Uveal melanoma (UM) is the most common intraocular malignancy and arises from melanocytes in the iris, ciliary body, or choroid. Early diagnosis and local treatment is crucial, as survival correlates with primary tumor size. However, approximately 50% of patients will develop metastatic disease with 6-12 months' survival from metastatic diagnosis. Genomic analyses have led to the development of gene-expression profiles that effectively predict metastatic progression; unfortunately, no adjuvant therapy has been shown to prolong survival to date. New insights into the molecular biology of UM have found frequent activating mutations in genes encoding for the G-protein α-subunit, GNAQ and GNA11, and improved understanding of the downstream signaling pathways MAPK, PI3K/Akt, and Hippo have afforded an array of new targets for treatment of this disease. Studies are under way with rationally developed regimens targeting these pathways, and novel agents are under development. We review the diagnosis, management, and surveillance of primary UM and the adjuvant therapy trials under way.

/pdf/uveal-melanoma-epidemiology-etiology-and-treatment-of-3vovismy5b.pdf

Uveal Melanoma: Epidemiology, Etiology, and Treatment of Primary Disease

Local Recurrence Significantly Increases the Risk of Metastatic Uveal Melanoma

Purpose: To report long-term experience with intravitreal anti–vascular endothelial growth factor treatment for radiation maculopathy. Methods: From 2005-2015, 120 consecutive patients underwent intravitreal anti-VEGF therapy for radiation maculopathy. Inclusion criteria included a diagnosis of uveal melanoma treated with plaque radiotherapy and subsequent macular radiation vasculopathy (exudate, retinal hemorrhage, intraretinal microangiopathy, neovascularization, edema). Anti-VEGF therapy involved continuous injections in 4- to 12-week intervals with doses of 1.25 mg/0.05 mL, 2.0 mg/0.08 mL, 2.5 mg/0.1 mL, or 3.0 mg/0.12 mL of bevacizumab as well as 0.5 mg/0.05 mL or 2.0 mg/0.05 mL of ranibizumab. Goals were maintenance of visual acuity and normative macular anatomy. Safety and tolerability (retinal detachment, hemorrhage, infection), visual acuity, central foveal thickness on optical coherence tomography imaging, and clinical features of radiation maculopathy were analyzed. r esults: Progressive reductions in macular edema, hemorrhages, exudates, cotton-wool spots, and microangi opathy were noted. At last follow-up, 80% remained within 2 lines of their initial visual acuity or better, with a mean treatment interval of 38 months (range 6-108 months). Kaplan-Meier analysis of the probability of remaining within 2 lines of initial visual acuity was 69% at 5 years and 38% at 8 years of anti-VEGF therapy. Discontinua tion of therapy was rare. Relatively few acute or long-term side effects were noted, allowing for good long-term patient accrual. Conclusions: Continuous intravitreal anti-VEGF therapy in patients with radiation maculopathy was well-tolerat ed and preserved vision. In most cases, reductions or resolution of retinal hemorrhages, cotton-wool spots, and retinal edema were noted for up to 10 years.

https://journals.sagepub.com/doi/pdf/10.5301/ejo.5000670

Intravitreal anti-VEGF therapy for macular radiation retinopathy: a 10-year study.

Approximately 90% of uveal melanoma develop in the choroid, with the remainder arising in the ciliary body or the iris. The treatment of uveal melanoma is aimed at conserving the eye and useful vision, and, if possible, preventing metastatic disease. Enucleation is now reserved for tumors that are large and/or involve the optic disc, having largely been replaced by various forms of radiotherapy (plaque brachy-therapy, proton beam or stereotactic radiotherapy) and laser therapy. Whereas iridectomy and iridocyclectomy are widely performed, transscleral exoresection of choroidal tumors is performed only in a few centers because it requires special skills and hypotensive anesthesia. Transretinal endoresection using vitrectomy equipment is easier but controversial because of concerns about tumor seeding. Long-term postoperative surveillance is necessary to identify and treat local tumor recurrence and any other complications, such as radiation-induced morbidity, and to provide counseling to the patient. Factors predicting metastasis include older age, large tumor size, ciliary body involvement, extraocular spread, epithelioid cytomorphology, chromosome 3 loss and chromosome 8q gain, class 2 gene expression profile, loss of BRCA1-associated protein-1 (BAP1), and the presence of inflammation. Prognostication is enhanced by multi-variable analysis combining clinical, histologic, and genetic factors, also taking the patient's age and sex into account. As there is a lack of options for treating metastases, much research is focused on identifying potential therapeutic targets.

Uveal Melanoma Treatment and Prognostication.

Introduction Survival in uveal melanoma has remained unchanged since the early 1970s. Because outcomes are highly related to the size of the tumour, timely and accurate diagnosis can increase the chance for cure. Methods A consensus-based guideline was developed to inform practitioners. PubMed was searched for publications related to this topic. Reference lists of key publications were hand-searched. The National Guidelines Clearinghouse and individual guideline organizations were searched for relevant guidelines. Consensus discussions by a group of content experts from medical, radiation, and surgical oncology were used to formulate the recommendations. Results Eighty-four publications, including five existing guidelines, formed the evidence base. Summary Key recommendations highlight that, for uveal melanoma and its indeterminate melanocytic lesions in the uveal tract, management is complex and requires experienced specialists with training in ophthalmologic oncology. Staging examinations include serum and radiologic investigations. Large lesions are still most often treated with enucleation, and yet radiotherapy is the most common treatment for tumours that qualify. Adjuvant therapy has yet to demonstrate efficacy in reducing the risk of metastasis, and no systemic therapy clearly improves outcomes in metastatic disease. Where available, enrolment in clinical trials is encouraged for patients with metastatic disease. Highly selected patients might benefit from surgical resection of liver metastases.

/pdf/management-of-uveal-melanoma-a-consensus-based-provincial-2b1suq5peq.pdf

R Doug Errington

Papers

The American Brachytherapy Society consensus guidelines for plaque brachytherapy of uveal melanoma and retinoblastoma