatively fewer late (more than 5 years) local recurrences. Of the 996 patients studied, all of the 11 late recurrences were in the patients treated with I-125 brachytherapy.
Stereotactic Radiation. Compared with other highly conformal external beam radiotherapy, (e.g. stereotactic radiosurgery), “non double-scattered” proton radiotherapy delivers the least dose to normal structures, especially the contralateral eye as well as distant sites such as the pelvis (Zytkovicz et al, 2007; Weber 2005).
Proton radiotherapy for uveal melanomas is sometimes complicated by exudation from the tumor scar and glaucoma, requiring enucleation. A randomized trial evaluating the addition of transpupillary thermotherapy was conducted in 151 patients that showed promise in decreasing the rate of enucleation for these complications (p=0.02) (Desjardins et al 2006). The additions of systemic therapies given concurrently with proton radiotherapy have not been well described.
The standard approach to local recurrence is enucleation, however, alternatives have been sought to preserve the eye. Re-irradiation with proton radiotherapy the second time around has been used to treat a small number of patients (Marucci et al 2006). Of 31 patients treated with a second course, (usually 70 CGE), 20 had no evidence of disease after re-treatment. The 5-year eye retention rate in this series was 55%.
Ocular melanoma is a rare but potentially devastating cancer that can result in loss of vision, loss of the eye, and death. Proton radiotherapy can be useful in certain patients, and although it is limited in availability currently, it is becoming more prevalent as more centers open.
Char DH, Kroll S, Phillips TL, Quivey JM. Late radiation failures after iodine 125 brachytherapy for uveal melanoma compared with charged-particle (proton or helium ion) therapy. Ophthalmology. 2002;109:1850-4.
Damato B. Developments in the management of uveal melanoma. Clin Experiment Ophthalmol. 2004;32:639-47.
Desjardins L, Lumbroso-Le Rouic L, Levy-Gabriel C, Dendale R, Delacroix S, Nauraye C, Estève M, Plancher C, Asselain B. Combined proton beam radiotherapy and transpupillary thermotherapy for large uveal melanomas: a randomized study of 151 patients. Ophthalmic Res. 2006;38:255-60.
Dendale R, Lumbroso-Le Rouic L, Noel G, Feuvret L, Levy C, Delacroix S, Meyer A, Nauraye C, Mazal A, Mammar H, Garcia P, D'Hermies F, Frau E, Plancher C, Asselain B, Schlienger P, Mazeron JJ, Desjardins L. Proton beam radiotherapy for uveal melanoma: results of Curie Institut-Orsay proton therapy center (ICPO). Int J Radiat Oncol Biol Phys. 2006; 65:780-7.
Dieckmann K, Georg D, Zehetmayer M, Bogner J, Georgopoulos M, Potter R. LINAC based stereotactic radiotherapy of uveal melanoma: 4 years clinical experience. Radiother Oncol 2003; 67:199– 206.
Gragoudas ES. Proton Beam Irradiation of Uveal Melanomas: The First 30 Years. Investigative Ophthalmology and Visual Science 2006;47:4666-4673.
Goitein M, Miller T. Planning proton therapy of the eye. Med Phys. 1983 May-Jun;10(3):275-83.
Höcht S, Bechrakis NE, Nausner M, Kreusel KM, Kluge H, Heese J, Heufelder J, Cordini D, Homeyer H, Fuchs H, Martus P, Foerster MH, Wiegel T, Hinkelbein W. Proton therapy of uveal melanomas in Berlin. 5 years of experience at the Hahn-Meitner Institute. Strahlenther Onkol.180:419-24.
Kodjikian L, Roy P, Rouberol F, Garweg JG, Chauvel P, Manon L, Jean-Louis B, Little RE, Sasco AJ, Grange JD. Survival after proton-beam irradiation of uveal melanomas. Am J Ophthalmol. 2004;137:1002-10.
Marucci L, Lane AM, Li W, Egan KM, Gragoudas ES, Adams JA, Collier JM, Munzenrider JE. Conservation treatment of the eye: Conformal proton reirradiation for recurrent uveal melanoma. Int J Radiat Oncol Biol Phys. 2006;64:1018-22.
Munzenrider JE, Verhey LJ, Gragoudas ES, Seddon JM, Urie M, Gentry R, et al. Conservative treatment of uveal melanoma: local recurrence after proton beam therapy. Int J Radiat Oncol Biol Phys 1989;17(3):493-8.
Munzenrider JE, Gragoudas ES, Seddon JM, Sisterson J, McNulty P, Birnbaum S, et al. Conservative treatment of uveal melanoma: probability of eye retention after proton treatment. Int J Radiat Oncol Biol Phys 1988;15(3):553-8.
Weber DC, Bogner J, Verwey J, Georg D, Dieckmann K, Escudé L, Caro M, Pötter R, Goitein G, Lomax AJ, Miralbell R. Proton beam radiotherapy versus fractionated stereotactic radiotherapy for uveal melanomas: A comparative study. Int J Radiat Oncol Biol Phys. 2005; 63:373-84.
Zytkovicz A, Daftari I, Phillips TL, Chuang CF, Verhey L, Petti PL. Peripheral dose in ocular treatments with CyberKnife and Gamma Knife radiosurgery compared to proton radiotherapy. Phys Med Biol. 2007 52:5957-71