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


METHODS
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.
Robinson
Emily S
ES
Channing Laboratory, 3rd Floor, 181 Longwood Avenue, Boston, MA 02115, USA. Erobinson11@partners.org
Matulonis
Ursula A
UA
Ivy
Percy
P
Berlin
Suzanne T
ST
Tyburski
Karin
K
Penson
Richard T
RT
Humphreys
Benjamin D
BD
D000284:Administration, Oral; D000328:Adult; D000367:Age Factors; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects*; D001794:Blood Pressure / Q000187:drug effects; D002277:Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016009:Chi-Square Distribution; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced* / Q000503:physiopathology; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D011507:Proteinuria / Q000139:chemically induced*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D013997:Time Factors; D016896:Treatment Outcome; D007211:Indoles
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D040262:Receptors, Vascular Endothelial Growth Factor; C500926:cediranib; D007211:Indoles