Useful Parameters in Dynamic Contrast-enhanced Ultrasonography for Identifying Early Response to Chemotherapy in a Rat Liver Tumor Model

Abstract

Objectives: The objective of the study is to determine a parameter on the time-intensity curve (TIC) of dynamic contrast-enhanced ultrasonography (DCE-US) that best correlates with tumor growth and to evaluate whether the parameter could correlate with the early response to irinotecan in a rat liver tumor model.

Material and methods: Twenty rats with tumors were evaluated (control: Saline, n = 6; treatment: Irinotecan, n = 14) regarding four parameters from TIC: Peak intensity (PI), k value, slope (PI × k), and time to peak (TTP). Relative changes in maximum tumor diameter between day 0 and 10, and parameters in the first 3 days were evaluated. The Mann-Whitney U-test was used to compare differences in tumor size and other parameters. Pearson's correlation coefficients (r) between tumor size and parameters in the control group were calculated. In the treatment group, relative changes of parameters in the first 3 days were compared between responder and non-responder (<20% and ≥20% increase in size on day 10, respectively).

Results: PI, k value, PI × k, and TTP significantly correlated with tumor growth (r = 0.513, 0.911, 0.665, and 0.741, respectively). The mean RC in k value among responders (n = 6) was significantly lower than non-responders (n = 8) (mean k value, 4.96 vs. 72.5; P = 0.003).

Conclusion: Parameters of DCE-US could be a useful parameter for identifying early response to irinotecan.

Keywords: Biomarkers; Colon cancer; Contrast media; Irinotecan; Rats; Ultrasonography.

Figure 1:

Experimental protocol. Maximum tumor diameter was measured on days 0, 3, and 10, and DCE-US was performed on days 0 and 3. Saline was injected in the first step (n = 6) and irinotecan in the second step (n=14). DCE-US: Dynamic contrast-enhanced ultrasonography.

Figure 2:

DCE-US and the fitted curve constructed from the raw data. DCE-US was conducted for 85 s and the following four parameters were extracted from the fitted curve: PI, k value, wash-in slope (PI × k), and TTP. DCE-U: Dynamic contrast-enhanced ultrasonography, PI: Peak intensity, TTP: Time to peak.

Figure 3:

Representative responder and non-responder fitted curves. Time-intensity curves on days 0 and 3 and fitted curves after modelization at baseline for a responder (a, b, and e, respectively) and a non-responder (c, d, and f, respectively). In the responder, TTP shortened 1.2 s and PI decreased 1.2 dB. In the non-responder, TTP shortened 5.2 s and PI increased 3.9 dB. The relative change of TTP in the non-responder was shorter than in the responder. TTP: Time to peak, PI: Peak intensity.

Figure 4:

Relative change in the four DCE-US parameters between days 0 and 3 (second step). The k value was significantly lower in the responder group (4.96%) than in the non-responder group (72.5%, P=0.003). Significant difference was also found for TTP between the responders (2.45%) and non-responders (−27.4%) groups (p = 0.044). DCE-US: Dynamic contrast-enhanced ultrasonography, TTP: Time to peak, PI: Peak intensity.