Prevention of VEGF inhibitor-induced toxicity by salt restriction: the SUN-SALT study
Authors: Van Doorn L , Visser W J , Van Dorst D C H , Mirabito Colafella K M M , Koolen S L W , Van Egmond-De Mik A M E , Oomen-De Hoop E , Bins S , Hoorn E J , Danser A H , Mathijssen A H , Versmissen J 
Published: October 2021

Abstract

Introduction
Vascular endothelial growth factor (VEGF) inhibitors target the formation of new blood vessels required for growth and metastatic spread of a malignant tumor. Although this is an effective anticancer treatment, many patients develop cardiovascular side effects such as hypertension, requiring dose reduction or early termination of treatment. In animals, VEGF inhibitor-induced hypertension is salt-sensitive.

Aim
To prospectively study whether salt restriction can prevent or attenuate the rise in blood pressure in response to anti-cancer treatment with VEGF inhibitors.

Method
This is a single centre prospective open-label intervention study. Patients are eligible when treated with a VEGF inhibitor according to standard of care and developing hypertension or a blood pressure rises of 20 mmHg or more during the first treatment cycle. A salt restricted diet (&lt;4 grams/day) including provided salt-less bread is started during the off-treatment period under guidance of a specialized dietitian. The primary endpoint is mean difference in blood pressure rise between the treatment cycle with and the treatment cycle without salt restriction. We aim for a total of 16 patients with a blood pressure rise of at least 20mmHg and/or development of hypertension undergoing the intervention.

Results
Between 28 November 2019 and 25 March 2021, 45 patients gave informed consent. Fourteen patients developed hypertension and/or a blood pressure rise of at least 20 mmHg after three- four weeks of treatment making them eligible for the intervention. In 10 patients, salt restriction was the only intervention to reduce the blood pressure rise during the following treatment cycle, leading to a reduction in blood pressure rise of 17 mmHg (10 vs 27 mmHg; p&lt;0.001). In four patients antihypertensive treatment was started during the first treatment cycle due to blood pressure rise above 170 mmHg. Salt restriction did not appear to have an important further blood pressure lowering effect, although in one patient the antihypertensive treatment was interrupted during the stop week and salt restriction was sufficient to limit the blood pressure rise in the second cycle. Importantly, the intervention was well tolerated and most patients continued salt restriction after the study finished.

Conclusion
Applying salt restriction might be an effective and well tolerated intervention to decrease blood pressure rise during treated with VEGF inhibitors. More importantly, this gives important information about the pathogenesis. Further studies of collected blood and 24h urine samples will allow conclusions on the role of endothelin-1, the renin aldosterone system and prostacyclins.

Funding Acknowledgement
Type of funding sources: Foundation. Main funding source(s): De Merel (Charity aiming for research directly benefiting patients; yearly award, success rate ∼30% “Stichting De Merel”)