CT perfusion in normal liver and liver metastases from neuroendocrine tumors treated with targeted antivascular agents
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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.
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.
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).
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.
KeywordsNeuroendocrine tumors Computerized tomography, perfusion Liver metastases Bevacizumab Everolimus
Compliance with ethical standards
NIH CCSG Grant (P30 CA016672), Novartis, Genentech and the John S. Dunn, Sr. Distinguished Chair in Diagnostic Imaging provided partial funding support for conduct of the study.
Conflicts of interest
Chaan S. Ng has received research funding from and is a Consultant for GE Healthcare. Adam G. Chandler is employed by GE Healthcare. The other authors (Wei Wei, Cihan Duran, Payel Ghosh, Ella F. Anderson, and James C. Yao) declare that they have no conflicts of interest.
This retrospective analysis was approved by our institutional review board (IRB), with waiver of informed consent. Patients for this analysis were drawn from an earlier prospective clinical trial which was undertaken in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration. Informed consent was obtained from all individual participants included in the prospective study.
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