Rapid Development of Hypertension and Proteinuria with Cediranib, an Oral Vascular Endothelial Growth Factor Receptor Inhibitor

Abstract

Background and objectives: Hypertension and proteinuria are common but poorly understood renal toxicities of vascular endothelial growth factor (VEGF) receptor signaling pathway inhibitors. In this phase II study of cediranib (AZD2171) for recurrent epithelial ovarian cancer, the time course and severity of BP changes and proteinuria were characterized.Design, setting, participants, & measurements: 46 women ages 41 to 77 years were treated with cediranib. 26% had baseline hypertension. Twice-daily BP was recorded. Urinalyses were performed every 2 weeks, and in some patients proteinuria was further quantified.Results: 31 women (67%) developed hypertension by day 3; 87% by the end of the study. 43% developed grade >3 hypertension. Mean systolic BP increase over 3 days was 18 mmHg. Women above the mean age (>57 years) had a larger rise in systolic BP by day 3 (15.9 versus 7.0 mmHg). 14 women developed proteinuria. There was a dose response (45 versus 30 mg daily). Proteinuria also developed rapidly, with 7 of 14 women developing proteinuria within 2 weeks. Only 7 of 20 women who developed grade 3 hypertension developed proteinuria.Conclusions: Cediranib induced a rapid but variable rise in BP within 3 days of initiation in most patients. Proteinuria was common and also developed rapidly. The rapid development of hypertension suggests that acute inhibition of VEGFdependent vasodilation might explain the BP rise with VEGF inhibitors. Clinicians must be vigilant in early detection and management of toxicities of this expanding drug class, especially in older patients.

Estimating the clinical risk of hypertension from VEGF signal inhibitors by a non-clinical approach using telemetered rats

“…DBP recovered to near baseline during the recovery period, except that DBP was slightly elevated from baseline with the highest dose of cediranib. Clinical studies of VEGF signal inhibitors showed that hypertension was induced within a few days of first administration (Maitland et al, 2009;Robinson et al, 2010a), and recovered following the end of administration (Azizi et al, 2008). Therefore, the trend of hypertension represented in this non-clinical study was similar to that in clinical studies.…”

Phase I Dose-Escalation Study and Biomarker Analysis of E7080 in Patients with Advanced Solid Tumors

“…These effects have been documented upon administration of several inhibitors of the VEGF signaling pathway, such as bevacuzimab and cediranib (24,25), due to a possible perturbation of endothelial cell function (23). In this present study, hypertension was well managed by antihypertensive agents and proteinuria was managed by dose reductions or delays, and did not cause dose interruptions at the MTD or lower doses.…”

Onconephrology

“…4,5 For instance, anti-vascular endothelial growth factor (VEGF) therapy is associated with increased incidence of hypertension, proteinuria, and CKD. 6 A better understanding of the renal complications of anti-VEGF therapy has also led to greater understanding of the functioning of the glomerular filter and the pathogenesis of preeclampsia. 7,8 As with anti-VEGF therapy, newer myeloma therapies have also increased survival of patients with CKD.…”