Intravoxel Incoherent Motion Diffusion-weighted Magnetic Resonance Imaging for Monitoring the Early Response to ZD6474 from Nasopharyngeal Carcinoma in Nude Mouse
Yong Zhang1 and Yanfen Cui2

1GE Healthcare China, Shanghai, China, Shanghai, China, People's Republic of, 2Department of Radiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China, People's Republic of


This study was to investigate the feasibility of IVIM DWI to evaluate the early therapeutic effects of ZD6474 upon human NPC xenografts in nude mouse. NPC mice underwent IVIM DWI at baseline and after 1, 3, and 7 days of treatment. In the treated group, the f and D* decreased significantly on day 1 while the ADC and D were significantly higher from day 3 compared with the control group, demonstrating that IVIM DWI is sensitive to detect the ZD6474-induced changes in human NPC nude mouse, and the D* and f parameters could predict early response to anti-angiogenic treatment.


Nasopharyngeal carcinoma (NPC) is one of the most common malignancies of the head and neck in Southeast Asia. Chemoradiotherapy is the main treatment of choice for the NPC. Vandetanib (ZD6474), an oral small-molecule multitargeted tyrosine kinase inhibitors (TKIs), has been revealed to exhibit anti-angiogenic and anti-proliferative effects in some kinds of tumors, including NPC1. By implementing a bi-exponential fitting model with multiple b values, perfusion-related parameters such as the perfusion fraction (f) and blood pseudodiffusion coefficient (D*), and diffusion-related parameters such as the true diffusion coefficient (D), can be separately measured2,3. Therefore, the purpose of the present study was to investigate the feasibility of IVIM DWI to evaluate the early therapeutic effects of ZD6474 upon human NPC xenografts in nude mouse.


24 CNE-2 human NPC mice were randomly allocated to either the control group or the ZD6474-treated group. Mice in the treated and control group were administered with ZD6474 or vehicle by oral gavage at a dose of 100 mg/kg once daily for 7 day. MRI was performed before treatment (day 0) and at 1, 3, and 7 days after treatment on a 3.0T MR scanner (GE Healthcare, Milwaukee, WI) with a custom-built-8-channel receiver coil. The IVIM DWI sequence was obtained using a single-shot EPI with 12 b-values of 0, 20, 50, 100, 150, 200, 400, 600, 800, 1200, 1600, and 2000 s/mm2 (TR/TE, 3000 ms/102.4 ms; flip angle, 90°; matrix, 64× 64; field of view, 80 × 80 mm2; section thickness, 2.4 mm; NEX, 4) (Fig. 1). All the IVIM parameter maps were generated automatically by the MADC program (Fig. 2). All the tumors were harvested and underwent histological assessment for HE, CD31, Ki-67 and terminal nucleotidyltransferase-mediated nick end labeling (TUNEL) assay. The Student’s t test or the Mann-Whitney test was used for analysis of all the ADC and IVIM parameters and all histopathological indices of the tumors between the control and treated groups.


For the diffusion-related parameters, both the mean value and relative changes in ADC and D values significantly higher than those in the control group starting from day 3 (Table 1, Fig.3A and 3B). For the perfusion-related parameters, the mean D* value in the treated group was lower than that in the control group from day 3 (Table 1), while the relative change in D* value in the treated group decreased significantly compared with that in the control group within only 1 day (Fig.3C). The mean and percentage of changes in f values of the tumor were significantly decreased in the treated group compared with those in the control group after only 1day (Table 1 and Fig.3D). As show in Fig.4, a decrease in cellular density with more necrotic areas and decreased MVD scores in ZD6474-treated tumors were seen compared to those of tumors in the control group on day 7. The proliferative index Ki-67 in the treated group was significantly lower than that in the control group, while the apoptosis index was significantly higher than that in the control group, indicating an effective therapeutic response.

Discussion and Conclusion

In this preliminary study, we found perfusion-related parameters f and D*, which reflect the blood volume and velocity inside the tumors, change earlier than diffusion-related parameters ADC and D, which reflect the rate of microscopic water diffusion as a marker of cellular density or necrosis. Therefore, the present study demonstrated that IVIM DWI is sensitive to detect the ZD6474-induced changes in human NPC in nude mouse, while the D* and f parameter could allow for prediction of the early tumoral response to anti-angiogenic treatment.


No acknowledgement found.


1. Xiao, X. et al. Induction of cell cycle arrest and apoptosis in human nasopharyngeal carcinoma cells by ZD6474, an inhibitor of VEGFR tyrosine kinase with additional activity against EGFR tyrosine kinase. International journal of cancer. Journal international du cancer 121, 2095-2104, doi:10.1002/ijc.22955 (2007). 2. Le Bihan, D. et al. Separation of diffusion and perfusion in intravoxel incoherent motion MR imaging. Radiology 168, 497-505, doi:10.1148/radiology.168.2.3393671 (1988). 3. Joo, I., Lee, J. M., Han, J. K. & Choi, B. I. Intravoxel incoherent motion diffusion-weighted MR imaging for monitoring the therapeutic efficacy of the vascular disrupting agent CKD-516 in rabbit VX2 liver tumors. Radiology 272, 417-426, doi:10.1148/radiol.14131165 (2014).


(A–L)IVIM DW images with 12 b-values .

Axial T2-weighted image (A) and DW imaging with b value for 2000 s/mm2 (B) and the corresponding IVIM parameter maps (C-F) of one animal in the control group. (C) ADC map.(D) D map. (E) D* map. (F) f map.

Bar graphs comparing the percent change in IVIM DWI parameters of the tumor between treated and control groups at each time point after treatment.

comparison of IVIM DW imaging parameters between the treated and control groups

Histologic assessment of tumor response.

Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)