Hypertension is the most common comorbidity seen in cancer patients. In fact many studies have shown it to be a risk factor for cancer due to abnormal proliferative pathways.4 Cancer therapeutic agents such as bevacizumab, sunitinib, sorafenib, etc. are known to increase BP by decreasing endothelial nitric oxide (NO) production due to VEGF inhibition.5 Trastuzumab, which is a humanized monoclonal antibody against HER2, also decreases VEGF expression;6 and EBRT causes a decrease in bioavailability of NO by impairing endothelium-dependent vasodilation of conduit arteries.8 Other cancer therapies such as leuprolide can also cause hypertension resulting in increased cardiovascular events.7
We observed resistance to antihypertensive agents targeting RAAS (ACEi/ARB) in our cancer patients; a phenomenon also observed in African American patients treated with ACEi/ARB monotherapy for hypertension. All of our patients had a history of hypertension prior to being initiated on chemotherapy. Their BPs were uncontrolled on ACEi/ARB but normalized on discontinuation of these agents. All of these patients reported adherence with their medications and had normal renal artery duplex scans. None of the physical exam findings or laboratory values suggested other causes of secondary hypertension.
Three of our patients were on VSP inhibitors with bevacizumab and trastuzumab. Preclinical experiments in rats have shown an inability of ACEi to modulate higher increases in BP induced by VEGF inhibition, and suggest effectiveness in treatment for only mild increases in BP (10-15 mmHg).10 They also observed reduced renin levels in the rats exposed to higher levels of cediranib (a potent VSP inhibitor), and thus concluded that RAAS gets downregulated to maintain normotension when exposed to these agents. Other preclinical studies have also shown suppression of RAAS by angiogenesis inhibition.5 Thus, the significance of RAAS in mediating antiangiogenic therapy-induced hypertension is still controversial and other mechanisms such as inhibition of endothelial derived relaxation factors, capillary rarefaction and alteration in pressure-natriuresis relationship, as well as other vasoconstrictive pathways, play a major role.11 Thus ACEi/ARBs can cause suboptimal BP lowering effects in cases of severe hypertension due to already suppressed RAAS in these patients. Nonetheless, in vivo studies have shown that ACEi increases release of NO and are thus recommended as first line agents for management of anti-VEGF induced hypertension;9 especially for their renoprotective effects given higher risk of proteinuria on VSP inhibition therapy.14 It is possible that BP control with ACEi/ARBs in this population occurs due to angiogenesis inhibition by RAAS antagonism and not due to their direct antihypertensive action.
Recommendations for agents best used in the management of hypertension in patients on cancer therapy are variable and somewhat controversial, particularly for those on VEGF inhibitors. ACEi/ARBs are commonly preferred in cancer patients due to improved mortality outcome.12,13 However, as discussed, these agents could lead to suboptimal BP lowering as a result of RAAS suppression; particularly in cases of severe VEGF inhibitor-induced hypertension. This mechanism is similar to that of the repressed RAAS system leading to ACEi/ARB resistant hypertension in persons of African ancestry15, and is a possible explanation for the uncontrolled hypertension observed in our case 1. This patient was also on treatment with bortezomib – a proteasome inhibitor that can rarely cause endothelial dysfunction leading to hypertension and vascular dysfunction.16 Case 2 was on cancer treatment with leuprolide ADT which is known to cause hypertension. However, the resistance to ACEi observed in Case 2 was contrary to expectation since both leuprolide and EBRT are implicated in causing hypertension by mechanisms related to impairment of endothelium-dependent vasodilation; thus, ACEi/ARB are expected to be effective.7,8 All these patients showed resistance to ACEi/ARB on different cancer therapies whereas malignancy was a commonality. Indeed, patients with various cancers are known to overexpress Angiotensin II receptor 1, which is involved in BP regulation.17
Our clinical experience shows that for those patients resistant to ACEi/ARBs, peripheral arterial vasodilators like hydralazine and dihydropyridine calcium channel blockers (CCBs) like amlodipine or nifedipine are more effective in managing hypertension in these patients. Curwen et al demonstrated reversal of marked captopril-resistant hypertension induced by cediranib in rats after treatment with nifedipine.10 Clinical studies have also shown effective BP management with dihydropyridine CCBs after treatment with bevacizumab.18,19 Long acting nitrates that increase NO bioavailability have also been shown to effectively control hypertension in patients on antiangiogenic therapy that was refractory to ACEi and CCBs.3 However, there is a potential risk of compromising antiangiogenic benefits as preclinical evidence suggest the role of endothelial NO production in VEGF associated angiogenesis20,21.
In conclusion, possible mechanisms of hypertension resistant to ACEi/ARB observed in certain cancer patients include overexpression of Angiotensin II receptor 1, low renin state or RAAS suppression. Thus, the efficacy of drugs targeting RAAS for BP control in this population on active VEGF-inhibitor or other cancer therapy is still unclear. Since there are no specific recommendations for management of hypertension in cancer patients, clinical experience with its management needs to be reported. The observation of difficult-to-treat hypertension with ACEi/ARBs in cancer patients on VSP inhibitor or other therapy requires further investigation.