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Canadian Journal of Cardiology

Hypertension Due to Antiangiogenic Cancer Therapy With Vascular Endothelial Growth Factor Inhibitors: Understanding and Managing a New Syndrome

Published:February 27, 2014DOI:https://doi.org/10.1016/j.cjca.2014.02.011

      Abstract

      Novel antiangiogenic cancer therapies, particularly agents that block vascular endothelial growth factor (VEGF) signalling, have improved outcomes in patients with cancers and are now used as first-line therapies for some tumours. However, with VEGF inhibitors (VEGFIs) are new complications, particularly hypertension. VEGFI-induced hypertension is a dose-dependent phenomenon due to on-target effects rather than off-target effects. Increased blood pressure occurs in almost 100% of patients who take VEGFIs, with a subset who develop severe hypertension. Molecular mechanisms underlying VEGFI-induced hypertension are unclear, but endothelial dysfunction and increased vascular resistance, due to impaired nitric oxide signalling, reduced prostacyclin production, endothelin-1 (ET-1) upregulation, oxidative stress, and rarefaction have been implicated. Treatment of hypertension should be aimed at reducing the risk of short-term morbidity associated with hypertension while maintaining effective dosing of antiangiogenic therapy for optimal cancer treatment. Although specific guidelines are not yet available for the management of VEGFI-induced hypertension, angiotensin-converting enzyme inhibitors and dihydropyridine calcium channel blockers are commonly used. Severe hypertension might require reduction of VEGFI dosing, or in some cases, interruption of treatment. As more potent VEGFIs are developed and as more cancer patients are treated with VEGFIs, the burden of hypertension toxicity will increase. This will be further compounded as the use of antiangiogenic drugs broadens to include older patients and those with pre-existing cardiovascular disease. Here we focus on VEGF as a target for antiangiogenesis and how this affects increased blood pressure. Putative mechanisms underlying VEGFI-induced hypertension are highlighted and therapeutic strategies to manage such hypertension are discussed.

      Résumé

      Les nouveaux traitements antiangiogéniques utilisés contre le cancer, particulièrement les agents qui bloquent la signalisation du facteur de croissance endothéliale vasculaire (FCEV), ont amélioré les résultats chez les patients souffrant de cancer et sont maintenant utilisés comme traitement de première intention de certaines tumeurs. Cependant, les inhibiteurs du FCEV (IFCEV) présentent de nouvelles complications, particulièrement l’hypertension artérielle. L’hypertension induite par les IFCEV est un phénomène dose-dépendant dû aux effets ciblés plutôt qu’aux effets non ciblés. L’augmentation de la pression artérielle apparaît chez presque 100 % des patients qui prennent les IFCEV, avec un sous-ensemble qui développe une hypertension grave. Les mécanismes moléculaires sous-jacents à l’hypertension induite par les IFCEV demeurent incertains, mais la dysfonction endothéliale et l’augmentation de la résistance vasculaire en raison de l’altération de la signalisation de l’oxyde nitrique, la réduction de la production de prostacycline, la régulation à la hausse de l’ET-1, le stress oxydatif et la raréfaction ont été impliqués. Le traitement de l’hypertension devrait avoir pour but de réduire le risque de morbidité à court terme associée à l’hypertension tout en maintenant le traitement antiangiogénique à un dosage efficace pour optimiser le traitement contre le cancer. Bien que des lignes directrices spécifiques à la prise en charge de l’hypertension induite par les IFCEV ne soient pas encore disponibles, les inhibiteurs de l’enzyme de conversion de l’angiotensine et les bloqueurs des canaux calciques de la classe des dihydropyridines sont fréquemment utilisés. L’hypertension grave exigerait la réduction du dosage des IFCEV, ou dans certains cas, l’interruption du traitement. Puisque des IFCEV plus puissants sont élaborés et puisque plus de patients atteints de cancer sont traités par les IFCEV, le fardeau de la toxicité liée à l’hypertension augmentera. Ce fardeau sera davantage aggravé puisque l’utilisation des médicaments antiangiogéniques s’étendra aux patients âgés et à ceux qui sont atteints d’une maladie cardiovasculaire. Ici, nous mettons l’accent sur les FCEV en tant que cible de l’antiangiogenèse et sur la manière qu’ils influencent l’augmentation de la pression artérielle. Les mécanismes présumés sous-jacents à l’hypertension induite par les IFCEV sont soulignés, et les stratégies thérapeutiques pour prendre en charge cette hypertension sont discutées.
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