Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the United States, and their age-adjusted risk is 5 per 1 million population. These less frequent melanomas are dissimilar to their more common cutaneous melanoma relative, with differing risk factors, primary treatment, anatomic spread, molecular changes, and responses to systemic therapy. Once uveal melanoma becomes metastatic, therapy options are limited and are often extrapolated from cutaneous melanoma therapies despite the routine exclusion of patients with uveal melanoma from clinical trials. Clinical trials directed at uveal melanoma have been completed or are in progress, and data from these well designed investigations will help guide future directions in this orphan disease. Cancer 2016;122:2299-312. V C 2016 American Cancer Society.KEYWORDS: breast cancer 1-associated protein 1 (BAP1), choroidal melanoma, diagnosis, guanine nucleotide binding protein a11 (GNA11), guanine nucleotide-binding protein Q polypeptide (GNAQ), ocular melanoma, review, science, treatment, uveal melanoma. BACKGROUND AND EPIDEMIOLOGYUveal melanoma is the most common primary intraocular malignancy. The uveal tract is the pigmented layer of the globe encompassing the iris, ciliary body, and choroid (Fig. 1). The terms choroidal melanoma and ocular melanoma are alternative terms for this cancer, because most of the uveal tract is choroidal. However, the term ocular melanoma should be avoided, because it implies the inclusion of conjunctival and adnexal melanomas, which behave and are managed like cutaneous rather than uveal primaries. Approximately 1500 new cases of uveal melanoma are diagnosed in the United States each year, most commonly arising in the choroid followed by the ciliary body. Iris melanomas are the least common location for uveal melanoma (Fig. 2).1 Although the disease has no sex preference, it is more common in middle-aged Caucasians (median age at presentation, 58 years). Risk factors include the presence of a choroidal nevus, which can be observed in 7% to 8% of the Caucasian population. Certain skin conditions, such as dysplastic nevus syndrome and nevus of Ota, are also associated with uveal melanoma.2 It has been theorized by some investigators that exposure to ultraviolet radiation increases the risk of this neoplasia, but this has not been definitively proven. Whereas certain somatic mutations are associated with neoplastic growth and distant metastasis, the malignancy is not inherited in a traditional genetic fashion, although it is believed that individuals who have germline breast cancer 1 (BRCA1)-associated protein 1 (BAP1) mutations are at higher risk for uveal and cutaneous melanoma as well as mesothelioma and renal cancers.
PURPOSE Metastatic uveal melanoma has poor overall survival (OS) and no approved systemic therapy options. Studies of single-agent immunotherapy regimens have shown minimal benefit. There is the potential for improved responses with the use of combination immunotherapy. PATIENTS AND METHODS We conducted a phase II study of nivolumab with ipilimumab in patients with metastatic uveal melanoma. Any number of prior treatments was permitted. Patients received nivolumab 1 mg/kg and ipilimumab 3 mg/kg for four cycles, followed by nivolumab maintenance therapy for up to 2 years. The primary outcome of the study was overall response rate (ORR) as determined by RECIST 1.1 criteria. Progression-free survival (PFS), OS, and adverse events were also assessed. RESULTS Thirty-five patients were enrolled, and 33 patients were evaluable for efficacy. The ORR was 18%, including one confirmed complete response and five confirmed partial responses. The median PFS was 5.5 months (95% CI, 3.4 to 9.5 months), and the median OS was 19.1 months (95% CI, 9.6 months to NR). Forty percent of patients experienced a grade 3-4 treatment-related adverse event. CONCLUSION The combination regimen of nivolumab plus ipilimumab demonstrates activity in metastatic uveal melanoma, with deep and sustained confirmed responses.
Sunitinib treatment in VHL patients showed acceptable toxicity. Significant response was observed in RCC but not in HB. Greater expression of pFRS2 in HB tissue than in RCC raises the hypothesis that treatment with fibroblast growth factor pathway-blocking agents may benefit patients with HB.
Aims: To evaluate how tumour size, retinal location, and patient age affect the outcome of retinoblastoma foci treated with chemotherapy. Methods: Retrospective review of retinoblastoma foci treated with primary chemotherapy alone. Individual tumours were coded with regard to their largest basal diameter, location within the eye (macula, macula to equator, equator to ora serrata), and patient's age at diagnosis. Successfully treated tumours required no further intervention while those requiring additional treatment were coded as failures. Results: 56 (72%) tumours responded successfully to chemotherapy alone while 22 (28%) required additional therapy. 26 of 31 macular tumours (84%) and 30 of 47 extramacular tumours (64%) responded to chemotherapy (p <0.060). Relative to size, 46 of 60 tumours (77%) greater than 2 mm in basal diameter were successfully treated with chemotherapy, while only 10 of 18 tumours (56%) less than or equal to 2 mm responded (p <0.088). Among the eight tumour foci diagnosed in children less than 2 months of age, five (63%) failed to respond to chemotherapy alone (p <0.032). Conclusion: Retinoblastoma is more likely to respond to primary chemotherapy if it is located in the macula and if the patient is older than 2 months of age. Tumours measuring less than 2 mm in diameter may be less responsive to this treatment.
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