Propranolol and Von Hippel-Lindau Disease

Propranolol (beta-blocker), is successfully used for the treatment of infantile hemangiomas, the most common vascular tumor of newborns. The mechanism is related to its anti-angiogenetic and pro-apoptotic effects. Recently, in vitro studies demonstrated that propranolol decreased the expression of target genes of the HIF (hypoxia-inducible factor, of which the VHL gene is the main regulator) pathway in hemangioblastoma cells and affected their viability. The efficacy of propranolol (stabilization of all HB and decrease in serum VEGF levels) was demonstrated in a phase III study, but only in retinal BHs . The only study that evaluated the effect of propranolol on CNS HB was retrospective and involved a limited number of patients. Nevertheless, it showed a decrease in the growth rate of HBs. The investigator therefore propose to carry out a randomized controlled trial to study the effect of propranolol on the growth of CNS HB in patients with VHL disease (von Hippel-Lindau).

The hypothesis of the present work is the following: the use of propranolol in VHL patients with CNS HB allows to decrease and/or slow down the tumor growth.

'Von Hippel-Lindau disease (VHL) is a familial syndrome, autosomal dominant, of predisposition to cancer, associating malignant tumors (renal carcinomas, neuroendocrine tumors of the pancreas), or benign tumors (retinal hemangioblastomas (HB), cerebellar, spinal cord, endolymphatic sac tumors and pheochromocytomas, which is a consequence of a high-penetrance mutations in the VHL tumor-suppression gene. A patient with multiple HB may require multiple interventions, which may leave progressively severe neurological sequelae. Several drug treatments (interferon, tyrosine kinase inhibitors, anti-angiogenic agents) have been proposed and tested as alternatives to surgery or to delay it. None of these studies have demonstrated a favorable benefit-risk balance that would support the use of any of these treatments, which sometimes have major side effects, in routine practice. Propranolol (beta-blocker) is successfully used for the treatment of infantile hemangiomas, the most common vascular tumor of newborns. The mechanism is related to its anti-angiogenetic and pro-apoptotic effects. Recently, in vitro studies demonstrated that propranolol decreased the expression of target genes of the HIF (hypoxia-inducible factor, of which the VHL gene is the main regulator) pathway in hemangioblastoma cells and affected their viability. The efficacy of propranolol (stabilization of all HB and decrease in serum VEGF levels) was demonstrated in a phase III study, but only in retinal HB. The only study that evaluated the effect of propranolol on CNS HB was retrospective and involved a limited number of patients. Nevertheless, it showed a decrease in the growth rate of HB. The investigator therefore propose to perform a randomized controlled trial to study the effect of propranolol on CNS HB growth in patients with VHL disease. Patients will be introduced to the study during a routine follow-up visit or during a telephone call by their neurosurgeon. Eligible patients who have signed the consent form will have a cardiology consultation to rule out a contraindication to the use of propranolol, prior to inclusion/randomization. If a contraindication is detected by the cardiologist, the patient will not be included in the study.

Patients without contraindications will then be included and randomized (1:1) to receive either oral propranolol (120 mg/d, started gradually (with BP and heart rate monitoring at visits) for 24 months or usual follow-up. Randomization will be stratified on the number of initial CNS HB (\<5 or ≥5).

Initial imaging (MRI) workup (brain and spinal cord) will be performed, with mapping and measurements of CNS HB, initially present.

Clinical (every three months) and radiological follow-up every 6 months (MRI) or when new neurological symptoms appear. Tolerance and secondary endpoints will also be assessed during these follow-up visits. Patients will be followed up to 26 months post-randomization.

The primary endpoint will be assessed centrally by two neuroradiologists, blinded to the patient's treatment arm. The other radiological endpoints (edema, growth velocity, de novo HB occurrence) will also be assessed centrally, by the same neuroradiologists, blinded to the treatment arm.

During follow-up, the use of surgery will not be modified by the protocol, and will be left to the discretion of the physician in charge of the patient, according to current recommendations. Statistical analysis:

Randomization will be performed in a 1:1 ratio between the two groups. It will be stratified on the initial number of CNS HB (\<5 or ≥5). Efficacy endpoint analyses will be performed on the intention-to-treat (ITT, all randomized patients) population, in which all patients will be analyzed according to the allocated group.

Eligibility Criteria:
Inclusion Criteria:

* Age ≥ 18
* VHL patient with one or more hemangioblastomas of the central nervous system, none of which require urgent surgery (within 3 months)
* Patient with written consent to participate in the study
* Enrolled in a social security plan or beneficiary

Exclusion Criteria:

* Contraindication to the use of propranolol:
* chronic obstructive pulmonary disease and asthma,
* uncontrolled heart failure,
* 2nd and 3rd degree atrioventricular blocks,
* bradycardia (\<50 beats/minute after 3 minutes of rest),
* Raynaud's phenomenon and peripheral arterial disorders,
* arterial hypotension,
* hypersensitivity to propranolol
* cardiogenic shock,
* Prinzmetal's angina,
* sinus disease (including sino-auricular block)
* untreated pheochromocytoma,
* history of anaphylactic reaction,
* in the context of primary and secondary prevention of digestive bleeding in cirrhotics: advanced liver failure with hyperbilirubinemia, massive ascites, hepatic encephalopathy
* predisposition to hypoglycemia (as after fasting or in case of abnormal response to hypoglycemia)
* metabolic acidosis
* Contraindication to MRI:
* claustrophobia,
* presence of a pace maker and other stimulators/implants
* ocular metallic foreign bodies,
* heart valves or ferromagnetic metal vascular clips
* Patients already on Propranolol or other beta blockers
* Patients under guardianship or conservatorship
* Pregnant or breastfeeding women - Woman with a medium-term pregnancy project