Radiation Therapy

Episcleral brachytherapy using plaques containing small radioactive seeds is the most common form of radiation used in the management of intraocular melanoma. Iodine I 125 (125I), cobalt Co 60 (60Co), palladium Pd 103 (103Pd), iridium Ir 192 (192Ir), and ruthenium Ru 106 (106Ru) are examples of radioactive isotopes used in the brachytherapy plaques. Isotopes with relatively low photon and electron emissions (125I, 103Pd, and 106Ru) are more easily shielded to reduce the exposure to adjacent normal tissues, and 125I is probably the most commonly used radioisotope.[15] Although plaque radiation therapy allows preservation of the eye, visual acuity is frequently lost over time.

In a case series of 1,106 patients who were treated with plaque radiation therapy for uveal melanoma and who had an initial acuity of at least 20/100, 68% developed poor acuity (i.e., 20/200 or worse) within 10 years.[16]

Factors associated with worse acuity outcomes included:[16]

125I brachytherapy yields equivalent overall and melanoma metastasis-specific survival rates to enucleation for medium-sized melanomas.[17][Level of evidence A1] The randomized COMS Medium Tumor Trial compared 125I episcleral-plaque brachytherapy (85 Gy at 0.42–1.06 Gy/hr) with enucleation in 1,317 patients with medium-sized choroidal tumors (tumor height 2.5–10.0 mm and tumor diameter ≤16.0 mm that were not contiguous with the optic disc).[17] Eighty-five percent of the patients treated with 125I brachytherapy retained their eye for 5 years or more, and 37% of them had visual acuity better than 20/200 in the irradiated eye 5 years after treatment.[17] No statistically significant differences in mortality were observed between the two study arms after 12 years of follow-up, either for death from all causes or death with histopathologically confirmed melanoma metastasis.[18] The 5- and 10-year all-cause mortality rates were 19% and 35% in both study arms. The cumulative all-cause mortality rate at 12 years was 43% in the 125I arm versus 41% in the enucleation arm (RR, 1.04; 95% CI, 0.86–1.24). The 5-year metastasis-specific mortality rates were 13% in both arms; at 10 years, the rates were 21% and 22% (RR for metastasis-specific mortality, 1.07; 95% CI, 0.81–1.41 through 12 years).

In a companion study within the COMS, 209 patients were prospectively assessed for quality of life during the first 5 years of follow-up.[19] Both study groups reported increasing difficulty with vision-oriented daily activities and ocular pain as time elapsed. Most measures of visual function were similar between the two groups. However, there were statistically significant differences favoring the brachytherapy group in comfort with driving for the first year after therapy and in reported peripheral vision for the first 2 years after therapy. These differences disappeared by year 5 of follow-up.[19][Level of evidence A3]

Charged-particle EBRT (using protons, carbon ions, or helium ions) is the other major form of radiation therapy used in the management of ocular melanomas.[20-23] This form of radiation therapy requires sophisticated equipment available only at selected centers. In addition, charged-particle EBRT involves patient cooperation during treatment (e.g., voluntarily fixating the eye on a particular point so the tumor is positioned properly in the radiation beam). A lower risk of early and late local radiation failures has been reported after charged-particle EBRT than after the use of brachytherapy, possibly resulting from differences in dose distribution in the two techniques.[20][Levels of evidence B3 and C3]

In a single-center, single-surgeon study, 184 patients with uveal melanomas smaller than 15 mm in diameter and smaller than 10 mm in thickness were randomly assigned to receive 125I brachytherapy versus helium ion radiation (to an estimated dose of 70 Gy equivalents in 5 fractions over 7 to 11 days in each arm).[24] The local tumor regrowth rate by 4 years was 13.3% in the brachytherapy arm compared with 0% in the helium ion arm (P < .001). However, the rates of metastasis, death from metastasis, and overall mortality were similar in both arms.[24][Level of evidence B3]

Because of its dose distribution, charged-particle irradiation can be better used than plaque brachytherapy to treat larger tumors and tumors closer to the fovea or optic disc. A large, single-center, single-surgeon series of 2,069 patients treated with proton-beam therapy had an actuarial local control rate of 95% (95% CI, 93%–96%) at 15 years. The cumulative rate of enucleation was 16% (95% CI, 13%–20%). Enucleations were primarily the result of neovascular glaucoma (46% of enucleations), blind uncomfortable eyes (31% of enucleations), or local recurrence (23% of enucleations). As with plaque radiation, risk factors for deterioration in visual acuity after charged-particle radiation were tumor size, location near the fovea or optic disc, baseline acuity, and underlying diabetes.[21]

Similarly, another large, single-center, single-surgeon, consecutive series of 886 patients treated with proton-beam irradiation reported a local control rate of 92.1% (95% CI, 89.8%–94.6%) and ocular conservation rate of 87.3% (95% CI, 83.9%–90.9%) at 10 years.[22][Level of evidence C3] The actuarial OS rate at 10 years was 64.1% (95% CI, 59.5%–69.0%).

In a single-center, phase I/II study of 57 evaluable patients treated with carbon ion-beam irradiation and followed for a median of 26 months, 26 patients developed neovascular glaucoma or severe eye pain from increased intraocular pressure, and 3 patients underwent enucleation. One patient had a local tumor recurrence.[23]

In an attempt to lower the complication rate and improve functional outcomes, one study compared a decreased dose of 50 cobalt Gy equivalents (CGE) with 70 CGE proton beam (each delivered in 5 fractions, usually within a 7-day period). Patients (n = 188) with tumors smaller than 15 mm in diameter and smaller than 5 mm in height, which were located near the optic disc or macula, were randomly assigned to the two doses in a double-masked study design. At 5 years, there were no statistically significant differences in local tumor control, rate of metastasis, visual acuity, or complication rates. However, the visual fields were better in the 50-CGE group.[25][Level of evidence B3]

As noted in the Surgery section, the role of pre-enucleation external photon-beam radiation therapy has been tested in a randomized trial and has shown no impact on OS for large choroidal tumors treated with enucleation.[8,9]

External-beam–photon-beam (gamma-ray) radiation therapy with gamma-knife stereotactic radiation surgery as a single-fraction [26] or fractionated stereotactic radiation [27,28] is being investigated as an alternative to brachytherapy or charged-beam radiation for posterior uveal melanomas, particularly for tumors too large or too close to the optic disc or macula to treat with brachytherapy. Because the dose rate of radiation has a slower delivery time than is the case with charged particles, specialized techniques are used to immobilize the eye [26] or to avoid delivery of the photons while the eye is moving or closed.[28] Experience is more limited with external-beam–photon therapy than for either brachytherapy or charged-particle EBRT, and there are no controlled comparisons with either of the other techniques. Early results from single-center series suggest similar levels of local tumor control and eye retention rates, but patient-selection factors may play a role.[28][Level of evidence C3]