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 dose-dependent [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^T315I, 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-VEGF-induced 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 anti-VEGF 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 semi-automatic devices providing serial measurements over time [27,28]. The latter have been convincingly shown to better predict cardiovascular outcomes compared with traditional blood pressure measurements in the clinic [27,28]. Additional parameters that might further enhance predictive capacity in both the general population and cancer patients treated with anti-VEGF drugs include assessment of the variability of repeated blood pressure measurements, estimated aortic (‘central’) blood pressure, and markers of arterial structure and function [29–31].

Given that most reported assessments of blood pressure in published clinical trials with anti-VEGF drugs have generally involved a limited number of measures performed at the study site, current recommendations for hypertension diagnosis and assessment are not adequately addressed [28]. Moreover, these studies were analyzed based upon pre-defined thresholds and category allocations, e.g. absence/presence of hypertension or Grade 1–4 hypertension, rather than absolute or relative changes in blood pressure. This approach could dilute any potential anti-VEGF-induced hypertensive effects and affect data interpretation. For example, a 25 mm Hg increase in systolic blood pressure in a patient with a baseline systolic blood pressure of 105 mm Hg would not contribute toward any increased prevalence of hypertension, based on the traditional 140 mm Hg cut-off point. The assessment of absolute or relative changes in blood pressure is routinely used in cardiovascular trials in order to assess baseline risk and the effect of interventions. This could provide a more sensitive approach toward estimating the effects of anti-VEGF drugs on blood pressure and, consequently, cancer outcomes. Moreover, because of the uncertainties in the pathophysiology, assessment, and management of anti-VEGF-induced hypertension, no evidence-based treatment guidelines are currently available.

Future studies assessing the role of anti-VEGF-induced hypertension in predicting cancer outcomes should take into account, whenever possible, the issues discussed above. In particular, a frequent assessment of absolute or relative changes in systolic, diastolic, and pulse pressure, using either home blood pressure monitoring or ambulatory blood pressure monitoring devices, would provide a more comprehensive picture of the incidence and severity of anti-VEGF-induced hypertension. Baseline clinical and demographic characteristics, as well as genetic polymorphisms, should also be taken into account using appropriate statistical approaches. Additional factors might also influence the association between anti-VEGF-induced hypertension and cancer outcomes. For example, individual cancer types, and their specific metabolic, haemodynamic, and neuro-hormonal signatures, could directly influence vascular homeostasis and blood pressure changes during anti-VEGF treatment. Anti-VEGF-related toxicities, e.g. proteinuria, could further enhance the predictive role of hypertension. Moreover, there is early evidence that the use of specific blood pressure lowering drugs might improve cancer outcomes in patients receiving anti-VEGF drugs [32]. Potential interactions between blood pressure lowering drugs and specific anti-VEGF drugs might be relevant in this context [33].

The increasing availability of clinical trial data and the conduct of further studies primarily investigating the complex interaction between cancer, anti-VEGF treatment, hypertension, and cancer outcomes offers significant opportunities for better characterizing and justifying the clinical use of blood pressure as a marker of treatment response in cancer care. It also provides important additional evidence for the development of specific anti-VEGF-induced hypertension management guidelines in this complex and vulnerable patient population.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.