MRI characterization of cobalt dichloride-N-acetyl cysteine (C4) contrast agent marker for prostate brachytherapy

Abstract

Brachytherapy, a radiotherapy technique for treating prostate cancer, involves the implantation of numerous radioactive seeds into the prostate. While the implanted seeds can be easily identified on a CT image, distinguishing the prostate and surrounding soft tissues is not as straightforward. Magnetic Resonance Imaging (MRI) offers superior anatomical delineation, but the seeds appear as dark voids and are difficult to identify, thus creating a conundrum. Cobalt dichloride-N-acetyl-cysteine (C4) has previously been shown to be promising as an encapsulated contrast agent marker. We performed spin-lattice relaxation time (T₁) and spin-spin relaxation time (T₂) measurements of C4 solutions with varying cobalt dichloride concentrations to determine the corresponding relaxivities, r₁ and r₂. These relaxation parameters were investigated at different field strengths, temperatures and orientations. T₁ measurements obtained at 1.5 T and 3.0 T, as well as at room and body temperature, showed that r₁ is field-independent and temperature-independent. Conversely, the T₂ values at 3.0 T were shorter than at 1.5 T, while the T₂ values at body temperature were slightly higher than at room temperature. By examining the relaxivities with the C4 vials aligned in three different planes, we found no orientation-dependence. With these relaxation characteristics, we aim to develop pulse sequences that will enhance the C4 signal against prostatic stroma. Ultimately, the use of C4 as a positive contrast agent marker will encourage the use of MRI to obtain an accurate representation of the radiation dose delivered to the prostate and surrounding normal anatomical structures.

1. Introduction

Low dose rate prostate implant brachytherapy is a radiation therapy technique in which numerous small radioactive seeds of a given isotope are permanently implanted into the prostate. As the radioactive isotope decays, the seeds release radiation, damaging the integrity of the nearby cells (Vacha and Engenhart-Cabillic 2003). To estimate the extent of the radiation exposure in both the cancerous and normal cells, two main pieces of information are needed: the radioactive seeds’ precise locations and the boundaries of the normal structures adjacent to the prostate, such as the bladder and rectum. The current standard of care is to perform a computed tomography (CT) scan after implantation to identify the radioactive seeds and verify the radiation dose distribution (Christodouleas et al 2010).

Although the radioactive seeds, which are encapsulated in metal, can be easily visualized on a CT scan, the prostate anatomy cannot be clearly visualized on a CT scan, especially in the presence of the metallic artifacts introduced by the seeds. It is well established that magnetic resonance imaging (MRI) provides superior soft-tissue visualization of the prostate and normal critical structures. However, the metallic radioactive seeds and spacers appear as negative voids on MRI images (see Figure 1 for a comparison of MRI and CT images), thus confounding automatic seed-localization algorithms to reliably detect seed position and orientation.

Figure 1.

Comparison of computed tomography (CT; left) and magnetic resonance imaging (MRI; right) postimplant images. Brachytherapy seeds can be more definitively identified using CT, but appear as signal voids with MRI. However, the anatomical details of the male pelvis are clearly more visible with MRI.

Currently available implantable markers have negative contrast on MRI and can be difficult to differentiate from other structures, such as needle tracks (Bridges 2009). Permanent or temporary implantable positive MRI contrast agent markers technology for brachytherapy was recently patented (Frank and Martirosyan 2013) and offers a unique opportunity for cancer radiation treatment planning, treatment, and subsequent response evaluation in vivo. The experimental positive contrast marker (C4) has been shown in both in vitro and in vivo experiments to help localize permanently implantable objects using MRI (Frank et al 2008). The C4 MRI marker does not alter the treatment or radiation dose distribution and has been shown to be safe at the dose and volume consistent with a volumetric prostate implant (Frank et al 2011, Mehlus et al 2013).

MRI contrast agents affect relaxation times (the time that excited protons of water molecules take to return to their equilibrium state) because the ions in these contrast agents serve as microscopic but powerful magnets that relax nearby water protons. T₁ shortening agents act as positive contrast agents by shortening the spin-lattice relaxation time (T₁) of these water protons, leading to more rapid magnetization recovery and increased measured signal intensity. Conversely, T₂ shortening agents act as negative contrast agents by shortening the spin-spin relaxation time (T₂), leading to increased dephasing of the transverse signal and decreased measured signal intensity. The capacity of contrast agents to shorten the relaxation times of bulk water protons is defined as relaxivity (Lauffer 1996).

By incorporating the C4 MRI marker into the prostate brachytherapy workflow, MRI may be used to more accurately assess the dose to the tumor and normal tissue. This can decrease the time and costs required of patients and hospital staff. In clinics utilizing MRI/CT fusion, the use of C4 MRI markers alleviates the need for an extra CT scan to localize the seeds, thereby eliminating additional ionizing radiation to the patient, reducing uncertainties caused by imprecise registration from MRI/CT fusion and improving the efficiency of the workflow. In institutions currently only using CT for post-implant dosimetry, better prevention of recurrence and prediction of side effects can improve the overall quality of life for patients, thus offsetting the greater upfront financial cost and time to undergo an MRI exam instead of a CT exam.

Previously MRI characterization of the C4 solution has not been studied. The purpose of this study was to determine the relaxation characteristics of C4. Using common imaging sequences, we measured relaxation times, relaxation rates, and relaxivities at two standard clinical field strengths (1.5 T and 3.0 T), for three conventional scan planes (coronal, sagittal, and axial), and at two temperatures (room temperature and body temperature).

2. Methods

2.1. Data collection

In the current study, C4 was obtained by dissolving CoCl₂·6H₂O (cobalt dichloride hexahydrate) and NAC (N-acetyl-L-cysteine) in water. Keeping the concentration of NAC in the solution fixed at 2%, we varied the concentration of cobalt dichloride (0.1%, 0.2%, 0.5%, 1.0%, 1.5%, 2.0%, and 5.0%). All stated percentages are weight percentages. To match the standard unit for relaxivity (mM⁻¹ s⁻¹), the weight percentages were converted into millimolar (mM), presented in Table 1.

Table 1.

Conversion from weight percentages to millimolar (mM) for various concentrations of cobalt dichloride.

Weight percentage (%)	Concentration (mM)
0.0	0.00
0.1	4.229
0.2	8.458
0.5	21.145
1.0	42.290
1.5	63.435
2.0	84.580
5.0	211.450

The solutions were separated by cobalt dichloride concentration into 7 cylindrical glass vials. Two additional vials, one filled only with water and another filled only with 2% NAC, were used as controls. The 9 vials were placed in a thin transparent plastic cup and arranged as shown in Figure 2. The plastic cup was then affixed to the center of a cylindrical plastic container. Water was poured into the space between the plastic cup and the container to reduce susceptibility artifacts. The container with the 9 samples was then centered in a receive-only head array for reception with the body coil used for excitation.

Figure 2.

Nine glass vials with increasing concentrations of cobalt dichloride, arranged in a clockwise fashion. The center vial contained water only and the top vial contained 2% N-acetyl-L-cysteine (NAC) only; the remaining vials contained 2% NAC and 0.1%, 0.2%, 0.5%, 1.0%, 1.5%, 2.0%, or 5.0% cobalt dichloride.

We investigated the dependence of relaxation on three parameters: field strength, orientation, and temperature. For field strength dependence measurements, the samples were scanned using a 1.5 T and a 3.0 T clinical MRI scanner (Excite HDxt and Discovery MR750 respectively; GE Healthcare, Waukesha, WI). For orientation dependence measurements, the samples were positioned such that the base of the vials were parallel to the chosen scan plane—coronal, sagittal, or axial. For temperature dependence measurements, the samples were placed in a water bath at room temperature (20.3°C as denoted on the console) or body temperature (37 ± 1°C).

Analysis was performed offline using Matlab 7.9.0. (The MathWorks, Inc., Natick, MA). A square 7-pixel by 7-pixel region-of-interest (ROI) was defined in the center of each vial on the image, away from the vial edges to prevent signal inhomogeneity. The mean and standard deviation of the signal within the ROI were recorded at each time point.

2.2. Measuring spin-lattice relaxation time (T₁)

T₁ measurements were obtained using a single-slice inversion recovery spin echo sequence, which is precise and is the pulse sequence most commonly used for T₁ determination. At 1.5 T, we used the following parameters: TI = 50, 100, 200, 400, 800, 1600, 3200 ms; matrix size = 128 × 128; FOV = 16 cm; TR/TE = 5000 ms/10 ms; bandwidth = ±122.109 kHz; NEX = 0.5; and slice thickness = 10 mm. At 3.0 T, we used the following parameters: TI = 50, 100, 200, 400, 800, 1600, 3200 ms; matrix size = 256 × 256; FOV = 16 cm; TR/TE = 5000 ms/10 ms; bandwidth = ±62.5 kHz; NEX = 5.0; and slice thickness = 5 mm.

The signal for inversion recovery is typically expressed as

$$S=M_0(1-2e^{-TI/T_1}+e^{-TR/T_1})$$

where M₀ is the equilibrium magnetization, TI denotes inversion time, and TR denotes repetition time. For a given concentration, at each TI, the signal was represented by the mean signal in the ROI and the standard deviation was used to estimate uncertainty. Because TR and M₀ were fixed, we estimated T₁ using the Levenberg-Marquardt least-squares algorithm (Levenberg 1944; Marquardt 1963). For each ROI defined in each vial, we used the time point with the lowest signal as our initial estimate for T₁, which ideally should be close to the null point. However, T₁ was expected to be extremely close to 0 at higher concentrations (1.5%, 2.0%, and 5% for 1.5 T and 5% for 3.0 T), so to ensure stability for these points, we used 10 ms for some of the initial estimates for T₁.

2.3. Measuring spin-spin relaxation time (T₂)

T₂ measurements were obtained using a 2D spin-echo sequence. At 1.5 T, we used the following parameters: TR = 1000 ms; TE = 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 500, 600 ms; matrix size = 128 × 128; bandwidth = ±122.109 kHz; FOV = 16 cm; NEX = 0.5; and slice thickness = 10 mm. At 3.0 T, we used the following parameters: TR = 5000 ms; TE = 10, 20, 30, 40, 50, 60, 70, 80 ms; matrix size = 256 × 128; bandwidth = ±62.5 kHz; FOV = 6 cm; NEX = 1; and slice thickness = 10 mm.

Because we used small echo spacing, we fit the measured echo amplitudes to

$$S=M_0{e}^{-TE/T_2}$$

For each ROI, a first-degree polynomial fitting was performed on the spin echo signals plotted against time to obtain the initial estimate for T₂.

Starting with the initial T₁ and T₂ estimates, we applied nonlinear regression to the signal plotted against each inversion/echo time and iteratively applied the least-squares method to estimate T₁ and T₂. Relaxivity was defined as the change in relaxation rate of bulk water per unit concentration of cobalt dichloride. The relaxation rates were calculated and plotted against cobalt dichloride concentration. Thus, the slopes from the linear fit to this plot result in relaxivity values r₁ and r₂.

3. Results

3.1. Effect of field strength

T₁ and T₂ values measured at 1.5 T and 3.0 T, for cobalt dichloride concentrations ranging from 0 mM to 211.45 mM, are shown in Figure 3. Corresponding relaxation rates are shown in Figure 4. The T₁ values were similar at both field strengths, even across different cobalt dichloride concentrations. Hence, the C4 r₁ relaxivity values obtained at the two different field strengths were similar, suggesting that r₁ is not dependent on field strength.

Figure 3.

Spin-lattice relaxation time, T₁, and spin-spin relaxation time, T₂, at 1.5 T and 3.0 T, for various cobalt dichloride concentrations.

Figure 4.

Spin-lattice relaxation rate, 1/T₁, and spin-spin relaxation rate, 1/T₂, at 1.5 T and 3.0 T, for various cobalt dichloride concentrations. The relaxivity (mM⁻¹ s⁻¹) was determined by the slope from a linear fit of relaxation rate (s⁻¹) plotted against cobalt dichloride concentration (mM).

However, the T₂ values of C4 at 3.0 T were slightly lower than at 1.5 T, translating to consistently higher spin-spin relaxation rates. Therefore, the value of the slope, which corresponds directly to the r₂ of C4, was higher at 3.0 T than at 1.5 T, suggesting that r₂ is dependent on field strength and that T₂ is likely to decrease with increasing field strengths. Because r₁ is not dependent on field strength, the increase in r₂ with field strength increases the relaxivity ratio r₂/r₁.

3.2. Effect of orientation

The T₁ and T₂ values measured at coronal, sagittal, and axial orientations are shown in Figure 5, and Figure 6 shows the relaxation rates across different cobalt dichloride concentrations. No significant differences in relaxation measurements were observed across different orientations of the vial with respect to the main magnetic field.

Figure 5.

Spin-lattice relaxation time, T₁, and spin-spin relaxation time, T₂, at three different vial orientations, for various cobalt dichloride concentrations.

Figure 6.

Spin-lattice relaxation rate, 1/T₁, and spin-spin relaxation rate, 1/T₂, at three different vial orientations, for various cobalt dichloride concentrations. The relaxivity (mM⁻¹ s⁻¹) was determined by the slope from a linear fit of relaxation rate (s⁻¹) plotted against cobalt dichloride concentration (mM).

3.3. Effect of temperature

Figure 7 shows the T₁ and T₂ values measured at room temperature and body temperature, and Figure 8 shows the corresponding relaxation rates across different cobalt dichloride concentrations. The T₁ values were similar at both room temperature and body temperature for all cobalt dichloride concentrations investigated. Therefore, the corresponding relaxation rates were similar for the two temperatures as well, suggesting that r₁ is not dependent on temperature.

Figure 7.

Spin-lattice relaxation time, T₁, and spin-spin relaxation time, T₂, at room temperature and body temperature, for various cobalt dichloride concentrations.

Figure 8.

Spin-lattice relaxation rate, 1/T₁, and spin-spin relaxation rate, 1/T₂, at room temperature and body temperature, for various cobalt dichloride concentrations. The relaxivity (mM⁻¹ s⁻¹) was determined by the slope from a linear fit of relaxation rate (s⁻¹) plotted against cobalt dichloride concentration (mM).

Conversely, the T₂ of C4 at body temperature was slightly higher than at room temperature, translating to lower spin-spin relaxation rates. Therefore, the value of the slope, which corresponds directly to the r₂ of C4, was lower at body temperature than at room temperature. These temperature data sets suggest that r₂ is dependent on temperature and that T₂ is likely to increase with increasing temperature. Because r₁ is not dependent on temperature, the decrease in r₂ with temperature decreases the relaxivity ratio r₂/r₁.

In summary, relaxivity measurements at different field strengths, orientations and temperatures are presented in Table 2.

Table 2.

Relaxivities (r₁ and r₂) for different field strengths, orientations, and temperatures.

	r1 (mM−1 s−1)	r2 (mM−1 s−1)
Field strength
1.5 T	0.158 ± 0.003	0.208 ± 0.002
3 T	0.148 ± 0.002	0.328 ± 0.006
Orientation
Coronal	0.145 ± 0.001	0.300 ± 0.005
Sagittal	0.144 ± 0.002	0.315 ± 0.006
Axial	0.149 ± 0.001	0.324 ± 0.005
Temperature
20.3°C	0.144 ± 0.002	0.337 ± 0.005
37°C	0.127 ± 0.002	0.186 ± 0.001

4. Discussion

The spin-lattice and spin-spin relaxation times and corresponding relaxivities of C4 at different field strengths, orientations, and temperatures indicate that C4 can be used effectively as an encapsulated positive contrast agent marker to enable MRI-only post-implant dosimetric evaluation.

Contrast in MRI mainly occurs because of the differences in signal intensities of various tissues. Different tissues have unique T₁ and T₂ values that can be affected by the presence of positive contrast agents: the greater the concentration of cobalt dichloride ions, the smaller the T₁ and T₂ relaxation times. Consistent with our expectations from previous investigations (Frank et al 2008), the T₁-shortening effect of C4 was very dominant; therefore, a very high signal (positive enhancement) from C4 against the prostatic background was expected. Because of the innate fast transverse relaxation of prostate tissue, the T₂ shortening effect was not as strong as the T₁ shortening effect.

As field strength increases, the corresponding Larmor frequency increases; hence the energy transfer to the lattice is less efficient. Thus, increased T₁ values are expected at high field strengths, and we did observe this slight increase in T₁ at the lower concentrations of cobalt dichloride. However, the T₁ values at the two field strengths agreed well overall. In contrast, T₂ values at 3.0 T decreased at a greater rate with increasing concentration compared with that at 1.5 T. For cobalt dichloride concentrations <1% (42.49 mM), simply increasing the concentration to enhance the signal is not feasible because the shorter T₂ values at 3.0 T reduces the effect of T₁-shortening. For cobalt dichloride concentrations >1%, increasing the concentration further offers little gain because the T₁-shortening effect plateaus. Thus, the concentration of 1% cobalt dichloride offered a reasonable compromise of the T₁ and T₂ changes at the two clinically relevant field strengths to generate a strong signal. In addition, 1% cobalt dichloride in C4 is a low concentration that has been shown to be safe for clinical use (Frank et al 2013).

Although the spin-spin relaxivity (r₂) is higher at 3.0 T than at 1.5 T, the MRI signal intensity is still dependent on the pulse sequence chosen. The higher r₂ values at higher field strengths simply reaffirm the increased T₂-lowering ability, with the same considerations as stated before.

The main purpose of studying the effects of orientation on the relaxation characteristics of C4 is to detect any possible MR artifacts. When the C4 marker is placed between the seeds, the seeds and MR markers could potentially tilt in any direction. Brachytherapy seeds have been shown to have artifacts that are dependent on the seeds’ orientation with respect to the main magnetic field (Thomas et al 2009). In the present study, the relaxation times, relaxation rates, and relaxivities obtained for all three orientations were similar. These parameters are intrinsic to the cobalt dichloride complex. Therefore, when imaging the encapsulated C4 marker, the investigation of the origin of any detected artifacts would be best directed toward scrutinizing extrinsic parameters.

As temperature increases, the correlation time for the interaction decreases, requiring longer relaxation times and causing relaxation rates to lower, thereby resulting in a decrease in relaxivity (Reichenbach et al 1996). In the present study, for cobalt dichloride concentration of 1%, the change in T₁ was not significant, whereas T₂ was slightly higher at body temperature. Pulse sequence parameter adjustments should ideally be done at body temperature to better simulate clinical conditions, in which the C4 marker will always be at body temperature. Note that in the present study we evaluated the effects of only two different temperatures on relaxation: room temperature and the more clinically relevant body temperature. Any extrapolation of our findings to storage ambient temperature concerns or nonmedical use clearly warrants further investigation.

Using specific pulse sequences, such as T₁-weighted or T₂-weighted sequences, can enhance the differences in signal intensities of various tissues. With knowledge of the relaxation times of the desired contrast agent concentration, we can optimize pulse sequence parameters to provide greater contrast between the C4 marker and surrounding tissue. Previously reported T₁ and T₂ values for the prostate measured at 3.0 T were 1597 ± 42 ms and 74 ± 9 ms, respectively (de Bazelaire et al 2004). In the present study, the reported T₁ and T₂ values for 1% cobalt dichloride at 3.0 T were 138 ± 5 ms and 61 ± 0.2 ms, respectively. Thus, for example, for a conventional spin echo sequence, we can estimate a suitable time to apply the 90° pulse such that the separation between C4 and prostate recovery curves is greatest while the curves for prostate and other tissues remain reasonably separated.

In addition, we can optimize pulse sequences to provide adequately thin image slices, such that we may obtain the orientation of the marker. Orientation information from the marker can be coupled with the seed’s dumbbell artifact to estimate the seed’s orientation. Thus, treatment planning systems can incorporate seed anisotropy calculations to generate more accurate dose distributions.

At 1.5 T and 3.0 T, the measured relaxivities in water for Gadolinium-based contrast agents range from 3 to 5 mM⁻¹ s⁻¹ (Hao et al 2012). The relaxivities we measured for C4 ranged from 0.1 to 0.4 mM⁻¹ s⁻¹, implying a weaker efficiency in influencing tissue relaxation rates compared with Gadolinium-based contrast agents. Cobalt has three unpaired electrons, whereas gadolinium has seven unpaired electrons. Therefore, a higher concentration of cobalt is needed to achieve the same influence as gadolinium. Note, however, that the C4 solution remains in the polymer casing with no administered tissue uptake, because the main indication for the C4 MRI marker is an encapsulated contrast agent marker to enable more accurate localization of brachytherapy seeds. Nevertheless, Frank et al (2011) showed that the C4 MRI marker is associated with negligible toxicity, enabling the use of very high concentrations to reach sufficient T1-shortening effects and induce positive contrast.

A caveat of using C4 as an encapsulated marker to be placed next to the seeds is that, contrary to conventional CT images, the bright signals do not represent the seeds themselves. Future work will include quantifying the uncertainties associated with extrapolating seed positions from marker positions and developing a new seed-identification algorithm to perform the extrapolation.

Compared to the use of CT, a limitation of using MRI is that geometric distortion may introduce uncertainty in the reconstructed seed positions. Given the current quality assurance methods to test MRI geometric distortion, gradient distortion correction techniques as well as the small size of the prostate, the error of reconstructed seed positions due to geometric distortion can be managed. However, care must be taken when investigating dose distributions to critical structures far from the center on images with large field-of-view. On the other hand, post-implant CT offers prostate geometrical distortion of another kind – edema, swelling or the inherent indistinct borders can cause the misrepresentation of anatomy. Although current post-implant CT images provide absolute coordinates of the seeds, we are also concerned with the relative distance to critical structures and the distribution of seeds within the prostate volume, thus dose-volume-histograms are used extensively. The impact of geometric distortion on dose-volume-histogram parameters of prostate implants can be illuminated in future studies.

Apart from the indications for prostate brachytherapy, C4 can potentially be used as a contrast agent or as fiducial markers for a variety of other image guided radiation therapy purposes. Similar to Gadolinium-based contrast agents, the spin-lattice and spin-spin relaxivities for C4 are approximately the same, suggesting the same T₁- or T₂-shortening capability. Hence, the C4 MRI marker could potentially be used as both a positive and a negative contrast agent. Another potential indication for the C4 MRI marker is to serve as a fiducial marker for other types of body imaging. The use of both permanent and temporary implantable fiducial markers is standard in many disease sites. For example, fiducial markers are placed in the prostate for daily image-guided radiation treatment, in the cervix for localization and treatment planning, in the breast for tumour localization prior to lumpectomy, and in the lung for tumour tracking during radiation therapy. There may also be exciting implications for recurrence prediction and management using multiparametric MRI. Future studies can look into the potential for correlating the dose distribution within the prostate on MRI images with additional information obtained using multiparametric MRI (e.g. apparent diffusion coefficient), to guide the differentiation between radiation necrosis and recurrent disease.

5. Conclusion

We have reported the spin-lattice and spin-spin relaxation times as a function of concentration, as well as the corresponding relaxivities. We have also reported the dependence of these parameters on field strength, orientation, and temperature.

The main indication for C4 is as an encapsulated MRI contrast agent marker for post-implant dosimetric evaluation. Further testing of the accuracy of the C4 marker (and hence, seed) localization using images generated from standard clinical pulse sequences is warranted. Efficacy and feasibility comparisons can also be made against methods that do not require the use of the C4 MRI marker, such as pulse sequence manipulation like the off-resonance imaging approach proposed by Whitehead and Ji (2010) that directly exploits the susceptibility artifacts of the seeds, or image manipulation by modifying the Hounsfield Units conversion model (Kapanen and Tenhunen 2013) that generates pseudo-CT images.

Clinical trials for the C4 MRI marker will further illuminate any clinical challenges. Depending on the pulse sequence used and time lapsed since the brachytherapy procedure, the C4 MRI marker’s signal may be obscured or confused with other hyperintense sources, such as adipose tissue, cysts, hemorrhage or edema from infections (Bridges 2009).

The relaxation values obtained indicate that C4 is promising for use as an encapsulated contrast agent marker to better quantify the radiation dose to cancerous and various surrounding normal tissue, such that a more accurate picture of acute and late effects of brachytherapy can be depicted. With a more accurate description of dose distribution is combined with pre-implant multiparametric-MRI data (Barentsz et al 2012), we could assess tumour response to the brachytherapy treatment. The C4 MRI marker may thus allow for the full integration of MRI for post-implant dosimetry, reducing costs, time, and unnecessary dose of radiation to the patient from CT.