title: Effective strategies for management of hypertension after vascular endothelial growth factor signaling inhibition therapy: results from a phase II randomized, factorial, double-blind study of Cediranib in patients with advanced solid tumors.
abstract: PURPOSE Hypertension is a commonly reported adverse effect after administration of vascular endothelial growth factor (VEGF) inhibitors. Cediranib is a highly potent and selective VEGF signaling inhibitor of all three VEGFRs. This study prospectively investigated hypertension management to help minimize dose interruptions/reductions to maximize cediranib dose intensity. PATIENTS AND METHODS Patients (n = 126) with advanced solid tumors were randomly assigned to one of four groups: cediranib 30 or 45 mg/d with or without antihypertensive prophylaxis. All patients developing hypertension on cediranib treatment were treated with a standardized, predefined hypertension management protocol. Results Cediranib was generally well tolerated, and all groups achieved high-dose intensities in the first 12 weeks (> 74% in all groups). Antihypertensive prophylaxis did not result in fewer dose reductions or interruptions. Increases in blood pressure, including moderate and severe readings of hypertension, were seen early in treatment in all groups and successfully managed. Severe hypertension occurred in one patient receiving prophylaxis versus 18 in the nonprophylaxis groups. Overall, there were nine partial responses, and 38 patients experienced stable disease >/= 8 weeks. CONCLUSION To our knowledge, this is the first prospective investigation of hypertension management during administration of a VEGF signaling inhibitor. All four regimens were well tolerated with high-dose intensities and no strategy was clearly superior. The current cediranib hypertension management protocol appears to be effective in managing hypertension compared with previous cediranib studies where no plan was in place, and early recognition and treatment of hypertension is likely to reduce the number of severe hypertension events. This protocol is included in all ongoing cediranib clinical studies.
authors.affiliation: Medical Oncology, University Medical Center Utrecht, PO Box 85500, 3508 GA Utrecht, the Netherlands.
authors.forename: Marlies H G
authors.initials: MH
authors.lastname: Langenberg
authors.forename: Carla M L
authors.initials: CM
authors.lastname: van Herpen
authors.forename: Johann
authors.initials: J
authors.lastname: De Bono
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: Clemens
authors.initials: C
authors.lastname: Unger
authors.forename: Klaas
authors.initials: K
authors.lastname: Hoekman
authors.forename: Hubert E
authors.initials: HE
authors.lastname: Blum
authors.forename: Walter
authors.initials: W
authors.lastname: Fiedler
authors.forename: Joachim
authors.initials: J
authors.lastname: Drevs
authors.forename: Florence
authors.initials: F
authors.lastname: Le Maulf
authors.forename: Anitra
authors.initials: A
authors.lastname: Fielding
authors.forename: Jane
authors.initials: J
authors.lastname: Robertson
authors.forename: Emile E
authors.initials: EE
authors.lastname: Voest
mesh_terms: D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced* / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011446:Prospective Studies; D011799:Quinazolines / Q000009:adverse effects* / Q000627:therapeutic use*; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055815:Young Adult; D007211:Indoles
chemical_list: D000959:Antihypertensive Agents; D011799:Quinazolines; D042461:Vascular Endothelial Growth Factor A; C500926:cediranib; D007211:Indoles