Monitoring the therapeutic efficacy of CA4P in the rabbit VX2 liver tumor using dynamic contrast-enhanced MRI

PURPOSEThe present work aims to evaluate whether dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can monitor the blocking effect of combretastatin-A4-phosphate (CA4P) on microvessels and assess the therapeutic efficacy.METHODSForty rabbits were implanted VX2 tumor specimens. Two weeks later, serial MRI (T1-weighted imaging, T2-weighted imaging, and DCE) were performed at 0 h, 4 h, 24 h, 3 days, and 7 days after CA4P (10 mg/kg) or saline treatment. The parameters of DCE (K^trans, K_ep, V_e and iAUC60) enhancement of tumor portions were measured. Then all tumor samples were stained to count microvessel density (MVD). Finally, two-way repeated measures ANOVA was used to analyze the difference between and within groups. Correlation between the DCE parameters and MVD was analyzed by using the Pearson correlation and Spearman rank correlation.RESULTSK^trans and iAUC60 values at 4 h after CA4P treatment were significantly lower than those in the control group (D-value: −0.133 min⁻¹, 95%CI: −0.169 to −0.097 min⁻¹, F= 59.109, p < 0.001 for K^trans; D-value: −10.533 mmol/s, 95%CI: −17.147 to −3.919 mmol/s, F= 11.110, and p = 0.003 for iAUC60). In the CA4P group, K^trans and iAUC60 reached the minimum values at 4 h, and both parameters showed significant difference between 4 h and other time points (all p < 0.01). Seven-day values of K^trans (r=0.532, p = 0.016 and r=0.681, p = 0.001, respectively) and iAUC60 (r=0.580, p = 0.007 and r=0.568, p = 0.009, respectively) showed correlation with MVD in both groups, while K_ep and V_e did not show correlation with MVD (p > 0.05).CONCLUSIONThe blocking effect of microvessels after CA4P treatment can be evaluated by DCE-MRI, and the parameters of quantitative K^trans and semi-quantitative iAUC60 can assess the change in tumor angiogenesis noninvasively.

Hepatocellular carcinoma (HCC) has the third highest mortality rate worldwide among cancers (1). Although the 5-year survival rate can reach up to 70% of HCC patients by surgical operation, only less than 30% are suitable for surgery. Transarterial chemoembolization (TACE) treated tumors can stimulate angiogenesis and require repeated treatment (2). As HCC is generally hypervascular, vascular targeting strategies can be used to improve the 5-year survival rate (3).There are two kinds of tumor vascular targeted agents (4): angiogenesis inhibitors (AIs) and vascular disrupting agents (VDAs). AIs can prevent the formation of new blood vessels by inhibiting angiogenesis. VDAs can damage the tumor endothelium directly, shutdown vascular development rapidly and selectively and cause tumor cell ischemia; tumor vascular shutdown occurs within 1 h of administration, and lasts for 24 hours (5, 6). Combretastatin A-4-phosphate (CA4P) is a new-style VDA that progressed into clinical trial stage (7–9).The vascular disrupting effects of VDAs can be assessed by microvessel density (MVD), which is the “gold standard” measurement to evaluate angiogenesis. However, the invasiveness of MVD measurement limits its use (10).During the development of targeted treatments, imaging plays an important role in monitoring the treatment efficacy against malignant tumors (11). Although change in tumor size may not be a reliable method to measure treatment efficacy, plenty of imaging sequences have been developed to overcome the drawbacks of traditional efficacy assessments by size measurement (12–14).DCE-MRI could reflect the microvascular structure and function indirectly, noninvasively and quantitatively, and it has been widely applied to predict and evaluate the treatment response (15). DCE-MRI is expected to be useful in evaluating early vascular disrupting efficacy after CA4P administration. But studies focusing on the changes of DCE parameters at different time points after CA4P administration in the VX2 rabbits have been scarce (16–18). The VX2 liver tumor is supplied by liver artery which is similar with high-grade human HCC, and can be used to simulate the microenvironment of human HCC (19).In this study, we aimed to investigate whether quantitative parameters in DCE-MRI can monitor the change in microvasculature of liver tumors at different time points after CA4P treatment.