Evaluation of metronomic chemotherapy response using diffusion and dynamic contrast-enhanced MRI

Purpose: To investigate the feasibility of using diffusion MRI (dMRI) and dynamic contrast-enhanced (DCE) MRI to evaluate the treatment response of metronomic chemotherapy (MCT) in the 4T1 mammary tumor model of locally advanced breast cancer.
Methods: Twelve Balb/c mice with metastatic breast cancer were divided into treated and untreated (control) groups. The treated group (n=6) received five treatments of anti-metabolite agent 5-Fluorouracil (5FU) in the span of two weeks. dMRI and DCE-MRI were acquired for both treated and control groups before and after MCT. Immunohistochemically staining and measurements were performed after the post-MRI measurements for comparison.
Results: The control mice had significantly ( p <0.005) larger tumors than the MCT treated mice. The DCE-MRI analysis showed a decrease in contrast enhancement for the control group, whereas the MCT mice had a more stable enhancement between the pre-chemo and post-chemo time points. This confirms the antiangiogenic effects of 5FU treatment. Comparing amplitude of enhancement revealed a significantly (p<0.05) higher enhancement in the MCT tumors than in the controls. Moreover, the MCT uptake rate was significantly (p<0.001) slower than the controls. dMRI analysis showed the MCT ADC values were significantly larger than the control group at the post-scan time point.
Conclusion: dMRI and DCE-MRI can be used as potential biomarkers for assessing the treatment response of MCT. The MRI and pathology observations suggested that in addition to the cytotoxic effect of cell kills, the MCT with a cytotoxic drug, 5FU, induced changes in the tumor vasculature similar to the anti-angiogenic effect.

研究目的：探究利用扩散磁共振成像（diffusion MRI, dMRI）与动态对比增强磁共振成像（dynamic contrast-enhanced MRI, DCE-MRI）评估节拍式化疗（metronomic chemotherapy, MCT）对局部晚期乳腺癌4T1乳腺肿瘤模型治疗响应的可行性。
研究方法：将12只携带转移性乳腺癌的BALB/c小鼠分为治疗组与未治疗（对照）组，其中治疗组（n=6）在两周内接受5次抗代谢药物5-氟尿嘧啶（5-Fluorouracil, 5FU）治疗。分别在节拍式化疗前后，对治疗组与对照组小鼠进行dMRI与DCE-MRI扫描。在MRI扫描完成后，采集小鼠组织进行免疫组织化学染色与相关检测，用于后续对比分析。
研究结果：对照组小鼠的肿瘤体积显著大于接受节拍式化疗的小鼠（p<0.005）。DCE-MRI分析显示，对照组小鼠的对比增强信号呈下降趋势，而节拍式化疗组小鼠在化疗前与化疗后两个时间点的增强信号更为稳定，这证实了5FU治疗的抗血管生成效应。对比增强幅度分析表明，节拍式化疗组肿瘤的增强幅度显著高于对照组（p<0.05）。此外，节拍式化疗组的对比剂摄取速率显著慢于对照组（p<0.001）。dMRI分析显示，在扫描后时间点，节拍式化疗组的表观扩散系数（apparent diffusion coefficient, ADC）值显著高于对照组。
研究结论：dMRI与DCE-MRI可作为评估节拍式化疗治疗响应的潜在生物标志物。MRI与病理学观察结果表明，除了杀伤肿瘤细胞的细胞毒性效应外，联合使用细胞毒性药物5FU的节拍式化疗还可诱导肿瘤血管系统发生类似抗血管生成的改变。