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.4 In vivo studies have shown that ACEi increase release of NO, and are thus recommended as first line agents for management of anti-VEGF induced hypertension.5 External beam radiation therapy also impairs endothelium-dependent vasodilation of conduit arteries, thus implicating a decrease in bioavailability of NO.6 Androgen Deprivation Therapy is also associated with increased cardiovascular events.7
We observed resistance to antihypertensive agents targeting RAAS in our cancer patients, a phenomenon observed in African American patients treated with ACEi/ARB monotherapy for hypertension. 4 of our 5 patients were Caucasians and all had a history of hypertension prior to being initiated on chemotherapy. Their BPs normalized once ACE-i/ARB was discontinued. All of these patients had normal renal artery duplex scans and secondary hypertension workup. 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).8 They also observed reduced renin levels in the rats exposed to higher levels of cediranib (a potent VEGF signaling 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.4 Thus, ACEi/ARBs which are suggested as first line for management of hypertension in cancer patients on VEGF inhibition therapy, may have suboptimal BP lowering effects in cases of severe hypertension.
No clinical evidence exists till date that favors one antihypertensive agent over the other in treating antiangiogenic therapy-induced hypertension. Nonetheless, Curwen et al demonstrated reversal of marked captopril-resistant hypertension induced by cediranib in rats after treatment with nifedipine.8 Clinical studies have also shown effective BP management with these agents after treatment with bevacizumab.9 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, given the risk of compromising antiangiogenic benefits due to VEGF inhibition, it is prudent to use other available alternatives.
In conclusion, efficacy of drugs targeting RAAS for BP control in cancer patients on active therapy is still unclear, and further clinical studies evaluating the same are required.