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Clinical Trial
. 2010 Mar;5(3):477-83.
doi: 10.2215/CJN.08111109. Epub 2010 Jan 7.

Rapid development of hypertension and proteinuria with cediranib, an oral vascular endothelial growth factor receptor inhibitor

Emily S Robinson  1 , Ursula A Matulonis, Percy Ivy, Suzanne T Berlin, Karin Tyburski, Richard T Penson, Benjamin D Humphreys
Affiliations
Clinical Trial

Rapid development of hypertension and proteinuria with cediranib, an oral vascular endothelial growth factor receptor inhibitor

Emily S Robinson et al. Clin J Am Soc Nephrol. 2010 Mar.

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 > or =3 hypertension. Mean systolic BP increase over 3 days was 18 mmHg. Women above the mean age (> or =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 VEGF-dependent 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.

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Figures

Figure 1.
Figure 1.
Kinetics of BP rise and addition of medications. Day 0 was before cedarinib treatment. The mean length of time in the study was 115 days, and the median was 84 days. Data are from all 46 patients, and each time point is for those patients still in the study at that time.
Figure 2.
Figure 2.
Variability in change in mean arterial pressure (MAP) over 3 days. Change in MAP from baseline before initiation of cediranib to MAP on day 3 of the study medication. Data are from all patients from whom we have data from baseline and day 3 (n = 44).
Figure 3.
Figure 3.
SBP and DBP throughout the study. SBP and DBP mean values and SD at each time point. Data are from all patients remaining in the study at each time point.
Figure 4.
Figure 4.
Kinetics of development of proteinuria. Baseline was before initiation of cediranib. Urinalysis was performed every 2 weeks, and all patients who developed proteinuria during the study had developed this toxicity by 6 weeks. Data are from all patients for whom we have urinalysis data for at least one follow-up (n = 45).
See this image and copyright information in PMC

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