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Anti-VEGF-induced hypertension and cancer outcomes: translating research into clinical practice

The vascular endothelial growth factor (VEGF) physiologically regulates angiogenesis and maintains vascular homeostasis in vitro and in vivo [1,2]. The two main receptors mediating the effects of VEGF are the structurally related tyrosine kinases, VEGFR1 (Flt-1) and VEGFR2 (Flk-1) [3]. However, alterations in VEGF expression and signaling play an important role in cancer angiogenesis and progression in several types of cancer [4]. Nitric oxide (NO), a key endogenous modulator of vascular homeostasis, has been shown to mediate the main physiological and pathophysiological effects of VEGF, mainly through activation of VEGFR2 [5]. Over the last decade, an increasing number of drugs inhibiting the effects of VEGF (anti-VEGF drugs) have been introduced in clinical practice for the management of patients with cancer and eye disease conditions [6,7]. The use of anti-VEGF drugs for these indications is based on their ability to inhibit excessive and/or inappropriate angiogenesis either locally (e.g. in the eye) or systemically, thereby slowing disease progression [6,7]. In cancer, systemic inhibition of angiogenesis primarily involves inhibition of the binding of systemic VEGF to both VEGFR1 and VEGFR2, either by targeting circulating VEGF or its receptors [3]. Both pharmacological and non-pharmacological VEGF inhibition leads to an increase in arterial blood pressure in animal models, an effect that supports the key role of VEGF in maintaining vascular homeostasis, particularly arterial tone and systemic vascular resistance [8]. Clinical trials and observational studies have also reported an increased incidence of hypertension during systemic, but not intra-ocular, treatment with all commercially available anti-VEGF drugs [3]. Differences in patient characteristics, type of cancer, anti-VEGF treatment regimens and methods for assessing blood pressure notwithstanding, the reported incidence of hypertension ranges between 9% and 67%, and the incidence of severe hypertension (Grade 3 or Grade 4) ranges between 3% and 18% [9]. The available evidence suggests that both the incidence and the severity of anti-VEGF-induced hypertension are dosedependent [10]. The development of hypertension is generally observed within the first few weeks of treatment, although this is influenced by the methods and the frequency of blood pressure measurements [11,12]. For example, in one study ambulatory blood pressure was increased within the first 24 hours of anti-VEGF treatment initiation [13]. Given the established role of hypertension as a cardiovascular risk factor, efforts have been made to exclude cancer patients with uncontrolled hypertension and high cardiovascular risk from receiving systemic anti-VEGF treatment, to identify patients’ characteristics (e.g. clinical, demographic, and genetic) predisposing to anti-VEGF-induced hypertension as well as cancer treatment efficacy, to understand the pathophysiological mechanisms involved, and to investigate safe and effective blood pressure lowering strategies in this context [3]. For example, post hoc analyses of clinical trials with the anti-VEGF ponatinib have identified patients with specific mutations, BCR-ABL1, as having good chronic myeloid leukemia treatment response despite dose reduction because of hypertension-related cardiovascular toxicity [14]. The availability of post-marketing exposure data will also provide useful information on the long-term impact of anti-VEGFinduced hypertension on the risk of cardiovascular events, and their sequelae, in this patient group. While anti-VEGF therapy may predispose to increased cardiovascular risk, an increasing body of evidence also suggests that the onset of anti-VEGF-induced hypertension can predict favorable cancer outcomes, in particular, improved overall survival and progression-free survival, although there is some inconsistency in published reports [15–22]. Indeed, several experts have suggested that the development of hypertension can be considered a surrogate marker of anti-VEGF activity. However, it is unknown whether this is the result of increased activity of specific anti-VEGF drugs, increased systemic antiVEGF exposure, or a combination of both [23]. There is also preliminary evidence supporting the use of blood pressure values following initiation of an anti-VEGF drug to guide dose titration [24,25]. The observed blood pressure increase with anti-VEGF drugs involves alterations in NO synthesis and signaling, endothelial dysfunction and capillary rarefaction, although other pathophysiological mechanisms have been postulated [23]. These effects might each be impacted upon differentially depending on the specific anti-VEGF therapies employed. Given the associations observed between anti-VEGF drugs, the onset of hypertension, and treatment response, routinely assessing changes in blood pressure, a simple and relatively inexpensive practice, might present a useful strategy for predicting early treatment response, or lack of, in cancer patients prescribed anti-VEGF drugs. This would have significant clinical implications in terms of potential early treatment regimen revision and/or selection of alternative protocols. An important consideration in this context is that the clinical approach to the diagnosis, assessment, and management of hypertension has significantly changed over the last 10–15 years. For example, individual blood pressure components, i.e. systolic, diastolic, and pulse pressure, have shown different capacity to predict cardiovascular and non-cardiovascular outcomes in epidemiological studies [26]. Methods for assessing blood pressure are moving away from busy clinical environments, and increasingly involve the use of automatic or semiautomatic devices providing serial measurements over time EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT, 2016 VOL. 1, NO. 2, 125–127 http://dx.doi.org/10.1080/23808993.2016.1155963