Outcome Measures of New Technologies in Uveal Melanoma: Review from the European Vision Institute Special Interest Focus Group Meeting.

Uveal Melanoma (UM) is the most common primary intra-ocular tumor in adults. New diagnostic procedures and basic science discoveries continue to change our patient management paradigms. A recent meeting of the European Vision Institute (EVI) special interest focus group was held on "Outcome Measures of New Technologies in Uveal Melanoma", addressing the latest advances in UM, starting with genetic developments, then moving on to imaging and treatment of the primary tumor, as well as to investigating the most recent developments in treating metastases, and eventually taking care of the patient's wellbeing. This review highlights the meeting's presentations in the context of the published literature.

Determinants of Long-Term Survival in Metastatic Choroidal and Ciliary Body Melanoma.

PURPOSE: To build and validate a prognostic model that predicts long-term overall survival (OS) in metastatic choroidal and ciliary body melanoma (CCBM) to facilitate patient counseling and planning, reporting, and interpreting clinical trials. DESIGN: Retrospective cohort study with validation. METHODS: We analyzed predictors of intermediate (IMT; 25-<42 months) and long-term (LT; ≥42 months) OS in a Finnish nationwide cohort of 330 patients with metastatic CCBM. Short-term (<25 months), IMT, and LT survival were compared with pairwise and ordinal logistic regression. A single-center cohort of 259 patients from Italy was used for validation. Models were compared with a deviance test. RESULTS: Median OS was 12 and 17 months in the building and validation datasets, respectively; 40 (12%) and 31 (9%) compared with 44 (17%) and 32 (12%) patients were IMT and LT survivors, respectively. Alkaline phosphatase or lactate dehydrogenase level never exceeded 2 times the upper normal limit (UNL) in either LT cohort. Conditional to both being ≤2 times the UNL, distant metastasis-free interval (DMFI) >42 months (odds ratio [OR] 4.09-4.64; P < .001) paired with age <60 years (OR 3.23; P = .002), having no symptoms (OR 4.19; P = .005), and the largest diameter of the largest metastasis <30 mm (Tumor, Node, Metastasis stage M1a; OR 3.05; P = .001) independently predicted higher odds of surviving longer (IMT or LT) without model preference. These results were confirmed in the validation dataset. CONCLUSIONS: Alkaline phosphatase or lactate dehydrogenase >2 times the UNL essentially precluded LT survival. The most robust predictor otherwise was DMFI >42 months, followed by age <60 years, absence of symptoms, and Tumor, Node, Metastasis stage M1a.

Metastatic uveal melanoma: The final frontier.

Treatment of primary intraocular uveal melanoma has developed considerably, its driver genes are largely unraveled, and the ways to assess its risk for metastases are very precise, being based on an international staging system and genetic data. Unfortunately, the risk of distant metastases, which emerge in approximately one half of all patients, is unaltered. Metastases are the leading single cause of death after uveal melanoma is diagnosed, yet no consensus exists regarding surveillance, staging, and treatment of disseminated disease, and survival has not improved until recently. The final frontier in conquering uveal melanoma lies in solving these issues to cure metastatic disease. Most studies on metastatic uveal melanoma are small, uncontrolled, retrospective, and do not report staging. Meta-analyses confirm a median overall survival of 10-13 months, and a cure rate that approaches nil, although survival exceeding 5 years is possible, estimated 2% either with first-line treatment or with best supportive care. Hepatic ultrasonography and magnetic resonance imaging as surveillance methods have a sensitivity of 95-100% and 83-100%, respectively, to detect metastases without radiation hazard according to prevailing evidence, but computed tomography is necessary for staging. No blood-based tests additional to liver function tests are generally accepted. Three validated staging systems predict, each in defined situations, overall survival after metastasis. Their essential components include measures of tumor burden, liver function, and performance status or metastasis free interval. Age and gender may additionally influence survival. Exceptional mutational events in metastases may make them susceptible to checkpoint inhibitors. In a large meta-analysis, surgical treatment was associated with 6 months longer median overall survival as compared to conventional chemotherapy and, recently, tebentafusp as first-line treatment at the first interim analysis of a randomized phase III trial likewise provided a 6 months longer median overall survival compared to investigator's choice, mostly pembrolizumab; these treatments currently apply to selected patients. Promoting dormancy of micrometastases, harmonizing surveillance protocols, promoting staging, identifying predictive factors, initiating controlled clinical trials, and standardizing reporting will be critical steppingstones in reaching the final frontier of curing metastatic uveal melanoma.

Impact of staging on survival outcomes: a nationwide real-world cohort study of metastatic uveal melanoma.

No data exist regarding whether any first-line treatment for metastatic uveal melanoma provides overall survival (OS) benefit, if staged and compared to best supportive care (BSC). We analyzed OS in a nationwide, consecutive cohort diagnosed with metastatic uveal melanoma between January 1999 and December 2016. The Helsinki University Hospital Working Formulation was used to assign patients to stage IVa, IVb and IVc, corresponding to predicted median OS ≥12, <12-6 and <6 months, respectively. OS of 216 actively treated patients was compared by treatment and working formulation stage against 108 similarly staged, concurrent patients managed with BSC using Kaplan-Meier analysis and Cox regression. The median OS with active treatment was 18 (range, 0.7-162), 6.9 (range, 1.3-30) and 1.9 (range, 0.2-18) months in working formulation stage IVa, IVb and IVc, respectively. Patients who received chemoimmunotherapy, selective internal radiation therapy, or underwent surgical resection survived longer - median OS 13, 16 and 24 months, respectively - than those receiving conventional chemotherapy - median OS 5.1 months - but only with surgical resection their OS exceeded that with BSC, both overall and in stage IVa (P < 0.001, P = 0.010). In stage IVb and IVc, no difference in OS was observed in any comparison. Staging of patients is crucial when comparing survival after metastatic uveal melanoma. Only surgical resection for stage IVa disease provided longer OS in our national cohort. We additionally recommend stage-specific comparison of novel treatments against available BSC data.

Hepatic Ultrasonography Compared With Computed Tomography and Magnetic Resonance Imaging at Diagnosis of Metastatic Uveal Melanoma.

PURPOSE: To evaluate the consistency of hepatic ultrasonography (US) with staging computed tomography (CT) and magnetic resonance imaging (MRI), to analyze why US was inconsistent with CT/MRI, and to compare CT/MRI. DESIGN: Reliability analysis. METHODS: Two hundred fifteen patients whose primary uveal melanoma was managed in the Helsinki University Hospital and who were diagnosed with hepatic metastases by US within 60 days of staging CT/MRI from January 1999 to December 2016 were included. Patients attended a real-life follow-up schedule including hepatic US, liver function tests (LFT), and a confirmatory CT/MRI. We evaluated the consistency of US with staging CT/MRI regarding the presence and number of metastases. RESULTS: The enrolled patients underwent 215 US, 167 CT, and 69 MRI examinations, and 67% of them had biopsy-confirmed metastases. Screening was regular for 98% of the patients, and 66% were asymptomatic. US was fully consistent with CT/MRI in detecting metastases in 113 (53%) patients, in 63 (29%) CT/MRI showed more metastases, and in 16 (7%) CT/MRI showed fewer metastases than US. CT/MRI was inconsistent with US in 23 (11%) patients. The sensitivity of US in detecting metastases was 96% (95% confidence interval, 92-98). US failed to suggest metastases in 10 patients. LFT were abnormal in 6 of them, and a newly detected hepatic lesion was present by US in 4. CONCLUSIONS: Hepatic US is a sensitive screening modality in detecting metastases in patients with primary uveal melanoma, if combined with LFT and, in case of any newly detected lesion, a confirmatory MRI.

Germline loss-of-function variants in MBD4 are rare in Finnish patients with uveal melanoma.

Uveal melanoma (UM) is a rare intraocular cancer with the highest incidence in northern latitudes. Metastases develop in approximately 50% of patients, whereafter the median survival is 13 months. Generally, the mutation burden of these tumors is low. Germline variants predisposing to UM have been previously described in BRCA1-associated protein 1 (BAP1). Recently, germline and somatic loss-of-function (LOF) variants in the methyl-CpG-binding domain 4 (MBD4) gene have been found to cause a hypermutated UM, and MBD4 also has been put forward as a gene predisposing to UM. We sequenced for MBD4 germline variants in 440 Finnish patients with UM and identified seven rare exonic missense variants in 16 (3.6%) patients, of which one likely alters MBD4 function. The frequency of likely pathogenic variants in our cohort is 0.23% (1/432; 95% CI, 0.01-1.28). We identified no LOF variants though their frequency in the Finnish population is 0.052%. Thus, our data do not support the suggestion that MBD4 germline variants predispose to UM. Somatic loss of MBD4 might modify the mutational burden in UM and change its response to immune checkpoint inhibitors.

Overall survival after treatment for metastatic uveal melanoma: a systematic review and meta-analysis.

The overall survival (OS) of patients with metastatic uveal melanoma is short, the evidence for effectiveness of treatments is limited, and no consensus on the choice of treatment exists. We aimed to advance interpretation of OS as an outcome by pooling peer-reviewed data. The design is a systematic review and meta-analysis. We searched PubMed from 1 January 1980, to 29 March 2017, for articles reporting patient-level survival in Kaplan-Meier or numerical form. We digitized survival graphs, pooled individual survival times, calculated median OS by treatment modality, and compared each modality by the log-rank test and Cox regression using conventional chemotherapy (CHT) as a reference. Individual-level data were obtained from 78 articles with 2494 patients. The median OS across all treatment modalities was 1.07 years (range: 0.59-2.50 years). Pooled OS reported after isolated hepatic perfusion [median OS: 1.34 years; hazard ratio (HR): 0.92, 95% confidence interval (CI): 0.87-0.97, P = 0.0040], immunoembolization (median OS: 1.63; HR: 0.97, 95% CI: 0.95-1.00, P = 0.0080), and surgery (median OS: 1.43; HR: 0.94, 95% CI: 0.92-0.96, P < 0.0001) was longer, and after checkpoint inhibitor shorter (median OS: 0.59; HR: 1.13, 95% CI: 1.06-1.20, P < 0.0001) than after CHT (median OS: 0.91 years), but subject to identifiable confounding factors. OS following other modalities did not differ from CHT. Reported OS was unassociated with the decade of publication, but depended on the percentage of first-line treated patients. Our results suggest no clinically significant difference in OS by treatment modality or decade. Most of the difference in reported OS likely is attributable to surveillance, selection, and publication bias rather than treatment-related prolongation. Our pooled data provide benchmarks for future trials.