Multimodality treatment in hormone-refractory prostate cancer patients with bone metastases

We agree with the interesting points made by Koutsikos et al. They confirm the feasibility of the combined use of bone-seeking radiopharmaceuticals and bisphosphonates and highlight the potential benefit of this combined treatment. We would like to stress the importance to study multimodality treatment strategies in well-designed clinical trials. These trials should evaluate the multidimensional character of pain, as well as survival, and they should incorporate imaging modalities for response stratification ..

Dosing Therapeutic Radiopharmaceuticals in Obese Patients

The prevalence of obesity has increased dramatically in the Western population. Obesity is known to influence not only the proportion of adipose tissue but also physiological processes that could alter drug pharmacokinetics. Yet, there are no specific dosing recommendations for radiopharmaceuticals in this patient population. This could potentially lead to underdosing and thus suboptimal treatment in obese patients, while it could also lead to drug toxicity due to high levels of radioactivity. In this review, relevant literature is summarized on radiopharmaceutical dosing and pharmacokinetic properties, and we aimed to translate these data into practical guidelines for dosing of radiopharmaceuticals in obese patients. For radium-223, dosing in obese patients is well established. Furthermore, for samarium-153-ethylenediaminetetramethylene (EDTMP), dose-escalation studies show that the maximum tolerated dose will probably not be reached in obese patients when dosing on MBq/kg. On the other hand, there is insufficient evidence to support dose recommendations in obese patients for rhenium-168-hydroxyethylidene diphosphonate (HEDP), sodium iodide-131, iodide 131-metaiodobenzylguanidine (MIBG), lutetium-177-dotatate, and lutetium-177-prostate-specific membrane antigen (PSMA). From a pharmacokinetic perspective, fixed dosing may be appropriate for these drugs. More research into obese patient populations is needed, especially in the light of increasing prevalence of obesity worldwide

Transarterial RAdioembolization versus ChemoEmbolization for the treatment of hepatocellular carcinoma (TRACE) : study protocol for a randomized controlled trial

Background: Hepatocellular carcinoma is a primary malignant tumor of the liver that accounts for an important health problem worldwide. Only 10 to 15% of hepatocellular carcinoma patients are suitable candidates for treatment with curative intent, such as hepatic resection and liver transplantation. A majority of patients have locally advanced, liver restricted disease (Barcelona Clinic Liver Cancer (BCLC) staging system intermediate stage). Transarterial loco regional treatment modalities offer palliative treatment options for these patients; transarterial chemoembolization (TACE) is the current standard treatment. During TACE, a catheter is advanced into the branches of the hepatic artery supplying the tumor, and a combination of embolic material and chemotherapeutics is delivered through the catheter directly into the tumor. Yttrium-90 radioembolization (Y-90-RE) involves the transarterial administration of minimally embolic microspheres loaded with Yttrium-90, a beta-emitting isotope, delivering selective internal radiation to the tumor. Y-90-RE is increasingly used in clinical practice for treatment of intermediate stage hepatocellular carcinoma, but its efficacy has never been prospectively compared to that of the standard treatment (TACE). In this study, we describe the protocol of a multicenter randomized controlled trial aimed at comparing the effectiveness of TACE and Y-90-RE for treatment of patients with unresectable (BCLC intermediate stage) hepatocellular carcinoma. Methods/design: In this pragmatic randomized controlled trial, 140 patients with unresectable (BCLC intermediate stage) hepatocellular carcinoma, with Eastern Cooperative Oncology Group performance status 0 to 1 and Child-Pugh A to B will be randomly assigned to either Y-90-RE or TACE with drug eluting beads. Patients assigned to Y-90-RE will first receive a diagnostic angiography, followed by the actual transarterial treatment, which can be divided into two sessions in case of bilobar disease. Patients assigned to TACE will receive a maximum of three consecutive transarterial treatment sessions. Patients will undergo structural follow-up for a timeframe of two years post treatment. Post procedural magnetic resonance imaging (MRI) will be performed at one and three months post trial entry and at three-monthly intervals thereafter for two years to assess tumor response. Primary outcome will be time to progression. Secondary outcomes will be overall survival, tumor response according to the modified RECIST criteria, toxicities/adverse events, treatment related effect on total liver function, quality of life, treatment-related costs and cost-effectiveness

166Holmium–99mTechnetium dual‑isotope imaging: scatter compensation and automatic healthy‑liver segmentation for 166Holmium radioembolization dosimetry

Background Partition modeling allows personalized activity calculation for holmium-166 (166Ho) radioembolization. However, it requires the definition of tumor and non-tumorous liver, by segmentation and registration of a separately acquired CT, which is time-consuming and prone to error. A protocol including 166Ho-scout, for treatment simulation, and technetium-99m (99mTc) stannous phytate for healthy-liver delineation was proposed. This study assessed the accuracy of automatic healthy-liver segmentation using 99mTc images derived from a phantom experiment. In addition, together with data from a patient study, the effect of different 99mTc activities on the 166Ho-scout images was investigated. To reproduce a typical scout procedure, the liver compartment, including two tumors, of an anthropomorphic phantom was filled with 250 MBq of 166Ho-chloride, with a tumor to non-tumorous liver activity concentration ratio of 10. Eight SPECT/CT scans were acquired, with varying levels of 99mTc added to the non-tumorous liver compartment (ranging from 25 to 126 MBq). For comparison, forty-two scans were performed in presence of only 99mTc from 8 to 240 MBq. 99mTc image quality was assessed by cold-sphere (tumor) contrast recovery coefficients. Automatic healthy-liver segmentation, obtained by thresholding 99mTc images, was evaluated by recovered volume and Sørensen–Dice index. The impact of 99mTc on 166Ho images and the role of the downscatter correction were evaluated on phantom scans and twenty-six patients’ scans by considering the reconstructed 166Ho count density in the healthy-liver. Results All 99mTc image reconstructions were found to be independent of the 166Ho activity present during the acquisition. In addition, cold-sphere contrast recovery coefficients were independent of 99mTc activity. The segmented healthy-liver volume was recovered fully, independent of 99mTc activity as well. The reconstructed 166Ho count density was not influenced by 99mTc activity, as long as an adequate downscatter correction was applied. Conclusion The 99mTc image reconstructions of the phantom scans all performed equally well for the purpose of automatic healthy-liver segmentation, for activities down to 8 MBq. Furthermore, 99mTc could be injected up to at least 126 MBq without compromising 166Ho image quality. Clinical trials The clinical study mentioned is registered with Clinicaltrials.gov (NCT02067988) on February 20, 2014

Holmium-166 Radioembolization: Current Status and Future Prospective

Since its first suggestion as possible option for liver radioembolization treatment, the therapeutic isotope holmium-166 (166Ho) caught the experts’ attention due to its imaging possibilities. Being not only a beta, but also a gamma emitter and a lanthanide, 166Ho can be imaged using single-photon emission computed tomography and magnetic resonance imaging, respectively. Another advantage of 166Ho is the possibility to perform the scout and treatment procedure with the same particle. This prospect paves the way to an individualized treatment procedure, gaining more control over dosimetry-based patient selection and treatment planning. In this review, an overview on 166Ho liver radioembolization will be presented. The current clinical workflow, together with the most relevant clinical findings and the future prospective will be provided

Radioembolization-Induced Changes in Hepatic [18F]FDG Metabolism in Non-Tumorous Liver Parenchyma.

Background: [18F]FDG-PET/CT is increasingly used for response assessments after oncologic treatment. The known response criteria for [18F]FDG-PET/CT use healthy liver parenchyma as the reference standard. However, the [18F]FDG liver metabolism results may change as a result of the given therapy. The aim of this study was to assess changes in [18F]FDG liver metabolism after hepatic 90Y resin radioembolization. Methods: [18F]FDG-PET/CT scans prior to radioembolization and one and three months after radioembolization (consistent with the PERCIST comparability criteria), as well as 90Y-PET/CT scans, were analyzed using 3 cm VOIs. The FDG activity concentration and absorbed dose were measured. A linear mixed-effects logistic regression model and logistic mixed-effects model were used to assess the correlation between the FDG-activity concentration, absorbed dose, and biochemical changes. Results: The median SULVOI,liver at baseline was 1.8 (range = 1.2−2.8). The mean change in SULVOI,liver per month with an increase in time was 0.05 (95%CI 0.02−0.09) at p < 0.001. The median absorbed dose per VOI was 31.3 Gy (range = 0.1−82.3 Gy). The mean percent change in ΔSULVOI,liver for every Gy increase in the absorbed dose was −0.04 (95%CI −0.22−0.14) at p = 0.67. The SULblood and SULspleen results showed no increase. Conclusions: The [18F]FDG metabolism in the normal liver parenchyma is significantly but mildly increased after radioembolization, which can interfere with its use as a threshold for therapy response

An International Phantom Study of Inter-Site Variability in Technetium-99m Image Quantification: Analyses From the Target Radioembolization Study

BACKGROUND: Personalised multi-compartment dosimetry based on [ RESULTS: Regarding the LSF, inter-site variation with planar site-specific protocols was minimal, as determined by comparing computed LSF between sites (interquartile range 9.6-10.1%). A standardised protocol did not improve variation (interquartile range 8.4-9.0%) but did improve mean accuracy compared to the site-specific protocols (5.0% error for standardised protocol vs 8.8% error for site-specific protocols). Regarding the CRC, inter-system variation was notable for site-specific SPECT protocols and could not be improved by the standardised protocol (CRC interquartile range for 37 mm sphere 0.5-0.7 and 0.6-0.8 respectively), however the standardised protocol did improve accuracy of sphere:background determination. Implementation of key image corrections did improve inter-site variation (CRC interquartile range for 37 mm sphere 0.6-0.7). CONCLUSION: Eliminating sources of variability in image corrections between imaging protocols reduces inter-site variation in quantification. A standardised protocol was not able to improve consistency of LSF or CRC but was able to improve accuracy

Quantitative 166Ho-microspheres SPECT derived from a dual-isotope acquisition with 99mTc-colloid is clinically feasible

Purpose: Accurate dosimetry is essential in radioembolization. To this purpose, an automatic protocol for healthy liver dosimetry based on dual isotope (DI) SPECT imaging, combining holmium-166 ( 166Ho)-microspheres, and technetium-99 m ( 99mTc)-colloid was developed: 166Ho-microspheres used as scout and therapeutic particles, and 99mTc-colloid to identify the healthy liver. DI SPECT allows for an automatic and accurate estimation of absorbed doses, introducing true personalized dosimetry. However, photon crosstalk between isotopes can compromise image quality. This study investigates the effect of 99mTc downscatter on 166Ho dosimetry, by comparing 166Ho-SPECT reconstructions of patient scans acquired before ( 166Ho-only) and after additional administration of 99mTc-colloid ( 166Ho-DI). Methods: The 166Ho-only and 166Ho-DI scans were performed in short succession by injecting 99mTc-colloid on the scanner table. To compensate for 99mTc downscatter, its influence was accounted for in the DI image reconstruction using energy window-based scatter correction methods. The qualitative assessment was performed by independent blinded comparison by two nuclear medicine physicians assessing 65 pairs of SPECT/CT. Inter-observer agreement was tested by Cohen’s kappa coefficient. For the quantitative analysis, two volumes of interest within the liver, VOI TUMOR, and VOI HEALTHY were manually delineated on the 166Ho-only reconstruction and transferred to the co-registered 166Ho-DI reconstruction. Absorbed dose within the resulting VOIs, and in the lungs (VOI LUNGS), was calculated based on the administered therapeutic activity. Results: The qualitative assessment showed no distinct clinical preference for either 166Ho-only or 166Ho-DI SPECT (kappa = 0.093). Quantitative analysis indicated that the mean absorbed dose difference between 166Ho-DI and 166Ho-only was − 2.00 ± 2.84 Gy (median 27 Gy; p value < 0.00001), − 5.27 ± 8.99 Gy (median 116 Gy; p value = 0.00035), and 0.80 ± 1.08 Gy (median 3 Gy; p value < 0.00001) for VOI HEALTHY, VOI TUMOR, and VOI LUNGS, respectively. The corresponding Pearson’s correlation coefficient between 166Ho-only and 166Ho-DI for absorbed dose was 0.97, 0.99, and 0.82, respectively. Conclusion: The DI protocol enables automatic dosimetry with undiminished image quality and accuracy. Clinical trials: The clinical study mentioned is registered with Clinicaltrials.gov (NCT02067988) on 20 February 2014

Gamma camera characterization at high holmium-166 activity in liver radioembolization

Background High activities of holmium-166 (166Ho)–labeled microspheres are used for therapeutic radioembolization, ideally directly followed by SPECT imaging for dosimetry purposes. The resulting high-count rate potentially impacts dead time, affecting the image quality and dosimetric accuracy. This study assesses gamma camera performance and SPECT image quality at high 166Ho activities of several GBq. To this purpose, the liver compartment, including two tumors, of an anthropomorphic phantom was filled with 166Ho-chloride, with a tumor to non-tumorous liver activity concentration ratio of 10:1. Multiple SPECT/CT scans were acquired over a range of activities up to 2.7 GBq. Images were reconstructed using a commercially available protocol incorporating attenuation and scatter correction. Dead time effects were assessed from the observed count rate in the photopeak (81 keV, 15% width) and upper scatter (118 keV, 12% width) window. Post reconstruction, each image was scaled with an individual conversion factor to match the known total activity in the phantom at scanning time. The resulting activity concentration was measured in the tumors and non-tumorous liver. The image quality as a function of activity was assessed by a visual check of the absence of artifacts by a nuclear medicine physician. The apparent lung shunt fraction (nonzero due to scatter) was estimated on planar and SPECT images. Results A 20% count loss due to dead time was observed around 0.7 GBq in the photopeak window. Independent of the count losses, the measured activity concentration was up to 100% of the real value for non-tumorous liver, when reconstructions were normalized to the known activity at scanning time. However, for tumor spheres, activity concentration recovery was ~80% at the lowest activity, decreasing with increasing activity in the phantom. Measured lung shunt fractions were relatively constant over the considered activity range. Conclusions At high 166Ho count rate, all images, visually assessed, presented no artifacts, even at considerable dead time losses. A quantitative evaluation revealed the possibility of reliable dosimetry within the healthy liver, as long as a post-reconstruction scaling to scanning activity is applied. Reliable tumor dosimetry, instead, remained hampered by the dead time