The first study on therapeutic efficacies of a vascular disrupting agent CA4P among primary hepatocellular carcinomas with a full spectrum of differentiation and vascularity: Correlation of MRI‐microangiography‐histopathology in rats

摘要

To better inform the next clinical trials of vascular disrupting agent combretastatin‐A4‐phosphate (CA4P) in patients with hepatic malignancies, this preclinical study aimed at evaluating CA4P therapeutic efficacy in rats with primary hepatocellular carcinomas (HCCs) of a full spectrum of differentiation and vascularity by magnetic resonance imaging (MRI), microangiography and histopathology. Ninety‐six HCCs were raised in 25 rats by diethylnitrosamine gavage. Tumor growth was monitored by T2‐/T1‐weighted‐MRI (T2WI, T1WI) using a 3.0 T scanner. Early vascular response and later intratumoral necrosis were detected by dynamic‐contrast‐enhanced (DCE) MRI and diffusion‐weighted‐imaging (DWI) before, 1 and 12 hr after CA4P iv‐administration. In vivo MRI‐findings were validated by postmortem‐techniques. Multi‐parametric MRI revealed rapid CA4P‐induced tumor vascular shutdown within 1 hr, followed by variable intratumoral necrosis at 12 hr. Tumor volumes decreased by 10% at 1 hr ( p ??0.05), but resumed at 12 hr. Correlations of semi‐quantitative DCE parameter initial‐area‐under‐the‐gadolinium‐curve (IAUGC30) with histopathology proved partial vascular closure and compensational reopening ( p ??0.05). The higher grades of vascularity prevented those residual tumor tissues from CA4P‐caused ischemic necrosis. By histopathology using a 4‐scale cellular‐differentiation criteria and a 4‐grade tumor‐vascularity classification, percentage of CA4P‐induced necrosis negatively correlated with HCC differentiation ( r ?=??0.404, p ??0.001) and tumor vascularity ( r ?=??0.370, p ??0.001). Ordinal‐logistic‐regression helped to predict early tumor responses to CA4P in terms of tumoral differentiation and vascularity. Our study demonstrated that CA4P could induce vascular shutdown in primary HCCs within 1 hr, resulting in various degrees of tumor necrosis at 12 hr. MRI as a real‐time imaging biomarker may help to define tumor vascularity and differentiation and further to predict CA4P therapeutic outcomes.