Perfusion computed tomography as functional biomarker in randomized run-in study of bevacizumab and everolimus in well-differentiated neuroendocrine tumors

Objectives: This study aimed to assess the antitumor activity of everolimus and bevacizumab among patients with advanced neuroendocrine tumors and to assess perfusion computed tomography (CT) as a potential functional biomarker. Methods: Patients with low- to intermediate-grade neuroendocrine tumors received one 3-week cycle of 15 mg/kg of bevacizumab on day 1 or 10 mg of everolimus daily. Subsequent cycles consisted of the combination of both drugs. Perfusion CTs were performed at baseline and at the end of cycles 1 and 3.Results: Therapy decreased blood flow (BF) proportional to baseline measurements. Bevacizumab was associated with a 44% decrease in BF (P < 0.0001). After the addition of everolimus, a further 29% decrease (P = 0.02) in BF was observed. Everolimus alone was associated with 13% increase in mean transit time (P = 0.02). Clinical activity was demonstrated, with a confirmed response rate of 21% and a median progression-free survival of 14.6 (95% confidence interval, 13.0-16.1) months. Pretreatment tumor permeability surface (P = 0.009), posttreatment mean transit time (P = 0.003), percent reduction in BF (P = 0.03), and percent reduction in blood volume (P = 0.002) were associated with best percent reduction in tumor diameters.Conclusions: Bevacizumab and everolimus demonstrated antitumor activity. Perfusion CT is a promising tool for the development of antiangiogenic strategies and for the selection of patients who are likely to benefit from therapy.