Comparison of Germline versus Somatic BAP1 Mutations for Risk of Metastasis in Uveal Melanoma.

BACKGROUND: Germline mutations in BAP1 have been associated with BAP1-Tumor Predisposition Syndrome (BAP1-TPDS), a predisposition to multiple tumors within a family that includes uveal melanoma (UM), cutaneous melanoma, malignant mesothelioma and renal cell carcinoma. Alternatively, somatic mutations in BAP1 in UM have been associated with high risk for metastasis. In this study, we compare the risk of metastasis in UM that carry germline versus somatic BAP1 mutations and mutation-negative tumors. METHODS: DNA extracted from 142 UM and matched blood samples was sequenced using Sanger or next generation sequencing to identify BAP1 gene mutations. RESULTS: Eleven of 142 UM (8%) carried germline BAP1 mutations, 43 (30%) had somatic mutations, and 88 (62%) were mutation-negative. All BAP1 mutations identified in blood samples were also present in the matched UM. There were 52 unique mutations in 54 tumors. All were pathogenic or likely pathogenic. A comparison of tumors carrying somatic vs. germline mutations, or no mutations, showed a higher frequency of metastasis in tumors carrying somatic mutations: 74% vs. 36%, P=0.03 and 74% vs. 26% P<0.001, respectively. Tumors with a somatic mutation compared to mutation-negative had an older age of diagnosis of (61.8 vs. 52.2 years, P=0.002), and shorter time to metastasis (16 vs. 26 months, P=0.04). Kaplan-Meier analysis further showed that tumors with somatic (vs. germline) mutations demonstrated a greater metastatic risk (P=0.03). Cox multivariate analysis showed in addition to chromosome-3 monosomy and larger tumor diameter, the presence of BAP1 somatic, but not germline mutations, was significantly associated with risk of metastasis(P=0.02). Personal or family history of BAP1-TPDS was available for 79 of the cases. All eight cases with germline mutations reported a history of BAP1-TPDS, which was significantly greater than what was observed in cases with somatic mutations (10 of 23, P=0.009) or mutation-negative cases (11 of 48, P<0.001). CONCLUSIONS: Defining germline vs. somatic nature of BAP1 mutations in UM can inform the individual about both the risk of metastasis, and the time to metastasis, which are critically important outcomes for the individual. This information can also change the cascade screening and surveillance of family members.

Intra-Arterial Chemotherapy for Retinoblastoma in Infants ≤10 kg: 74 Treated Eyes with 222 IAC Sessions.

BACKGROUND AND PURPOSE: Intra-arterial chemotherapy for retinoblastoma has dramatically altered the natural history of the disease. The remarkable outcomes associated with a high safety profile have pushed the envelope to offer treatment for patients weighing ≤10 kg. The purpose was to determine the efficacy and safety of IAC infusions performed in infants weighing ≤10 kg with intraocular retinoblastoma. MATERIALS AND METHODS: A retrospective chart review was performed for patients diagnosed with retinoblastoma and managed with intra-arterial chemotherapy. RESULTS: The total study cohort included 207 retinoblastoma tumors of 207 eyes in 196 consecutive patients who underwent 658 intra-arterial chemotherapy infusions overall. Of these, patient weights were ≤10 kg in 69 (35.2%) and >10 kg in 127 (64.8%) patients. Comparison (≤10 kg versus >10 kg) revealed that the total number of intra-arterial chemotherapy infusions was 222 versus 436. Periprocedural complications were not significantly different (2 [0.9%] versus 2 [0.5%]; P = .49). Cumulative radiation exposure per eye was significantly lower in infants weighing ≤10 kg (5.0 Gym2 versus 7.7 Gym2; P = .01). Patients weighing ≤10 kg had a greater frequency of complete tumor regression (82.6% versus 60.9%; P = .02). Mean fluoroscopy time was not significantly different (7.5 versus 7.2; P = .71). There was a significant difference in the frequency of enucleation (16 [21.6%] versus 52 [39.1%]; P = .01). Patients weighing ≤10 kg had greater number of aborted procedures (12 [5.4%] versus 7 [1.6%]; P = .01). On multivariate analysis, weight ≤10 kg was not an independent predictor of complications or procedure failure. CONCLUSIONS: Intra-arterial chemotherapy in patients weighing ≤10 kg is a safe and effective treatment.

Polypoidal choroidal vasculopathy following photodynamic therapy for choroidal hemangioma.

PURPOSE: To report a case of circumscribed choroidal hemangioma (CCH) that responded to photodynamic therapy (PDT) but 3 years later developed polypoidal choroidal vasculopathy (PCV) with exudative retinopathy. METHODS: Case report. RESULTS: A 59-year-old woman with a juxtapapillary CCH in her left eye was treated with a single 83-second, 7.5 mm PDT laser spot at 689 nm (50 J/cm2) 15 minutes after the injection of intravenous verteporfin (6 mg/m2). Three years later, the patient presented with photopsia in her left eye. Fundus examination of the left eye showed CCH regressed completely to a flat atrophic scar. There was diffuse macular edema and exudative retinopathy along the inferotemporal vascular arcade. On indocyanine green angiography, there were hyperfluorescent dilated choroidal vessels inferior to the foveola with late staining and leakage consistent with PCV. Hypofluorescence superior and nasal to the optic disc at the site of the treated hemangioma, consistent with choroidal ischemia, was observed. She was treated with 1.25 mg (0.05 cc) intravitreal bevacizumab. After 21 months of follow-up, the exudative retinopathy and macular edema completely regressed. CONCLUSIONS: PDT is an effective treatment for CCH. Side effects of PDT for CCH are rare but include PCV.

Retinal sensitivity and photoreceptor arrangement changes secondary to congenital simple hamartoma of retinal pigment epithelium.

BACKGROUND: The congenital simple hamartoma of the retinal pigment epithelium is a benign lesion and previous observations with noninvasive imaging have detected potential photoreceptor abnormalities and retinal function interplay. CASE PRESENTATION: A 35-year-old woman was found to have an asymptomatic, solitary, circumscribed, pigmented lesion in her left eye. The patient underwent ophthalmic examination including multimodal evaluation with fluorescein angiography, near-infrared reflectance scanning laser ophthalmoscopy, blue autofluorescence, enhanced-depth imaging spectralis B-scan optical coherence tomography (EDI-SBOCT), en face OCT angiography (OCT-A) and microperimetry plus adaptive optics imaging. Ophthalmoscopic examination revealed a juxtafoveolar pigmented lesion with feeding retinal arteriole, consistent with congenital simple hamartoma of RPE. There was no macular edema, exudation, hemorrhage, traction or subretinal fluid. Multimodal imaging of the mass using fluorescein angiography revealed intra-lesion late staining, near-infrared reflectance imaging demonstrated intrinsic hyperreflectivity, short-wavelength autofluorescence and red-free filter photography revealed blocked signal, and SBOCT showed abrupt shadowing. On OCT-A, an exclusive ring-shaped vascular circuit with increased foveal avascular zone was noted. Adaptive optics revealed cell density arrangement and retinal sensitivity correlations on microperimetry. CONCLUSION: These findings suggest that this hamartomatous lesion might cause specific cellular changes that impact retinal sensitivity response and potentially result from vasculature malnourishment to the outer retinal layers.

Uveal melanoma: relatively rare but deadly cancer.

Although it is a relatively rare disease, primarily found in the Caucasian population, uveal melanoma is the most common primary intraocular tumor in adults with a mean age-adjusted incidence of 5.1 cases per million per year. Tumors are located either in iris (4%), ciliary body (6%), or choroid (90%). The host susceptibility factors for uveal melanoma include fair skin, light eye color, inability to tan, ocular or oculodermal melanocytosis, cutaneous or iris or choroidal nevus, and BRCA1-associated protein 1 mutation. Currently, the most widely used first-line treatment options for this malignancy are resection, radiation therapy, and enucleation. There are two main types of radiation therapy: plaque brachytherapy (iodine-125, ruthenium-106, or palladium-103, or cobalt-60) and teletherapy (proton beam, helium ion, or stereotactic radiosurgery using cyber knife, gamma knife, or linear accelerator). The alternative to radiation is enucleation. Although these therapies achieve satisfactory local disease control, long-term survival rate for patients with uveal melanoma remains guarded, with risk for liver metastasis. There have been advances in early diagnosis over the past few years, and with the hope survival rates could improve as smaller tumors are treated. As in many other cancer indications, both early detection and early treatment could be critical for a positive long-term survival outcome in uveal melanoma. These observations call attention to an unmet medical need for the early treatment of small melanocytic lesions or small melanomas in the eye to achieve local disease control and vision preservation with the possibility to prevent metastases and improve overall patient survival.

Bilateral primary choroidal melanoma treated with bilateral plaque radiotherapy: a report of three cases.

PURPOSE: To report three cases of bilateral primary choroidal melanoma treated with bilateral plaque radiotherapy. METHODS: Retrospective, single-center case series. RESULTS: Case 1: In 1981, a 50-year-old man was diagnosed with a 5-mm-thick choroidal melanoma in the right eye (OD) and treated with plaque radiotherapy. In 1994, a 6.8-mm-thick choroidal melanoma in the left eye (OS) was treated with plaque radiotherapy. Final visual acuity was light perception OD and 20/20 OS at 24 years follow-up. Case 2: In 1983, a 53-year-old woman was diagnosed with a 3.5-mm-thick choroidal melanoma OS and treated with plaque radiotherapy. In 2001, an enlarging 2.5-mm-thick choroidal melanoma OD was treated with plaque radiotherapy. Final visual acuity was 20/30 OD and 20/20 OS at 22 years follow-up. Case 3: In 2001, a 92-year-old man was diagnosed with a 7.9-mm-thick choroidal melanoma OD treated with plaque radiotherapy. In 2003, an enlarging 2.8-mm-thick juxtapapillary choroidal melanoma was treated with plaque radiotherapy. Final visual acuity was 20/70 OD and 20/60 OS at 2.5 years follow-up. No patient showed ocular melanocytosis. Stable tumor regression was achieved in all six eyes. Metastatic disease did not develop in any case over 16 years of follow-up. CONCLUSIONS: Monitoring of both eyes of patients with uveal melanoma is important for the remote possibility of melanoma in the second eye. In these three patients, plaque radiotherapy allowed for preservation of the globes and some vision.

Rarity of somatic and germline mutations of the cyclin-dependent kinase 4 inhibitor gene, CDK4I, in melanoma.

Evidence from cytogenetics, multipoint linkage analyses of familial melanoma, and loss of heterozygosity studies of familial and sporadic melanomas support localization of a melanoma susceptibility or tumor suppressor gene at chromosomal region 9p21-23. Recently, the inhibitor of cyclin-dependent kinase 4 (CDK4I; also known as p16INK4, multiple tumor suppressor 1, or CDKN2 gene) has been mapped to 9p21 and shown to be mutated or deleted in a large fraction of cell lines derived from many tumor types, including melanoma, suggesting that this gene could be a melanoma suppressor gene. In order to test for somatic mutations in the CDK4I gene in tumors, DNAs from 30 surgically resected melanomas of both cutaneous and uveal origins were sequenced. No mutations were detected in the coding region of the CDK4I gene, while mutations or deletions were detected in 60% (9 of 15) of the cultured melanoma cell line DNAs. Among presumptive familial cases, nine of which were members of families with one or two other documented melanoma cases, no germline mutations were detected by sequence analysis. A deletion in the second exon of the CDK4I gene was found in one germline allele of a familial melanoma patient from a family with eight affected first degree relatives. These results not only support the suggestion that the CDK4I gene is a familial malignant melanoma gene, they also suggest the presence of another suppressor gene locus within 9p21 which is the target of loss of heterozygosity in sporadic melanomas.

Functional vision is improved in the majority of patients treated with external-beam radiotherapy for choroid metastases: a multivariate analysis of 188 patients.

PURPOSE: Metastatic deposits are the most common intraocular malignancies. We evaluated the efficacy of external-beam radiotherapy (EBRT) in the palliation of posterior uveal metastases in terms of clinically relevant outcomes: functional vision, tumor control, and globe preservation. PATIENTS AND METHODS: Four hundred eighty-three consecutive patients (578 eyes) were diagnosed with intraocular metastatic disease from solid tumors between 1972 and 1995. Of these, 233 eyes (188 patients) had lesions of the posterior uveal tract and received EBRT. Best-corrected visual acuity (VA) was documented pre- and post-EBRT. Visual function was considered excellent if VA < or = 20/50, navigational if 20/60 to 20/200, and legally blind if > or = 20/400. Most patients received 30 to 40 Gy in 2- to 3-Gy fractions to the posterior or entire globe. RESULTS: Fifty-seven percent of all assessable eyes had improved visual function or maintained at least navigational vision following EBRT. Thirty-six percent of legally blind eyes regained useful vision. Ninety-three percent experienced no clinical evidence of tumor progression and the globe preservation rate was 98%. The following characteristics independently predicted improvement to or maintenance of excellent vision on multivariate analysis: excellent vision pre-EBRT (P = .001), age less than 55 years (P = .004), white race (v black/Hispanic) (P = .003), and tumor base diameter less than 15 mm (P < .001). CONCLUSION: EBRT effectively restores and maintains useful vision in patients with choroid metastases, with a globe preservation rate of 98%. Patients less than 55 years with pretreatment VA better than 20/60 and tumor diameter less than 15 mm are most likely to benefit from this therapeutic intervention.

Chemoreduction and local ophthalmic therapy for intraocular retinoblastoma.

PURPOSE: To study the effectiveness of combined systemic chemotherapy and local ophthalmic therapy for retinoblastoma with the goal of avoiding enucleation and external-beam radiation therapy (EBRT). PATIENTS AND METHODS: This was a prospective, nonrandomized, single-arm clinical trial. Seventy-five eyes were followed in 47 children. Patients were treated with a six-cycle protocol of vincristine, etoposide, and carboplatin. Most (83%) also received ophthalmic treatment (cryotherapy, laser photocoagulation, thermotherapy, or plaque radiation therapy) during and/or after the chemotherapy. RESULTS: With a median follow-up of 13 months, event-free survival was 74%, with an event defined as enucleation and/or EBRT. Six children required EBRT in seven eyes (9%); five required enucleation of one eye (7%); five required a combination of EBRT and enucleation in six eyes (8%). Reese-Ellsworth groups 1, 2, and 3 eyes had excellent results, with avoidance of EBRT or enucleation in all 39. Treatment of groups 4 and 5 was less successful, with 33% of six eyes and 53% of 30 eyes, respectively, requiring EBRT and/or enucleation. Toxicities from chemotherapy were mild and included cytopenias (89%), fever and neutropenia (28%), infection (9%), and gastrointestinal symptoms, dehydration, and vincristine neurotoxicity (40%). No patients developed a second malignancy, metastatic disease, renal disease, or ototoxicity. CONCLUSION: In retinoblastoma patients with Reese-Ellsworth eye groups 1, 2, or 3, systemic chemotherapy used with local ophthalmic therapies can eliminate the need for enucleation or EBRT without significant systemic toxicity. More effective therapy is required for Reese-Ellsworth eye groups 4 and 5.

Prognosis of uveal melanoma based on race in 8100 patients: The 2015 Doyne Lecture.

A retrospective, nonrandomized, interventional case series of 8100 patients with uveal melanoma were evaluated for melanoma-related metastasis based on patient race. The patient race was Caucasian (n=7918, 98%), Hispanic (n=105, 1%), Asian (n=44, <1%), or African American (n=33, <1%). On the basis of race (Caucasian, Hispanic, Asian, and African American), significant differences were noted in mean age at presentation (58, 48, 44, and 52 years; P<0.001), distance of posterior tumor margin to foveola (5, 5, 6, and 4 mm; P<0.001), distance of posterior tumor margin to optic disc (5, 5, 6, and 4 mm) (P<0.001), tumor base (11, 12, 12, and 13 mm; P<0.001), tumor thickness (5.4, 7.1, 6.5, and 7.5 mm; P<0.001), intraocular hemorrhage (10, 14, 11, and 24%; P=0.02), and rupture of Bruch's membrane (20, 27, 39, and 36%; P=0.001). On the basis of multivariate analysis, the rate of metastasis increased with increasing age (P<0.001), ciliary body location (P<0.001), increasing tumor base (P<0.001), increasing tumor thickness (P<0.001), pigmented tumor (P=0.001), subretinal fluid (P=0.001), intraocular hemorrhage (P=0.045), and extraocular extension (P=0.036). Kaplan-Meier estimates of metastasis at 3, 5, and 10 were 8, 15, and 25% in Caucasians; 13, 13, and 13% in Hispanics; 4, 4, and 36% in Asians; and 8, 8, and 8% in African Americans. Compared with Caucasians, despite relative risk for metastasis of 0.31 for African Americans, 0.73 for Hispanics, and 1.42 for Asians, there was no statistical difference in metastasis, or death from uveal melanoma based on race. In summary, uveal melanoma showed similar prognosis for all races.

Rescue intra-arterial chemotherapy following retinoblastoma recurrence after initial intra-arterial chemotherapy.

PURPOSE: To determine the efficacy of rescue intra-arterial chemotherapy (IAC) for retinoblastoma recurrence following failed initial IAC. METHODS: Retrospective, non-comparative, interventional case series of 12 eyes in 12 patients. INTERVENTION: Rescue IAC employed chemotherapy agents of melphalan (5mg, 7.5mg) alone or with additional topotecan (1mg). MAIN OUTCOME MEASURE: Tumor control and globe salvage. RESULTS: The median patient age at initial presentation was 16 months. At initial examination, the International Classification of Retinoblastoma grouping was group B (n=1), group D (n=7), or group E (n=4). The initial IAC was primary in 5 cases (42%) and secondary following failure of intravenous chemotherapy in 7 (58%). In all cases, initial IAC was delivered using melphalan 3mg (n=3), melphalan 5mg (n=7), or combination melphalan 5mg/topotecan 1mg (n=2) for a median of 3 cycles. The mean interval from initial IAC to recurrence necessitating rescue IAC was 5 months (median 4, range 2-10 months). Of the 12 patients, 3 (25%) had undergone previous enucleation of the opposite eye and the rescue IAC was planned for the only remaining eye. Rescue IAC was delivered for recurrent solid tumor (n=1), recurrent subretinal seeds (n=7), recurrent vitreous seeds (n=1), or combination recurrent subretinal/vitreous seeds (n=3). IAC was technically successful through the ophthalmic artery in 9 cases (75%) or the middle meningeal artery in 3 (25%). Rescue IAC involved median 3 cycles (mean 3, range 2-4 cycles) of higher dose melphalan in 4 cases (33%) or combination melphalan/topotecan in 8 (67%). At mean follow-up of 20 months (median 14 months, range 7-36 months), complete tumor control was achieved in 9 eyes (75%) and globe salvage in 8 eyes (67%). Of the 3 failure eyes, all were initially groups D or E, previously treated with initial IAC, and 2 had previous intravenous chemotherapy. There were 4 eyes that came to enucleation for persistent subretinal/vitreous seeds (n=3) or neovascular glaucoma without viable tumor (n=1). There was no case of cerebrovascular stroke, systemic metastasis, or death. CONCLUSION: Rescue IAC following retinoblastoma recurrence after initial IAC provided tumor control in 75% of cases and globe salvage in 67%. Rescue IAC can be considered in children who fail initial IAC, especially if the opposite eye has been enucleated.

Diagnosis and treatment of uveal melanoma.

Most malignant melanomas in the ocular region arise in the uveal tract (iris, ciliary body, and choroid). Uveal melanoma generally has characteristic clinical features and the diagnosis can usually be made by an experienced ophthalmologist using slit lamp biomicroscopy or indirect ophthalmoscopy. Ancillary studies such as fluorescein angiography, ultrasonography, magnetic resonance imaging, and fine needle biopsy can occasionally be used to establish the diagnosis in atypical cases. Today, most affected patients are managed by specialists in ocular oncology. The management of uveal melanoma has been the subject of considerable controversy. Iris melanoma can usually be excised without enucleation of the affected eye. With regard to posterior uveal melanoma (ciliary body and choroid), enucleation of the affected eye was once the undisputed method of treatment. More recently, however, removal of the eye is performed less often and alternatives to enucleation have gained popularity. Several years ago, laser photocoagulation and plaque brachytherapy were the most popular alternatives to enucleation. Now, techniques of local tumor excision and transpupillary thermotherapy are gaining popularity in selected cases. Even more recently, various combinations of these methods have been judiciously used in many instances. The selected method of treatment in a given case depends on a number of complex clinical factors. Philosophies regarding the management of these lesions continue to change. This review covers the current diagnosis and management of uveal melanoma with emphasis on methods of management.

Genetic aspects of uveal melanoma: a brief review.

Uveal melanoma usually occurs sporadically in the absence of obvious genetic predisposing factors. However, in rare patients, there is a suggestion that there may be genetic predisposition. Rare occurrences of familial uveal melanoma are believed to be inherited in an autosomal dominant mode. There are a few clinical conditions that can predispose to or be associated with uveal melanoma, including ocular melanocytosis, neurofibromatosis type I, and familial atypical mole and melanoma syndrome. Nonrandom cytogenetic changes in uveal melanoma are characterized by monosomy 3, trisomy 8, and structural or numerical abnormalities of chromosome 6. Alterations of chromosome 9p are less frequently observed. CDKN2 gene, a cutaneous melanoma predisposition gene, is probably not a uveal melanoma predisposition gene as evidenced by the lack of somatic mutations involving this gene in uveal melanoma samples and the absence of germline mutations in familial uveal melanoma patients. Transgenic mouse models developed using a tyrosinase promoter tagged with a mutated ras gene or SV40-Tag oncoprotein develop retinal pigment epithelium tumors that resemble uveal melanoma. We propose that uveal melanoma cases be categorized on genetic basis according to a new classification system. This classification scheme will help to identify and uniformly categorize uveal melanoma patients with genetic predisposition. Such patients offer unique opportunities for studying the genetic aspects of uveal melanoma and, therefore, appropriate tissue samples should be obtained from them for molecular genetic studies. Further studies are needed to fully understand the genetic aspects of uveal melanoma.

External beam radiation for retinoblastoma: results, patterns of failure, and a proposal for treatment guidelines.

PURPOSE: To analyze treatment results and patterns of failure following external beam radiation for retinoblastoma and propose treatment guidelines according to specific clinical variables. METHODS AND MATERIALS: We analyzed 27 patients (34 eyes) with retinoblastoma who received external beam radiation as initial treatment at Hahnemann University Hospital from October 1980 to December 1991 and have been followed for at least 1 year. Of the 34 eyes, 14 were Groups I-II (Reese-Ellsworth classification), 7 were Group III, and 13 were Groups IV-V. Doses ranged from 34.5-49.5 Gy (mean 44.3 Gy, median 45 Gy) in 1.5-2.0 Gy fractions generally delivered through anterior and lateral wedged pair fields. RESULTS: At a mean follow up of 35.2 months (range 12-93 months), local tumor control was obtained in 44% (15 out of 34) of eyes with external beam radiation alone. Salvage therapy (plaque brachytherapy, cryotherapy, and/or photocoagulation) controlled an additional 10 eyes (29.5%), so that overall ocular survival has been 73.5%. Local tumor control with external beam radiotherapy alone was obtained in 78.5% (11 out of 14) of eyes in Groups I-II, but in only 20% (4 out of 20) of eyes in Groups III-V. A total of 67 existing tumors were identified prior to treatment in the 34 treated eyes and local control with external beam radiation alone was obtained in 87% (46 out of 53) of tumors measuring 15 mm or less and in 50% (7 out of 14) of tumors measuring more than 15 mm. When analyzing patterns of failure in the 19 eyes that relapsed, a total of 28 failure sites were identified and consisted of progression of vitreous seeds in seven instances (25% of failure sites) recurrences from previously existing tumors in 10 instances (36% of failure sites) and development of new tumors in previously uninvolved retina in 11 instances (39% of failure sites). CONCLUSIONS: 1) We find that external beam radiation to a dose of 45 Gy in fractions of 1.5 to 2.0 Gy provides adequate tumor control in retinoblastoma eyes Groups I-II (Reese-Ellsworth classification) or tumors measuring 15 mm in diameter or less. Eyes in more advanced group staging or containing tumors larger than the 15 mm seem to require higher radiation doses. We propose treatment guidelines for external beam radiation of retinoblastoma that specifically take into account the important clinical variables of tumor stage and patient age. 2) External beam radiation does not prevent the appearance of new tumors in clinically uninvolved retina. Therefore, the traditional belief that external beam radiation can treat the retina "prophylactically" should be seriously questioned. Due to this finding and their significant less morbidity, focal treatment modalities (plaque brachytherapy, photocoagulation, and/or cryotherapy), when clinically feasible, should be considered the treatment of choice for intraocular retinoblastoma. External beam radiation should be considered only when focal treatment modalities are not clinically indicated.

External beam irradiation for choroid metastases: identification of factors predisposing to long-term sequelae.

PURPOSE: To improve overall quality of life, palliative treatments should attempt to minimize associated complications while effectively controlling specific symptoms. We reviewed our experience treating posterior uveal metastases with external beam radiotherapy (EBRT) to determine the complication rate and to identify the relationship between patient, tumor, or treatment-related factors and the development of ocular complications. METHODS AND MATERIALS: 483 consecutive patients (pts) (578 eyes) were diagnosed with intraocular metastatic disease from solid tumors between 1972-1995. Of these, 233 eyes (188 pts) had lesions of the posterior uveal tract and received EBRT. Median follow-up time was 5.8 months (range: 0.7-170.0 months). Follow-up information regarding the development of complications was documented for 230 eyes. Complete EBRT details were available for 189 eyes. Seventy-two percent of the patients received 30.0-40.0 Gy in 2.0-3.0 Gy fractions. Biologically effective dose (BED) was calculated to allow meaningful comparisons between various fractionation regimens and total doses. Concurrent chemotherapy and/or hormonal therapy was used for 101 eyes (44%). RESULTS: Median BED was 61 Gy3 (range, 6.7-105 Gy3), and 80% of treated eyes received BED 50-70 Gy3. EBRT energies included photons (70%), 60Co (19%), electrons (6%), mixed energies (3%), and orthovoltage (2%). Lens-sparing techniques were used in 136 eyes (71%). At last follow-up 28 eyes (12%) developed one or more significant complications, including cataracts (16 eyes), radiation retinopathy (6 eyes), optic neuropathy (5 eyes), exposure keratopathy (5 eyes), and neovascularization of the iris (4 eyes). Two eyes developed narrow-angle glaucoma, and one of these required enucleation. On univariate analysis, Caucasian race (vs. Black/Hispanic, p = 0.03), increased intraocular pressure at diagnosis (>21 mmHg, p = 0.02), and diagnosis by biopsy (vs. no biopsy, p = 0.03) predisposed toward the development of complications. Factors not correlated with complications included BED (p = 0.18), energy type (p = 0.81), lens-sparing technique (versus whole globe, p = 0.57), and concurrent systemic treatment (p = 0.60). The small number of complications did not support a multivariate analysis. CONCLUSIONS: Despite the employment of a variety of EBRT treatment techniques and the proximity of choroidal metastases to radiosensitive structures, significant complications of palliative EBRT were infrequent. Although complications do occur, they are related to host factors and do not appear to be a function of irradiation parameters. We conclude that the potential benefits of vision and globe preservation after palliative EBRT outweigh the small risk of treatment induced complications.