MRI-based biodistribution assessment of holmium-166 poly(L-lactic acid) microspheres after radioembolisation.

OBJECTIVES: To demonstrate the feasibility of MRI-based assessment of the intrahepatic Ho-PLLA-MS biodistribution after radioembolisation in order to estimate the absorbed radiation dose. METHODS: Fifteen patients were treated with holmium-166 ((166)Ho) poly(L-lactic acid)-loaded microspheres (Ho-PLLA-MS, mean 484 mg; range 408-593 mg) in a phase I study. Multi-echo gradient-echo MR images were acquired from which R (2) maps were constructed. The amount of Ho-PLLA-MS in the liver was determined by using the relaxivity r (2) of the Ho-PLLA-MS and compared with the administered amount. Quantitative single photon emission computed tomography (SPECT) was used for comparison with MRI regarding the whole liver absorbed radiation dose. RESULTS: R (2) maps visualised the deposition of Ho-PLLA-MS with great detail. The mean total amount of Ho-PLLA-MS detected in the liver based on MRI was 431 mg (range 236-666 mg) or 89 ± 19 % of the delivered amount (correlation coefficient r = 0.7; P < 0.01). A good correlation was found between the whole liver mean absorbed radiation dose as assessed by MRI and SPECT (correlation coefficient r = 0.927; P < 0.001). CONCLUSION: MRI-based dosimetry for holmium-166 radioembolisation is feasible. Biodistribution is visualised with great detail and quantitative measurements are possible.

Improving MRI-based dosimetry for holmium-166 transarterial radioembolization using a nonrigid image registration for voxelwise Δ R 2 ∗ $\Delta R_2

BACKGROUND: Transarterial radioembolization (TARE) is a treatment modality for liver tumors during which radioactive microspheres are injected into the hepatic arterial system. These microspheres distribute throughout the liver as a result of the blood flow until they are trapped in the arterioles because of their size. Holmium-166 (166 Ho)-loaded microspheres used for TARE can be visualized and quantified with MRI, as holmium is a paramagnetic metal and locally increases the transverse relaxation rate R 2 ∗ $R_2^*$ . The current 166 Ho quantification method does not take regional differences in baseline R 2 ∗ $R_2^*$ values (such as between tumors and healthy tissue) into account, which intrinsically results in a systematic error in the estimated absorbed dose distribution. As this estimated absorbed dose distribution can be used to predict response to treatment of tumors and potential toxicity in healthy tissue, a high accuracy of absorbed dose estimation is required. PURPOSE: To evaluate pre-existing differences in R 2 ∗ $R_2^*$ distributions between tumor tissue and healthy tissue and assess the feasibility and accuracy of voxelwise subtraction-based Δ R 2 ∗ $\Delta R_2^*$ calculation for MRI-based dosimetry of holmium-166 transarterial radioembolization (166 Ho TARE). METHODS: MRI data obtained in six patients who underwent 166 Ho TARE of the liver as part of a clinical study was retrospectively evaluated. Pretreatment differences in R 2 ∗ $R_2^*$ distributions between tumor tissue and healthy tissue were characterized. Same-day pre- and post-treatment R 2 ∗ $R_2^*$ maps were aligned using a deformable registration algorithm and subsequently subtracted to generate voxelwise Δ R 2 ∗ $\Delta R_2^*$ maps and resultant absorbed dose maps. Image registration accuracy was quantified using the dice similarity coefficient (DSC), relative overlay (RO), and surface dice (≤4 mm; SDSC). Voxelwise subtraction-based absorbed dose maps were quantitatively (root-mean-square error, RMSE) and visually compared to the current MRI-based mean subtraction method and routinely used SPECT-based dosimetry. RESULTS: Pretreatment R 2 ∗ $R_2^*$ values were lower in tumors than in healthy liver tissue (mean 36.8 s-1 vs. 55.7 s-1 , P = 0.004). Image registration improved the mean DSC of 0.83 (range: 0.70-0.88) to 0.95 (range: 0.92-0.97), mean RO of 0.71 (range 0.53-0.78) to 0.90 (range: 0.86-0.94), and mean SDSC ≤4 mm of 0.47 (range: 0.28-0.67) to 0.97 (range: 0.96-0.98). Voxelwise subtraction-based absorbed dose maps yielded a higher tumor-absorbed dose (median increase of 9.0%) and lower healthy liver-absorbed dose (median decrease of 13.8%) compared to the mean subtraction method. Voxelwise subtraction-based absorbed dose maps corresponded better to SPECT-based absorbed dose maps, reflected by a lower RMSE in three of six patients. CONCLUSIONS: Voxelwise subtraction presents a robust alternative method for MRI-based dosimetry of 166 Ho microspheres that accounts for pre-existing R 2 ∗ $R_2^*$ differences, and appears to correspond better with SPECT-based dosimetry compared to the currently implemented mean subtraction method.

Quantification of holmium-166 loaded microspheres: estimating high local concentrations using a conventional multiple gradient echo sequence with S0-fitting.

PURPOSE: To provide a best estimate of the R 2* value and hence of the local concentration of highly paramagnetic holmium-166 loaded microspheres (HoMS) in voxels for which R 2* cannot be characterized by conventional fitting of multigradient echo (MGE) data because of fast signal decay due to high local concentrations. MATERIALS AND METHODS: A postprocessing method, S(0)-fitting, was implemented in a conventional R 2* fitting method that is used for quantification of HoMS. S(0)-fitting incorporates the estimated initial amplitude of the free induction decay (FID) curve, S(0), of neighboring voxels into the fitting procedure for voxels for which the conventional algorithm failed. The method was applied to HoMS in vitro and ex vivo in a rabbit liver. The performance of the S(0)-fitting method was evaluated by comparing results qualitatively and quantitatively with results obtained with quantitative ultrashort TE imaging (qUTE). RESULTS: Applying S(0)-fitting provided a best estimate for R 2* up to a value of about 2300 s(-1) compared with a maximum value of about 1000 s(-1) that could be characterized using conventional fitting. A good agreement was observed both qualitatively and quantitatively for in vitro experiments as well as for ex vivo rabbit liver experiments between results obtained with S(0)-fitting and results obtained with qUTE imaging. CONCLUSION: S(0)-fitting is a postprocessing method that can provide a best estimate of high R 2* values that cannot be characterized by conventional relaxometry. The method can be applied to conventional MGE datasets and was shown to be beneficial for quantification of high local concentrations of holmium-loaded microspheres.

Alginate-lanthanide microspheres for MRI-guided embolotherapy.

In cancer therapy, a promising treatment option to accomplish a high tumor-to-normal-tissue ratio is endovascular intervention with microsized particles, such as embolotherapy. In this study, alginate microspheres (ams) were prepared with the JetCutter technique, which is based on cutting a sodium alginate solution jet stream into small droplets of uniform size which are then cross-linked with different lanthanides or iron-III, resulting in microspheres of a predefined size which can be visualized by magnetic resonance imaging (MRI). The microspheres were investigated for their size and morphology (light microscopy and scanning electron microscopy analysis), cation content and MRI properties. The lanthanide-ams formulations, with a uniform size of 250 µm and a cation content between 0.72-0.94%, showed promising results for MR imaging. This was further demonstrated for Ho(3+)-cross-linked alginate microspheres (Ho(3+)-ams), the most potent microsphere formulation with respect to MR visualization, allowing single sphere detection and detailed microsphere distribution examination. Intravascular infusion of Ho(3+)-ams by catherization of ex vivo rabbit and porcine liver tissue and assessment of the procedure with MRI clearly showed accumulation and subsequently embolization of the targeted vessels, allowing accurate monitoring of the microsphere biodistribution throughout the tissue. Therefore, the different alginate-lanthanide microsphere formulations developed in this study show great potential for utilization as image-guided embolotherapy agents.

On the utility of spectroscopic imaging as a tool for generating geometrically accurate MR images and parameter maps in the presence of field inhomogeneities and chemical shift effects.

Lack of spatial accuracy is a recognized problem in magnetic resonance imaging (MRI) which severely detracts from its value as a stand-alone modality for applications that put high demands on geometric fidelity, such as radiotherapy treatment planning and stereotactic neurosurgery. In this paper, we illustrate the potential and discuss the limitations of spectroscopic imaging as a tool for generating purely phase-encoded MR images and parameter maps that preserve the geometry of an object and allow localization of object features in world coordinates. Experiments were done on a clinical system with standard facilities for imaging and spectroscopy. Images were acquired with a regular spin echo sequence and a corresponding spectroscopic imaging sequence. In the latter, successive samples of the acquired echo were used for the reconstruction of a series of evenly spaced images in the time and frequency domain. Experiments were done with a spatial linearity phantom and a series of test objects representing a wide range of susceptibility- and chemical-shift-induced off-resonance conditions. In contrast to regular spin echo imaging, spectroscopic imaging was shown to be immune to off-resonance effects, such as those caused by field inhomogeneity, susceptibility, chemical shift, f(0) offset and field drift, and to yield geometrically accurate images and parameter maps that allowed object structures to be localized in world coordinates. From these illustrative examples and a discussion of the limitations of purely phase-encoded imaging techniques, it is concluded that spectroscopic imaging offers a fundamental solution to the geometric deficiencies of MRI which may evolve toward a practical solution when full advantage will be taken of current developments with regard to scan time reduction. This perspective is backed up by a demonstration of the significant scan time reduction that may be achieved by the use of compressed sensing for a simple phantom.

In vivo dosimetry based on SPECT and MR imaging of 166Ho-microspheres for treatment of liver malignancies.

UNLABELLED: (166)Ho-poly(l-lactic acid) microspheres allow for quantitative imaging with MR imaging or SPECT for microsphere biodistribution assessment after radioembolization. The purpose of this study was to evaluate SPECT- and MR imaging-based dosimetry in the first patients treated with (166)Ho radioembolization. METHODS: Fifteen patients with unresectable, chemorefractory liver metastases of any origin were enrolled in this phase 1 study and were treated with (166)Ho radioembolization according to a dose escalation protocol (20-80 Gy). The contours of all liver segments and all discernible tumors were manually delineated on T2-weighted posttreatment MR images and registered to the posttreatment SPECT images (n = 9) or SPECT/CT images (n = 6) and MR imaging-based R2* maps (n = 14). Dosimetry was based on SPECT (n = 15) and MR imaging (n = 9) for all volumes of interest, tumor-to-nontumor (T/N) activity concentration ratios were calculated, and correlation and agreement of MR imaging- and SPECT-based measurements were evaluated. RESULTS: The median overall T/N ratio was 1.4 based on SPECT (range, 0.9-2.8) and 1.4 based on MR imaging (range, 1.1-3.1). In 6 of 15 patients (40%), all tumors had received an activity concentration equal to or higher than the normal liver (T/N ratio ≥ 1). Analysis of SPECT and MR imaging measurements for dose to liver segments yielded a high correlation (R(2) = 0.91) and a moderate agreement (mean bias, 3.7 Gy; 95% limits of agreement, -11.2 to 18.7). CONCLUSION: With the use of (166)Ho-microspheres, in vivo dosimetry is feasible on the basis of both SPECT and MR imaging, which enables personalized treatment by selective targeting of inadequately treated tumors.

Magnetic resonance imaging-based radiation-absorbed dose estimation of 166Ho microspheres in liver radioembolization.

PURPOSE: To investigate the potential of magnetic resonance imaging (MRI) for accurate assessment of the three-dimensional (166)Ho activity distribution to estimate radiation-absorbed dose distributions in (166)Ho-loaded poly (L-lactic acid) microsphere ((166)Ho-PLLA-MS) liver radioembolization. METHODS AND MATERIALS: MRI, computed tomography (CT), and single photon emission CT (SPECT) experiments were conducted on an anthropomorphic gel phantom with tumor-simulating gel samples and on an excised human tumor-bearing liver, both containing known amounts of (166)Ho-PLLA-MS. Three-dimensional radiation-absorbed dose distributions were estimated at the voxel level by convolving the (166)Ho activity distribution, derived from quantitative MRI data, with a (166)Ho dose point-kernel generated by MCNP (Monte Carlo N-Particle transport code) and from Medical Internal Radiation Dose Pamphlet 17. MRI-based radiation-absorbed dose distributions were qualitatively compared with CT and autoradiography images and quantitatively compared with SPECT-based dose distributions. Both MRI- and SPECT-based activity estimations were validated against dose calibrator measurements. RESULTS: Evaluation on an anthropomorphic phantom showed that MRI enables accurate assessment of local (166)Ho-PLLA-MS mass and activity distributions, as supported by a regression coefficient of 1.05 and a correlation coefficient of 0.99, relating local MRI-based mass and activity calculations to reference values obtained with a dose calibrator. Estimated MRI-based radiation-absorbed dose distributions of (166)Ho-PLLA-MS in an ex vivo human liver visually showed high correspondence to SPECT-based radiation-absorbed dose distributions. Quantitative analysis revealed that the differences in local and total amounts of (166)Ho-PLLA-MS estimated by MRI, SPECT, and the dose calibrator were within 10%. Excellent agreement was observed between MRI- and SPECT-based dose-volume histograms. CONCLUSIONS: Quantitative MRI was demonstrated to provide accurate three-dimensional (166)Ho-PLLA-MS activity distributions, enabling localized intrahepatic radiation-absorbed dose estimation by convolution with a (166)Ho dose point-kernel for liver radioembolization treatment optimization and evaluation.