Chapter 1 - Cardiac Complications of Cancer and Anti-Cancer Treatment
Hypertension is a relatively common and dose-related side effect of several antiangiogenic drugs (see below). It can occur at any time after therapy initiation; however, pre-existing hypertension is an important risk factor for complications.
Clinical trials of bevacizumab reported grade 3–4 hypertension in approximately 10% of patients, with rare cases of hypertensive crisis, encephalopathy or intracranial haemorrhage. In trials with antiangiogenic multitarget kinase inhibitors, such as sunitinib or sorafenib, the incidence of grade 3–4 hypertension was even higher, and in some rare cases hypertension was associated with reversible posterior leukoencephalopathy syndrome, a clinical event characterised by headache, seizures, impaired vision and acute hypertension (Todaro et al, 2013).
Several mechanisms have been proposed to explain antiangiogenic-induced hypertension, including decreased nitric oxide signalling in the wall of arterioles, increased endothelin-1 production and capillary rarefaction. Arterial hypertension developing through these mechanisms is an on-target side effect, and may play a role as a pharmacodynamic biomarker for vascular endothelial growth factor (VEGF) inhibition.
However, hypertension may also be secondary to renal thrombotic microangiopathy or to glomerular damage, hence the importance of investigating renal abnormalities through evaluation of creatinine clearance, proteinuria and microscopic haematuria while on active therapy. Proteinuria is usually monitored during treatment by dipstick urine analysis. Patients who develop proteinuria (confirmed using 24-hour urine collection) or reduced renal function (glomerular filtration rate [GFR] <60 ml/min per 1.73 m2) should be referred to a nephrologist. It should also be considered whether to put on hold, or definitively discontinue, treatment according to the severity of proteinuria, based on the manufacturer’s recommendations.
As hypertension and cancer can frequently coexist in the same patient, patients who are candidates for treatment with antiangiogenic agents should be screened at baseline for hypertension and for existing kidney disease. Anti-hypertensive therapy should be implemented or optimised before starting treatment, to prevent antiangiogenic-induced uncontrolled hypertension and avoid the development of serious complications. Repeated BP measurements are recommended during treatment with anti-angiogenic drugs, with the aim of implementing early active anti-hypertensive therapy to maintain BP <140/90 mmHg, rather than withdrawing treatment. Since these patients are at increased risk of LVD, preferred antihypertensive agents should include ACE inhibitors and dihydropyridine calcium channel blockers (CCBs), although there are minimal data to suggest the superiority of a class of agents. Non-dihydropyridine CCBs should be avoided in sorafenib-induced hypertension, due to drug interactions that may result in higher levels of sorafenib. Discontinuation of treatment may be applicable if systolic BP is >200 mmHg, diastolic BP >100 mmHg, or in case of hypertensive crisis.