INCREASED ADVERSE EVENTS WITH CEDIRANIB

NEW YORK (Reuters Health) Jan 19 - Most cancer patients who take cediranib develop hypertension, often within days, and many develop proteinuria within a few weeks as well, a phase II trial has shown.

Cediranib is an oral inhibitor of the vascular endothelial growth factor (VEGF) receptor signaling pathway. Because cediranib is more potent than older VEGF inhibitors, lead author Dr. Emily S. Robinson, from Brigham and Women's Hospital, Boston, and co-investigators theorized that it might produce more side effects.

In fact, as they reported online January 7th in the Clinical Journal of the American Society of Nephrology, prevalence rates for hypertension and proteinuria "are much higher" with cediranib than with older VEGF receptor signaling pathway inhibitors.

The open-labeled, single-agent trial took place between 2005 and 2008 and involved 46 women, ages 41 to 77, with recurrent epithelial ovarian carcinoma.

Women stayed in the study for a median of 84 days (range 6 to 544 days). When the study began, cediranib was started at 45 mg, but the initial dose was dropped to 30 mg after the first 11 patients had excessive side effects, mainly fatigue and diarrhea.

Hypertension developed in 67% of the women within 3 days, in 73% within 7 days, and in 87% by the end of the study. Forty-three percent developed Grade 3 hypertension (or worse).

Average systolic blood pressure rose from 120 mm Hg at baseline to 139 mm Hg by day 3, while diastolic blood pressure increased from 73 to 90 mm Hg (p <>

The only predictor of hypertension by day 3 was an age of 56 years or older. In addition, by day 3, women aged 57 or older had a mean systolic pressure increase of 15.9 mmHg, whereas younger women had a mean increase of 7.0 mmHg.

Antihypertensive treatment prevented blood pressure from rising further.

Thirty percent of the patients developed grade 1 or 2 proteinuria, half within 2 weeks and the remainder by 6 weeks. The only significant risk factor for proteinuria was the starting dose of cediranib, the research team reports.

The authors point out that up to 65% of patients with grade 3 or worse hypertension did not develop proteinuria, and in at least one patient, proteinuria developed before the hypertension - suggesting that VEGF receptor signaling pathway inhibitors produce the two side effects via different mechanisms.

The early onset of hypertension might be the result of acute inhibition of VEGF-mediated vasodilation, they add.

Neither hypertension, proteinuria nor a combination of the two was correlated with treatment response, "but the confidence intervals were wide for these analyses," Dr. Robinson and colleagues maintain.

"Clinicians must be vigilant in early detection and management of toxicities of this expanding drug class, especially in older patients," they conclude.

Clin J Am Soc Nephrol 2010.