Objective:To investigate overall survival (OS) and health-related quality of life (HRQOL) of first-line isolated hepatic perfusion (IHP) compared to best alternative care for patients with uveal melanoma liver metastases.Background:Approximately half of the patients with uveal melanoma develop metastatic disease, most commonly in the liver, and systemic treatment options are limited. IHP is a locoregional therapy with high response rates but with an unclear effect on OS.Methods:In this phase III randomized controlled multicenter trial (the SCANDIUM trial), patients with previously untreated isolated uveal melanoma liver metastases were included between 2013 and 2021, with at least 24 months of follow-up. The planned accrual was 90 patients randomized 1:1 to receive a one-time treatment with IHP or best alternative care. Crossover to IHP was not allowed. The primary endpoint was the 24-month OS rate, with the hypothesis of a treatment effect leading to a 50% OS rate in the IHP group compared to 20% in the control group. HRQOL was measured by the EuroQol 5-domains 3-levels (EQ-5D-3L) questionnaire over 12 months.Results:The intention-to-treat population included 87 patients randomized to the IHP group [43 patients; 41 (89%) received IHP] or the control group (44 patients). The control group received chemotherapy (49%), immunotherapy (39%), or localized interventions (9%). In the intention-to-treat population, the median progression-free survival was 7.4 months in the IHP group compared with 3.3 months in the control group, with a hazard ratio of 0.21 (95% CI, 0.12-0.36). The 24-month OS rate was 46.5% in the IHP group versus 29.5% in the control group (P=0.12). The median OS was 21.7 months versus 17.6 months, with a hazard ratio of 0.64 (95% CI, 0.37-1.10). EQ-5D-3L showed a sustained high health status for the IHP group over 12 months, compared to a deteriorating trend in the control group.Conclusions:For patients with liver metastases from uveal melanoma, IHP offers high response rates translating to a benefit in progression-free survival including a trend of better HRQOL compared to the control group. However, the primary endpoint of OS at 24 months was not met.