Background von Hippel-Lindau disease (VHL) is a multisystem cancer syndrome caused by mutations in the VHL gene. Retinal hemangioblastoma is one of the most common tumours, and when it appears near the optic nerve, its treatment is challenging and risky. To date, no treatment has proven effective in changing the course of the disease. This study was designed to evaluate the safety and effectiveness of propranolol in controlling these tumours.
Methods Seven patients were included. All patients took a daily dose of 120 mg of propranolol for 1 year. Clinical variables were assessed at baseline, and at 1, 3, 6, 9 and 12 months. The primary endpoint of the study was the number and size of retinal hemangioblastomas. On every visit, retinal outcomes and blood biomarkers (such as vascular endothelial growth factor (VEGF) and miR210) were analysed.
Results Number and size of retinal hemangioblastomas remained stable in all patients. All of them had initially increased levels of VEGF and miR210. There was a gradual reabsorption of retinal exudation in two patients, correlating with a progressive decrease of both biomarkers. The only adverse effect reported was hypotension in one patient.
Conclusions Propranolol could be used to treat retinal hemangioblastomas in VHL patients, although more studies are needed to determine the ideal dose and long-term effect. VEGF and miR210 should be explored as biomarkers of disease activity. As far as we know, these are the first biomarkers proposed to monitor the VHL disease activity.
Trial registration number 2014-003671-30
- hypoxia-inducible factors
- von Hippel-Lindau
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Presented at Two posters about this work were presented at the 9th European Conference on Rare Diseases & Orphan Products (ECRD 2018 Vienna) and at the 13th International VHL Medical/Research Symposium (MD Anderson Cancer Center, Houston, Texas, USA, 2018).
Contributors KV and RMJ planned the study. KV wrote the clinical trial protocol and carried out all the authorisation processes and contact with patients. LR participated in the selection of patients to assure they could take propranolol. He performed the cardiological evaluations and follow-up, from a cardiologic point of view. RMJ participated in the evaluation of patients to determine their eligibility according the inclusion criteria. She directed and coordinated the clinical visits, follow-up and complementary diagnostic tests. RMJ and BG performed the ophthalmological evaluations, some of them after the end of the clinical trial. DTA performed the neurological evaluations. LMB directed and coordinated the in vitro experiments, the design strategies and the experimental approach. VA and AMC carried out the experimental work, assisted by Lucia R. BG, RMJ and KV analysed the clinical results. BG wrote the first draft of the document and KV reviewed it and added content. KV, BG and AMC worked in the first review of the document. KV and BG worked in improving the final version of the manuscript. All authors read and approved the final manuscript.
Funding This clinical trial was supported by grants from Alianza VHL Spain, Fundación Iberdrola, Bodegas Protos and Fundación Port Aventura. Alianza VHL informed the families about the clinical trial for the recruitment of patients, performed the administrative procedures for authorisation and monitoring and financed the travel expenses of the patients for the visits.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval The protocol study and informed consent form were reviewed and approved by the Ethical Committee of the Complejo Hospitalario de Toledo. The study was classified by the Spanish Agency of Medicines and Medical Devices (AEMPS) as a phase III clinical trial, authorised, and registered in EU Clinical Trials Register (EMA).
Provenance and peer review Not commissioned; externally peer reviewed.