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Ross W Stephens,1 Gregory D Tredwell,1 Karen J Knox,1 Lee A Philip,1 David W King,1 Kelly M Debono,2 Jessica L Bell,1 Tim J Senden,1 Marcel R Tanudji,3 Jillean G Winter,3 Stephanie A Bickley,3 Michael J Tapner,3 Stephen K Jones3 1The Biomedical Radiochemistry Laboratory, Department of Applied Mathematics, Research School of Physics and Engineering, Australian National University, Canberra, ACT, Australia; 2Animal Services Division, Research School of Biology, Australian National University, Canberra, ACT, Australia; 3Research and Development, Sirtex Medical Limited, Sydney, NSW, Australia Purpose: Selective internal radiation therapy (SIRT) is an effective treatment option for liver tumors, using Y-90-loaded polymer microspheres that are delivered via catheterization of the hepatic artery. Since Y-90 is a beta emitter and not conveniently imaged by standard clinical instrumentation, dosimetry is currently evaluated in each patient using a surrogate particle, 99mTechnetium-labeled macroaggregated albumin (99mTc-MAA). We report a new composite consisting of 99mTc-labeled nanoparticles attached to the same polymer microspheres as used for SIRT, which can be imaged with standard SPECT.Methods: Carbon nanoparticles with an encapsulated core of 99mTc were coated with the polycation protamine sulfate to provide electrostatic attachment to anionic polystyrene sulfonate microspheres of different sizes (30, 12, and 8 µm). The in vivo stability of these composites was determined via intravenous injection and entrapment in the capillary network of normal rabbit lungs for up to 3 hours. Furthermore, we evaluated their biodistribution in normal rabbit livers, and livers implanted with VX2 tumors, following intrahepatic artery instillation. Results: We report distribution tests for three different sizes of radiolabeled microspheres and compare the results with those obtained using 99mTc-MAA. Lung retention of the radiolabeled microspheres ranged from 72.8% to 92.9%, with the smaller diameter microspheres showing the lowest retention. Liver retention of the microspheres was higher, with retention in normal livers ranging from 99.2% to 99.8%, and in livers with VX2 tumors from 98.2% to 99.2%. The radiolabeled microspheres clearly demonstrated preferential uptake at tumor sites due to the increased arterial perfusion produced by angiogenesis.Conclusion: We describe a novel use of radiolabeled carbon nanoparticles to generate an imageable microsphere that is stable in vivo under the shear stress conditions of arterial networks. Following intra-arterial instillation in the normal rabbit liver, they distribute in a distinct segmented pattern, with the smaller microspheres extending throughout the organ in finer detail, while still being well retained within the liver. Furthermore, in livers hosting an implanted VX2 tumor, they reveal the increased arterial perfusion of tumor tissue resulting from angiogenesis. These novel composites may have potential as a more representative mimic of the vascular distribution of therapeutic microspheres in patients undergoing SIRT. Keywords: liver cancer, SIRT, radiolabeled microspheres, medical imaging

Background: Yttrium-90 ( 90 Y) radioembolization involves the intra-arterial delivery of radioactive microspheres to treat hepatic malignancies. Though this therapy involves careful pre-treatment planning and imaging, little is known about the precise location of the microspheres once they are administered. Recently, there has been growing interest post-radioembolization imaging using positron-emission tomography (PET) for quantitative dosimetry and identifying lesions that may benefit from additional salvage therapy. In this study, we aim to measure the inter-center variability of 90 Y PET measurements as measured on PET/MRI in preparation for a multi-institutional prospective phase I/II clinical trial. Eight institutions participated in this study and followed a standardized phantom filling and imaging protocol. The NEMA NU2-2012 body phantom was filled with 3 GBq of 90 Y chloride solution. The phantom was imaged for 30 min in listmode on a Siemens Biograph mMR non-TOF PET/MRI scanner at five time points across 10 days (0.3-3.0 GBq). Raw PET data were sent to a central site for image reconstruction and data analysis. Images were reconstructed with optimal parameters determined from a previous study. Volumes of interest (VOIs) matching the known sphere diameters were drawn on the vendor-provided attenuation map and propagated to the PET images. Recovery coefficients (RCs) and coefficient of variation of the RCs (COV) were calculated from these VOIs for each sphere size and activity level., Results: Mean RCs ranged from 14.5 to 75.4%, with the lowest mean RC coming from the smallest sphere (10 mm) on the last day of imaging (0.16 MBq/ml) and the highest mean RC coming from the largest sphere (37 mm) on the first day of imaging (2.16 MBq/ml). The smaller spheres tended to exhibit higher COVs. In contrast, the larger spheres tended to exhibit lower COVs. COVs from the 37 mm sphere were < 25.3% in all scans. For scans with ≥ 0.60 MBq/ml, COVs were ≤ 25% in spheres ≥ 22 mm. However, for all other spheres sizes and activity levels, COVs were usually > 25%., Conclusions: Post-radioembolization dosimetry of lesions or other VOIs ≥ 22 mm in diameter can be consistently obtained (< 25% variability) at a multi-institutional level using PET/MRI for any clinically significant activity for 90 Y radioembolization.

Background: The aim of this study was to investigate the relationship between absorbed dose and response of colorectal cancer liver metastases treated with [ 90 Y]-resin microspheres and to explore possible clinical and imaging derived prognostic factors., Methods: FDG PET/CT was used to measure response of individual lesions to a measured absorbed dose, derived from post-treatment 90 Y PET imaging. Predicted dose was also derived from planning [ 99m Tc]-MAA SPECT data. Peak standardised uptake value and total lesion glycolysis (TLG) were explored as response measures, and compared to dose metrics including average dose (D avg ), biologically effective dose, minimum dose to 70% of lesion volume and volume receiving at least 50 Gy. Prognostic factors examined included baseline TLG, RAS mutation status, FDG heterogeneity and dose heterogeneity. In an exploratory analysis, response and clinico-pathological variables were evaluated and compared to overall survival., Results: Sixty-three lesions were analysed from 22 patients. Poor agreement was seen between predicted and measured dose values. TLG was a superior measure of response, and all dose metrics were significant prognostic factors, with a D avg of ~50 Gy derived as the critical threshold for a significant response (>50% reduction in TLG). No significant correlation was found between baseline TLG or RAS mutation status and response. Measured dose heterogeneity was a significant prognostic factor and when combined with D avg had a positive predictive value for response >80%. In the exploratory analysis for prognostic factors of survival, low hepatic tumour burden and mean reduction in TLG >65% were independently associated with improved overall survival., Conclusions: Lesions receiving an average dose greater than 50 Gy are likely to have a significant response. For lesions receiving less than 50 Gy, dose heterogeneity is a significant prognostic factor. Lesions receiving an average dose less than 20 Gy are unlikely to respond. A reduction in TLG may be associated with improved overall survival.

Background: PET/CT has recently been shown to be a viable alternative to traditional post-infusion imaging methods providing good quality images of 90 Y-laden microspheres after selective internal radiation therapy (SIRT). In the present paper, first we assessed the quantitative accuracy of 90 Y-PET using an anthropomorphic phantom provided with lungs, liver, spine, and a cylindrical homemade lesion located into the hepatic compartment. Then, we explored the accuracy of different computational approaches on dose calculation, including (I) direct Monte Carlo radiation transport using Raydose, (II) Kernel convolution using Philips Stratos, (III) local deposition algorithm, (IV) Monte Carlo technique (MCNP) considering a uniform activity distribution, and (V) MIRD (Medical Internal Radiation Dose) analytical approach. Finally, calculated absorbed doses were compared with those obtained performing measurements with LiF:Mg,Cu,P TLD chips in a liquid environment., Results: Our results indicate that despite 90 Y-PET being likely to provide high-resolution images, the 90 Y low branch ratio, along with other image-degrading factors, may produce non-uniform activity maps, even in the presence of uniform activity. A systematic underestimation of the recovered activity, both for the tumor insert and for the liver background, was found. This is particularly true if no partial volume correction is applied through recovery coefficients. All dose algorithms performed well, the worst case scenario providing an agreement between absorbed dose evaluations within 20%. Average absorbed doses determined with the local deposition method are in excellent agreement with those obtained using the MIRD and the kernel-convolution dose calculation approach. Finally, absorbed dose assessed with MC codes are in good agreement with those obtained using TLD in liquid solution, thus confirming the soundness of both calculation approaches. This is especially true for Raydose, which provided an absorbed dose value within 3% of the measured dose, well within the stated uncertainties., Conclusions: Patient-specific dosimetry is possible even in a scenario with low true coincidences and high random fraction, as in 90 Y-PET imaging, granted that accurate absolute PET calibration is performed and acquisition times are sufficiently long. Despite Monte Carlo calculations seeming to outperform all dose estimation algorithms, our data provide a strong argument for encouraging the use of the local deposition algorithm for routine 90 Y dosimetry based on PET/CT imaging, due to its simplicity of implementation.

Background: The use of selective internal radiation therapy (SIRT) is rapidly increasing, and the need for quantification and dosimetry is becoming more widespread to facilitate treatment planning and verification. The aim of this project was to develop an anthropomorphic phantom that can be used as a validation tool for post-SIRT imaging and its application to dosimetry., Method: The phantom design was based on anatomical data obtained from a T1-weighted volume-interpolated breath-hold examination (VIBE) on a Siemens Aera 1.5 T MRI scanner. The liver, lungs and abdominal trunk were segmented using the Hermes image processing workstation. Organ volumes were then uploaded to the Delft Visualization and Image processing Development Environment for smoothing and surface rendering. Triangular meshes defining the iso-surfaces were saved as stereo lithography (STL) files and imported into the Autodesk® Meshmixer software. Organ volumes were subtracted from the abdomen and a removable base designed to allow access to the liver cavity. Connection points for placing lesion inserts and filling holes were also included. The phantom was manufactured using a Stratasys Connex3 PolyJet 3D printer. The printer uses stereolithography technology combined with ink jet printing. Print material is a solid acrylic plastic, with similar properties to polymethylmethacrylate (PMMA)., Results: Measured Hounsfield units and calculated attenuation coefficients of the material were shown to also be similar to PMMA. Total print time for the phantom was approximately 5 days. Initial scans of the phantom have been performed with Y-90 bremsstrahlung SPECT/CT, Y-90 PET/CT and Tc-99m SPECT/CT. The CT component of these images compared well with the original anatomical reference, and measurements of volume agreed to within 9 %. Quantitative analysis of the phantom was performed using all three imaging techniques. Lesion and normal liver absorbed doses were calculated from the quantitative images in three dimensions using the local deposition method., Conclusions: 3D printing is a flexible and cost-efficient technology for manufacture of anthropomorphic phantom. Application of such phantoms will enable quantitative imaging and dosimetry methodologies to be evaluated, which with optimisation could help improve outcome for patients.