INTRODUCTION

Clinical use of MRI contrast media has not changed in 30 years [1-3] and is based on seminal papers demonstrating efficacy of a single bolus injection. This early work resulted in major improvements clinical imaging. However, since this early work there have been dramatic advances in MRI technology including significant increases in field strength and improvements in contrast agents. To take advantage of new MRI and contrast media technology, we propose innovative clinical applications of a split contrast media dose injection for dynamic contrast enhanced (DCE) MRI. Data acquired following the low dose provides an accurate arterial input function (AIF) and facilitates quantitative analysis. Comparison of the response to low and high doses may provide information about water exchange, which is a marker for cancer [4].

This study evaluated a split dose injection of gadoterate meglumine (Dotarem, Guerbet LLC, Princeton NJ, USA). 30% of a standard dose of Dotarem was injected, and then after two minutes 70% of standard dose was injected. The signal intensity form of the Tofts pharmacokinetic model (SI-Tofts; [5]) was used to quantitatively analyze data from both the 30% and 70% doses. In addition, we combined information from the two doses using binary logistic regression to obtain novel diagnostic information.

METHODS

Thirteen patients with biopsy-confirmed prostate cancer were included in this IRB-approved study. MRI data were acquired on a Philips Achieva 3T-TX scanner without an endorectal coil. After T2-weighted and diffusion-weighted imaging, DCE 3D T1-FFE data were acquired pre- and post- DOTAREM injection of 0.03 mmol/kg (TR/TE=4.153/1.52 ms, FOV=200×200 mm², matrix size=224×224, flip angle=10°, slice thickness=3 mm, number of slices=24, SENSE factor=1.5, half scan factor=0.675) for 95 dynamic scans with temporal resolution of 3.01 sec/image. Finally, the DCE 3D protocol was repeated pre- and post- DOTAREM injection of 0.07 mmol/kg (TR/TE=6.115/1.52 ms) for 150 dynamic scans with temporal resolution of 4.43 sec/image.

Regions-of-interest (ROIs) for prostate cancer (n=22) and normal tissue (n=30) in different prostate zones were drawn on T2W images and transferred to DCE images. ROIs for blood vessels were manually traced on the iliac artery on a slice with cancer. Average signal intensity (S(t)) as function of time (t) was calculated for each ROI. To minimize noise effects, blood signal intensity ($$$S_{br}(t)=\frac{S_b(t)-S_b(0)}{S_b(0)}$$$) was fitted with an empirical mathematical model (EMM) [6]:
$$S_{br}(t)=\arctan(10t)\cdot[1+\sum_{n=1}^2A_n\exp(-(t-\tau_n)^2/2\sigma_n^2)]{\cdot}B\cdot\exp(-\beta{t}),-----(1)$$
where t is in minutes, A_n and B are scaling constants, τ_n and σ_n (n=1, 2) are the center and width of a Gaussian function, and β is the decay constant. Only one Gaussian function was used for 70% of standard dose. For cancer and tissue signal intensity ($$$S_{r}(t)=\frac{S(t)-S(0)}{S(0)}$$$ ), the physiological parameters (K^trans and v_e) were extracted by using SI-Tofts model as follows [5]:
$$S_{r}(t)=\lambda\frac{S_b(0)}{S(0)(1-Hct)}K^{trans}\int_{0}^{t} S_{br}(t)\exp(-\lambda(t-\tau){K^{trans}}/v_e)d\tau,-----(2)$$
where Hct=hematocrit (=0.42), 𝜆=T1(blood)/T1(tissue) with literature values of T1(blood)=1.70 sec and T1(prostate-tissue)=1.55 sec. Student’s T-test was performed to test differences in calculated parameters between cancer and normal tissue and between data from 30% and 70% of standard dose. Receiver operating characteristic (ROC) analysis was used to evaluate performance in differentiating cancer from normal tissue. Binary logistic regression was used to assess combinations of parameters from the 30% and 70% doses.

RESULTS

Figure 1 (a-b) shows an example of blood S_br(t) measured from 67 years old patient for (a) 30% and (b) 70% of standard dose with corresponding EMM fits, and (c-d) shows cancer/tissue S_r(t) with corresponding the SI-Tofts model fits. The average EMM fitted parameters for S_br(t) from thirteen patients are given in Table 1. The parameter A₁ is significantly larger for 30% dose than 70% dose, which means the S_br(t) had higher peak magnitude for 30% than 70% dose. Figure 2 compares physiological parameters (a, c) K^trans and (b, d) v_e between prostate cancers (red) and normal tissue (green) for 30% (top row) and 70% (bottom row) of standard dose. On average, cancer had larger K^trans and smaller v_e than normal tissue for both doses. The difference is significant for K^trans from the 70% of dose. For combined K^trans and v_e, ROC analysis yielded area under the curve (AUC) of 0.711 and 0.745 for 30% and 70% of the standard dose, respectively. The AUC increased significantly to 0.776 when parameters from both injections were combined (Table 2).

DISCUSSION

Dotarem 30%/70% split dose protocol with quantitative analysis using the SI-Tofts model differentiated cancer from normal tissue. Due to higher dose-normalized peak magnitude of S_br(t) for 30% of standard dose, the corresponding K^trans was significantly smaller than the K^trans obtained from 70% of standard dose. In future work we will test use of the dose normalized AIF from the 30% dose to analyze data from the 70% dose. The blood S_br(t) obtained from 30% of standard dose showed clear 1^st and 2^nd passes. The combination of parameters obtained from both doses increased diagnostic efficacy. This may be because the 30% dose provides a more accurate AIF, while the two doses combined provides information concerning water exchange rate – an important marker for cancer [4].

CONCLUSION

The split dose protocol for injection of Dotarem could increase diagnostic accuracy using quantitative analysis with the SI-Tofts model. Combination of parameters from the two doses increases diagnostic accuracy, possibly due to sensitivity to water exchange.

Acknowledgements

This research is supported by National Institutes of Health (R01 CA172801, R01CA218700, 1S10OD018448-01) and Guerbet LLC.