Hepatic Arterial Buffer Response in Liver Radioembolization and Potential Use for Improved Cancer Therapy

Abstract

Liver radioembolization is a treatment option for unresectable liver cancers, performed by infusion of ⁹⁰Y or ¹⁶⁶Ho loaded spheres in the hepatic artery. As tumoral cells are mainly perfused via the liver artery unlike hepatic lobules, a twofold tumor to normal liver dose ratio is commonly obtained. To improve tumoral cell killing while preserving lobules, co-infusion of arterial vasoconstrictor has been proposed but with limited success: the hepatic arterial buffer response (HABR) and hepatic vascular escape mechanism hamper the arterioles vasoconstriction. The proposed project aims to take benefit from the HABR by co-infusing a mesenteric arterial vasodilator: the portal flow enhancement inducing the vasoconstriction of the intra sinusoids arterioles barely impacts liver tumors that are mainly fed by novel and anarchic external arterioles. Animal studies were reviewed and dopexamine was identified as a promising safe candidate, reducing by four the hepatic lobules arterial flow. A clinical trial design is proposed. A four to sixfold improvement of the tumoral to normal tissue dose ratio is expected, pushing the therapy towards a real curative intention, especially in HCC where ultra-selective spheres delivery is often not possible.

Keywords: SIRT; TARE; cancer therapy; dose optimization; liver radioembolization.

Figure 1

(a) Arterial blood flow, (b) tumor to normal tissue dose ratio (T/N) improvement, and (c) peripheral blood pressure during a continuous 10 μg/min AT-II arterial infusion (reprinted from [8] with authorization of Willey and Sons). Note the decrease of T/N improvement after 80 s despite the continuing AT-II infusion.

Figure 2

(A) Portal flow and (B) arterial to portal blood velocity ratio, both monitored by Doppler ultrasonography after ingestion of a standard liquid meal of 500 kcal. In (B), full and dashed curves correspond to left and right hepatic arteries, respectively. The number of observations and p for the student t-test for each measurement against the baseline appear under the error bars: * p < 0.05; ** p < 0.005; *** p < 0.0005. (reprinted from [18] with authorization of Springer Nature).

Figure 3

Portal and arterial hepatic blood flow in conscious rats as a function of the acetate infusion rate after 10 min of infusion (derived from [19]).

Figure 4

Schematic representation of the intra lobule vascularization to the central vein from one of the six triads. 1,2,3: lymphatic fluid flows. (reprinted from [39] with permission of Elsevier).

Figure 5

Changes in portal flow (PV) and in hepatic artery flow (HA) post-ingestion of a 700 kcal meal in six healthy volunteers and 12 cirrhotic patients measured by 4D flow MRI (reprinted from [42] with permission of Willey and Sons). Note that the data correspond to the global arterial flow; healthy lobules likely underwent a higher arterial flow reduction.

Figure 6

Contrast enhanced liver CT. (a–c): Arterial, portal, and equilibrium phase, respectively (reprinted from [55] under the license CC BY 4.0). Yellow arrow: left liver apex mass which re-enhanced contrast during the arterial phase.