Uveal melanoma represents the most common primary malignant tumor of the eye in adults with a peak incidence between ages 55 and 70 years. It affects 6–7 people per million each year, and approximately 50 % of patients with diagnosed melanomas of the chorioid or ciliary body will die from this tumor within 15 years [17]. The incidence is rare in patients younger than 20 years. The incidence of cutaneous melanomas has been increasing in frequency over the past several decades and the dependence on latitude has been observed, reflecting levels of exposure to ultraviolet light. This trend has not been evident for patients with uveal melanomas. Uveal melanomas are neoplasm arising from the uveal tract, which includes the iris, ciliary body, and chorioid. Two types of tumor growth were recognized, nodular and infiltrative. Histologically, the tumor consists of spindle cells, epithelioid cells, and intermediate cells similar to those of cutaneous melanoma, but the prognosis is better than that associated with cutaneous melanomas.

The uveal tract is a vascular structure with no lymphatic drainage. Lymphatic node involvement (auricular, submandibular, and cervical nodes) can be diagnosed on rare occasions when subconjunctival extension of primary tumor has been observed. The major routes of spread are local growth and by bloodstream, with a predilection for hematogenous dissemination to the liver, lung, and brain. Liver metastases are diagnosed in two-thirds of patients with disseminated diseases. Systemic examination is recommended for all patients and includes CT of the chest and abdomen, and MRI of the brain to detect metastases. Wide variations in the grading of malignancy can be observed, from relatively benign types with several years’ survival without dissemination, to other tumors with fast multiorgan dissemination, which lead to the patient’s death within a few months.

The iris melanomas (incidence about 10 %) are single or multiple elevated lesions with changes of iris color. These types of melanomas are much more benign, smaller in size, readily visible, and early diagnosed. It can be difficult to assess the potential of the malignant cells, even in those with documented growth, because iris nevi may also grow. For this reason, local resection is usually effective whenever it seems to be necessary.

Choroidal melanomas typically grow in nodular form, and in cases of continuing growth many tumors break through the Bruch membrane. The Bruch membrane is a basement membrane–connective tissue complex lying between the retina pigment epithelium and the choriocapillaries. When the melanomas break through the Bruch membrane, they extend into the subsensory retina space, which gives them a mushroom or collar-button shape. These characteristics, as well as the detachment of the retina, are typical for uveal melanomas. This type of tumor growth is sometimes accompanied by vitreous hemorrhage with symptoms of sudden visual loss.

Melanomas involving the ciliary body are rare, carry a poor prognosis, and are often diagnosed late. Melanomas can also have diffuse, infiltrative growth to the ciliary body and a pattern called ring melanoma. These tumors are diagnosed with difficulty and late, because they are accompanied by relatively little visible tumor mass effect and they occur in the diagnostically “silent” eye area. Any extra scleral extension of the tumor usually confers a poor prognosis. The diffuse growing melanomas are usually more aggressive, with more malignant cell types.

Tumor growth is also influenced on the potential doubling time (T pot) which varies widely between 60 and 350 days (the median of T pot being about 70 days) [18]. A longer T pot for a significant proportion of tumors can explain the relatively long survival of these patients and also the relatively slow tumor response after irradiation.

Surgical methods include resection of the eye wall (for very small visible melanomas of the iris), enucleation, and orbital exenteration [20]. The role of enucleation in the management of posterior to equator localized melanomas is controversial, but enucleation remains the standard option for most large choroidal melanomas that cause severe secondary glaucoma or are invading the optic nerve.

Preoperative or postoperative irradiation is a promising approach under evaluation that could also decrease the chances of malignant dissemination, however recent study observed no benefit [21]. Postoperative external beam radiotherapy has been used in patients with large tumors with extrascleral or extraocular extension. The recommended total applied dose is 60 Gy with daily fractionation.

The most frequently used therapeutic system for delivering radiation is brachytherapy (plaque radiotherapy). A number of radionuclides, including cobalt-60, gold-198, iodine-125, ruthenium-106, iridium-192, and palladium-103, have been used for plaque therapy with varying results according to the retrospective studies [22, 23]. A metal shield containing small radioactive seeds is sutured to the outside of the sclera overlying the tumor with radiation doses principally delivered to the base of the tumor. The radioactive plaque is left in place for approximately 5–7 days. Cobalt-60 was one of the first isotopes to be used in brachytherapy, but it is a high-energy gamma emitter and thus there exists a risk of damaging healthy ocular structures several millimeters from the source. Other isotopes have been used: iodine-125 is also a gamma emitter but has lower energy than cobalt-60 and, because of this, it is associated with a lower rate of complications. Brachytherapy leads to long-term local tumor control in 85–90 % of patients and can be used to treat small melanomas [22, 23]. The best results can be achieved in tumors less than 10 mm in height and with a base diameter not exceeding 16 mm. Patients with extrascleral tumor extension, ring melanoma, and tumor involvement of more than half of the eye are not suitable for plaque therapy.

Patients with tumors too large for brachytherapy or tumors considered too close to the optic nerve have been recommended for proton beam therapy (PBT). Early studies with PBT recognized that severe damage was caused to the eyelid and the anterior parts of the eye. Patients with tumors localized near the eye surface had a higher incidence of severe toxicity because the sparing effect of Bragg peak was absent. Many of these patients had chronically painful and cosmetically unsatisfactory eyes. Local tumor control in 90–98 % of patients was achieved by this method in a large series [24]. The technique was subsequently improved and the complication rate has dropped accordingly.

Helium ion irradiation is uniquely suited to the precise localization of irradiation because of the sharp falloff of the dose at the distal end of the Bragg peak, the sharp lateral edges of the beam, and the ability to tailor the depth penetration and spread by a modulated Bragg peak. Uveal melanomas are indicated for this treatment. When the charged particles are used to treat the uveal melanoma, the normal tissue of the anterior part of the eye can receive a radiation dose comparable with the tumor dose. This fact causes radiation toxicity in the anterior parts of the eye leading to side effects such as eyelash loss, lacrimal damage, conjunctival changes, dry eye syndrome, keratitis, and neovascular glaucoma [25, 26]. Local tumor control is achieved in 96 % of patients and the enucleation rate is 19 % (3 % for local failure and 16 % due to complications) [26].

The advantage of stereotactic irradiation using a linear accelerator is the possibility of fractionated treatments compared with the Leksell Gamma Knife. Fractionation may decrease late-radiation-related toxicity, and this fact was the subject of intensive study [8, 9, 11, 16, 27–29]. The reported mean applied minimal dose ranged from 25 to 45 Gy in two fractions and 15 Gy in three equal fractions. Local tumor control, defined as freedom of local progression, was reported in 98 % of patients [29]. Further clinical studies using fractionated stereotactic irradiation are justified to optimize the effective dose and fractionation pattern.

The first experiments with radiosurgery for the treatment of uveal melanomas were conducted using the rabbit eye melanoma model, with reported tumor lethal dose range from 60 to 90 Gy applied in a single session. A preliminary study of 11 treated patients with uveal melanomas was published in 1992 and suggested that local tumor control could be achieved with a minimal dose between 60 and 90 Gy in a single dose using the Leksell Gamma Knife. Some observations were made on patients after radiosurgery who had their eyes secondarily enucleated. All eyes with secondary enucleations presented an initial height exceeding 9 mm and also had a large number of ciliary body tumors [30]. Several authors reported the results of radiosurgery in uveal melanomas and some of them observed relatively high radiation-related toxicity [4, 30, 31].

Dinca et al. reported the UK experience in treating ocular melanoma over the last 20 years [3]. One hundred seventy patients who were treated with Gamma Knife radiosurgery were compared with 620 patients treated with eye enucleation. Different peripheral doses (at the 50 % isodose) were employed. There was no significant difference in survival between the 35-Gy, 45-Gy, and 50–70-Gy groups when compared between themselves (p = 0.168) and with the enucleation group (p = 0.454). The 5-year survival rates were: 64 % for 35 Gy, 62.71 % for 45 Gy, 63.6 % for 50–70 Gy, and 65.2 % for enucleated patients. Clinical variables influencing survival for radiosurgery patients were tumor volume (p = 0.014) and location (median 66.4 months for juxtapapillary vs. 37.36 months for peripheral tumors, (p = 0.001). Regarding complications, using 35 Gy led to more than a 50 % decrease in the incidence of cataract, glaucoma and retinal detachment, compared with the 45-Gy dose. Retinopathy, optic neuropathy, and vitreous hemorrhage were not significantly influenced. Blindness decreased dramatically from 83.7 % for 45 Gy to 31.4 % for 35 Gy (p = 0.006), as well as post-radiosurgery enucleation: 23.9 % for 45 Gy vs. 6.45 % for 35 Gy (p = 0.018). Visual acuity, recorded up to 5 years post-radiosurgery, was significantly better preserved for 35 Gy than for 45 Gy (p = 0.0003). It appears that using 35 Gy results in a dramatic decrease in complications, visual loss, and salvage enucleation, while not compromising patient survival.

Sarici et al. reported on 50 eyes from 50 consecutive patients with uveal melanoma that were treated with GKRS and had a median follow-up time of 40 months. They used a dose of 30 Gy, which is an eye-sparing outpatient option for patients with medium- or large-sized posterior uveal melanomas who are not eligible for brachytherapy or particle therapy. The tumor control rate was 90 %, and the eye retention rate was 82 %. Metastases developed in 18 % of patients with 14 % dying of metastases during follow-up. Cataracts (34 %) and radiation maculopathy (30 %) were the most frequent complications, and 14 % of patients developed neovascular glaucoma. Visual acuity (VA) also decreased significantly after treatment (p < 0.0001) [32].

Šimonová, et al. studied a group of 126 patients with uveal melanoma treated using the Leksell Gamma Knife over a period of 8 years with all survivors undergoing minimal follow-up 24 months after the treatment. The late effect of normal tissue (LENT) subjective objective management analysis (SOMA) scoring system is acceptable for measurement of radiation side effects (Table 62.4).