CT perfusion in normal liver and liver metastases from neuroendocrine tumors treated with targeted antivascular agents

Objective: To assess the effects of bevacizumab and everolimus, individually and combined, on CT perfusion (CTp) parameters in liver metastases from neuroendocrine tumors (mNET) and normal liver. Methods: This retrospective study comprised 27 evaluable patients with mNETs who had participated in a two-arm randomized clinical trial of mono-therapy with bevacizumab (Arm B) or everolimus (Arm E) for 3 weeks, followed by combination of both targeted agents. CTp was undertaken at baseline, 3 and 9 weeks, to evaluate blood flow (BF), blood volume (BV), mean transit time (MTT), permeability surface area product (PS), and hepatic arterial fraction (HAF) of mNET and normal liver, using a dual-input distributed parameter physiological model. Linear mixed models were used to estimate and compare CTp parameter values between time-points. Results: In tumor, mono-therapy with bevacizumab significantly reduced BV (p = 0.05); everolimus had no effects on CTp parameters. Following dual-therapy, BV and BF were significantly lower than baseline in both arms (p ≤ 0.04), and PS was significantly lower in Arm E (p < 0.0001). In normal liver, mono-therapy with either agent had no significant effects on CTp parameters: dual-therapy significantly reduced BV, MTT, and PS, and increased HAF, relative to baseline in Arm E (p ≤ 0.04); in Arm B, only PS reduced (p = 0.04). Conclusions: Bevacizumab and everolimus, individually and when combined, have significant and differential effects on CTp parameters in mNETs and normal liver, which is evident soon after starting therapy. CTp may offer an early non-invasive means to investigate the effects of drugs in tumor and normal tissue.