Angiogenesis Inhibitors and Hypertension: An Emerging Issue

Any of a number of therapeutic agents or chemical substances can induce transient or more long-lasting forms of hypertension. Drugs that cause hypertension do so by either stimulating pressor responses, increasing extracellular volume, and/or by decreasing vascular compliance. In the process, the effects of numerous antihypertensive therapies can be overidden. The list of compounds capable of increasing blood pressure (BP) is quite extensive and continues to grow. It would seem that vascular endothelial growth factor (VEGF) antagonists (or angiogenesis inhibitors) can now be added to an already lengthy list of compounds linked to the onset of a hypertensive state. Several angiogenesis inhibitors have now been implicated in the development of hypertension. Early studies with bevacizumab offered the first clue as to the prevalence of hypertension with angiogenesis inhibitors. In the study of Hurwitz et al, 402 patients were treated with bevacizumab (5 mg/kg every 2 weeks) and hypertension was seen in 22% of cases (control population rate, 8.3%). Grade 3 hypertension (or that requiring therapy) was noted in 11% of the bevacizumab-treated cohort. Yang et al evaluated two different doses of bevacizumab (3 and 10 mg/kg) in patients with metastatic renal cell carcinoma. Hypertension and asymptomatic proteinuria were associated with bevacizumab therapy, particularly in the high-dose group. Among all bevacizumabtreated patients who required therapy for newly diagnosed hypertension (for whom the dates of onset could be most accurately determined), the median interval from the first dose of bevacizumab to the onset of hypertension was 131 days (range, 7 to 316). Hypertension and proteinuria uniformly decreased with the cessation of therapy; however, documentation of complete resolution of these adverse effects was not possible because of multiple confounders relating to death and commencement of other therapies. In a phase III trial conducted by Miller et al in metastatic breast cancer patients grade 3 hypertension was observed in 17.9% of those receiving capecitabine and bevacizumab (15 mg/kg given intravenously on day 1 of every 3-week cycle) compared to capecitabine alone. Preinfusion systolic and diastolic BP values fell by a mean of 2.6 and 0.7 mmHg, respectively, in the capecitabine alone group, while increasing by 5.5 and 4.6 mmHg in the capecitabine and bevacizumab combination group; no relationship was observed with duration of bevacizumab therapy or pre-existing hypertension. In these studies, four patients had bevacizumab stopped as a result of hypertension. An apparent association between hypertension and proteinuria was noted in the combination arm of this study: patients who developed proteinuria were more likely to become hypertensive (47.1% v 16.9%; P .001) than patients who did not happen to develop proteinuria. Several lines of reasoning would suggest a likelihood of BP decreasing initially with angiogenic growth factor therapy and increasing with angiogenesis inhibitor therapy. First, a number of studies in animals and humans have noted a drop in BP with angiogenic growth factor administration. In the VEGF in Ischemia for Vascular Angiogenesis Trial (VIVA), both intracoronary and intravenous infusions of recombinant human VEGF were accompanied by falls in systolic BP of up to 22% at the highest doses. Second, VEGF both enhances endothelial nitric oxide synthase (eNOS) activity and upregulates the message and protein levels of VEGF in human endothelial cells; thus, nitric oxide generation is an essential component of the response pattern to angiogenic growth factors. Finally, angiogenic growth factors offer a strong stimulus for the construction of new capillaries and the recruitment of endothelial progenitor cells. This enhancement of angiogenesis/arteriogenesis can be expected to decrease vascular resistance. It has been recognized for some time that small arteries and precapillary arterioles are critical determinants of vascular resistance and a reduction in their density—so-called capillary and arteriolar rarefaction—is observed in many animal models of hypertension. In this issue of the Journal of Clinical Oncology, Veronese et al carefully describe the BP changes observed with BAY 43-9006. BAY 43-9006 is a novel bi-aryl urea initially developed as a specific inhibitor of C-Raf and B-Raf. Subsequent studies have shown this compound to also inhibit several important tyrosine kinases involved in tumor progression including VEGF. More recently, the apoptotic potential of this compound has been described to at least, in part, relate to a down-regulation of myeloid cell leukemia1. These investigators have observed significant increases in BP in a large proportion of patients receiving BAY 43-9006. To this end, 12 of 20 (60%) of those studied experienced a systolic BP increase of 20 mmHg or more after 3 weeks of BAY 43-9006 at a dose of 400 mg twice daily. Further, these investigators gathered strong supporting evidence suggesting that activation of hypertensionproducing neurohumoral pathways and/or overt volume expansion are not major contributing factors to BAY 43-9006related hypertension. These studies, did on the other hand, note a rise in vascular stiffness although it could not be established whether this was a cause or an effect of the BP elevation. JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 24 NUMBER 9 MARCH 2