[90Y]Yttria Alumino Silicate Glass Microspheres: A Biosimilar Formulation to "TheraSphere" for Cost-Effective Treatment of Liver Cancer.

Background: Selective internal radiation therapy (SIRT) using a suitable ß--emitting radionuclide is a promising treatment modality for unresectable liver carcinoma. Yttrium-90 (90Y) [T1/2 = 64.2 h, Eß(max) = 2.28 MeV, no detectable γ-photon] is the most preferred radioisotope for SIRT owing to its favorable decay characteristics. Objective: The present study describes indigenous development and evaluation of intrinsically radiolabeled [90Y]yttria alumino silicate ([90Y]YAS) glass microsphere, a formulation biosimilar to "TheraSphere" (commercially available, U.S. FDA-approved formulation), for SIRT of unresectable liver carcinoma in human patients. Methods: YAS glass microspheres of composition 40Y2O3-20Al2O3-40SiO2 (w/w) and diameter ranging between 20 and 36 µm were synthesized with almost 100% conversion efficiency and >99% sphericity. Intrinsically labeled [90Y]YAS glass microspheres were produced by thermal neutron irradiation of cold YAS glass microspheres in a research reactor. Subsequent to in vitro evaluations and in vivo studies in healthy Wistar rats, customized doses of [90Y]YAS glass microspheres were administered in human patients. Results: [90Y]YAS glass microspheres were produced with 137.7 ± 8.6 MBq/mg YAS glass (∼6800 Bq per microsphere) specific activity and 99.94% ± 0.02% radionuclidic purity at the end of irradiation. The formulation exhibited excellent in vitro stability in human serum and showed >97% retention in the liver up to 7 d post-administration when biodistribution studies were carried out in healthy Wistar rats. Yttrium-90 positron emission tomography scans recorded at different time points post-administration of customized dose of [90Y]YAS glass microspheres in human patients showed near-quantitative retention of the formulation in the injected lobe. Conclusions: The study confirmed the suitability of indigenously prepared [90Y]YAS glass microspheres for clinical use in the treatment of unresectable hepatocellular carcinoma.

Monte Carlo dosimetry of a novel Yttrium-90 disc source for episcleral brachytherapy.

PURPOSE: To calculate the dose distribution using Monte Carlo simulations for a novel high-dose-rate Yttrium-90 (Y-90) disc source recently developed for episcleral brachytherapy and provide a lookup table for treatment planning. METHODS: Monte Carlo simulations were performed to calculate the in-water dose distribution of the Y-90 disc source using the "GATE", a software based on the "Geant4" Monte Carlo simulation toolkit developed by the international OpenGATE collaboration. The geometry of this novel beta source, its capsule, and the surrounding water medium were accurately modeled in the simulation input files. The standard Y-90 element beta spectrum from ICRU 72 was used, and the physics processes for beta and photon interactions with matters were all included. The dose distribution of this Y-90 disc source was measured in a separate study using Gafchromic EBT-3 films and the results were reported elsewhere. To match the setup of the experiment, a Gafchromic EBT-3 film was also included in the simulation geometry. The simulated dose profiles were exported from the 3D dose distribution results and compared with the measured dose profiles. Transverse dose profiles at different distances from the seed surface were also obtained to study the lateral coverage of the source. RESULTS: The measured percent depth dose (PDD) curves along the central axis perpendicular to the surface of the Y-90 disc were constructed from the experimental and simulated data, and normalized to the reference point at 1 mm from the source capsule. Both PDD curves agreed well up to 4 mm from the source surface (maximum difference ± 10%) but deviated from each other beyond 4 mm. The deviation might be caused by the increased measurement uncertainty in the low-dose region. The dose rate at the reference point calculated from the Monte Carlo simulation was 1.09 cGy/mCi-s and agreed very well with the measured dose rate of 1.05 cGy/mCi-s. If the 80% isodose line is selected as the lateral coverage, the lateral dose coverage is maximal (∼4.5 mm) at the plane next to the source surface, and gradually decreases with the increasing distance, approaching 3.5 mm when the plane is 5 mm from the 6-mm diameter source surface. CONCLUSION: Monte Carlo simulations were successfully performed to confirm the measured PDD curve of the novel Y-90 disc source. This simulation work laid a solid foundation for characterizing the full dosimetry parameters of this source for episcleral brachytherapy applications.

Dosimetric assessment of Gadolinium-159 for hepatic radioembolization: Tomographic images and Monte Carlo simulation.

A common therapeutic radionuclide used in hepatic radioembolization is yttrium-90 (90Y). However, the absence of gamma emissions makes it difficult to verify the post-treatment distribution of 90Y microspheres. Gadolinium-159 (159Gd) has physical properties that are suitable for therapy and post-treatment imaging in hepatic radioembolization procedures. The current study is innovative for conducting a dosimetric investigation of the use of 159Gd in hepatic radioembolization by simulating tomographic images using the Geant4 application for tomographic emission (GATE) Monte Carlo (MC) simulation. For registration and segmentation, tomographic images of five patients with hepatocellular carcinoma (HCC) who had undergone transarterial radioembolization (TARE) therapy were processed using a 3D slicer. The tomographic images with 159Gd and 90Y separately were simulated using the GATE MC Package. The output of simulation (dose image) was uploaded to 3D slicer to compute the absorbed dose for each organ of interests. 159Gd were able to provide a recommended dose of 120 Gy to the tumour, with normal liver and lungs absorbed doses close to that of 90Y and less than the respective maximum permitted doses of 70 Gy and 30 Gy, respectively. Compared to 90Y, 159Gd requires higher administered activity approximately 4.92 times to achieve a tumour dose of 120 Gy. Thus; this research gives new insights into the use of 159Gd as a theranostic radioisotope, with the potential to be used as a90Y alternative for liver radioembolization.

Economic evaluations of radioembolization with yttrium-90 microspheres in liver metastases of colorectal cancer: a systematic review.

BACKGROUND: Transarterial radioembolization with yttrium-90 (Y-90 TARE) microspheres therapy has demonstrated positive clinical benefits for the treatment of liver metastases from colorectal cancer (lmCRC). This study aims to conduct a systematic review of the available economic evaluations of Y-90 TARE for lmCRC. METHODS: English and Spanish publications were identified from PubMed, Embase, Cochrane, MEDES health technology assessment agencies, and scientific congress databases published up to May 2021. The inclusion criteria considered only economic evaluations; thus, other types of studies were excluded. Purchasing-power-parity exchange rates for the year 2020 ($US PPP) were applied for cost harmonisation. RESULTS: From 423 records screened, seven economic evaluations (2 cost-analyses [CA] and 5 cost-utility-analyses [CUA]) were included (6 European and 1 USA). All included studies (n = 7) were evaluated from a payer and the social perspective (n = 1). Included studies evaluated patients with unresectable liver-predominant metastases of CRC, refractory to chemotherapy (n = 6), or chemotherapy-naïve (n = 1). Y-90 TARE was compared to best supportive care (BSC) (n = 4), an association of folinic acid, fluorouracil and oxaliplatin (FOLFOX) (n = 1), and hepatic artery infusion (HAI) (n = 2). Y-90 TARE increased life-years gained (LYG) versus BSC (1.12 and 1.35 LYG) and versus HAI (0.37 LYG). Y-90 TARE increased the quality-adjusted-life-year (QALY) versus BSC (0.81 and 0.83 QALY) and versus HAI (0.35 QALY). When considering a lifetime horizon, Y-90 TARE reported incremental cost compared to BSC (range 19,225 to 25,320 $US PPP) and versus HAI (14,307 $US PPP). Y-90 TARE reported incremental cost-utility ratios (ICURs) between 23,875 $US PPP/QALY to 31,185 $US PPP/QALY. The probability of Y-90 TARE being cost-effective at £ 30,000/QALY threshold was between 56% and 57%. CONCLUSIONS: Our review highlights that Y-90 TARE could be a cost-effective therapy either as a monotherapy or when combined with systemic therapy for treating ImCRC. However, despite the current clinical evidence on Y-90 TARE in the treatment of ImCRC, the global economic evaluation reported for Y-90 TARE in ImCRC is limited (n = 7), therefore, we recommend future economic evaluations on Y-90 TARE versus alternative options in treating ImCRC from the societal perspective.

Yttrium-90 Ibritumomab Tiuxetan is Cost-Effective Compared to Bendamustine + Rituximab in Low-grade Lymphomas.

BACKGROUND: Yttrium-90 ibritumomab tiuxetan [(90)Y-IT] is a CD20-targeted radio-immunotherapeutic agent. It has shown an excellent therapeutic activity with high tolerability against previously untreated follicular lymphoma (FL) and marginal zone B cell lymphoma (MZL). It is an attractive therapeutic option as the treatment schedule is short and convenient. The aim of our study is to determine the cost-effectiveness of (90)Y-IT in comparison to the standard-of-care bendamustine + rituximab (BR) in the first-line treatment of low-grade FL (LG-FL) and MZL in the real world. PATIENTS AND METHODS: We included all patients who were treated with standard-dose (90)Y-IT for previously untreated LG-FL and MZL at the Mayo Clinic Cancer Center (N = 51). A comparator arm with a historical cohort of previously untreated LG-FL and MZL patients who received BR was used (N = 92). RESULTS: Inverse propensity weighting was utilized to balance the 2 study arms. There were no differences in terms of overall response rate (100% vs. 98%, P = .18), complete response rate (94% vs. 95%, P = .91), or 5 years progression-free survival (76% vs. 75%, P = .63) between patients who received (90)Y-IT and BR, respectively. Within the first year, patients who received (90)Y-IT required an average of 4.5 fewer oncology clinic visits (P < .001), an average of 10 fewer days of therapeutic use (P < .001), and 40% less use of growth factors (P < .001) as compared to the BR group. The direct therapeutic cost of (90)Y-IT treatment was 54% less than that of 6 cycles of BR. CONCLUSION: The findings suggest that (90) Y-IT is more cost-effective than BR and is a viable alternative in up-front management of LG-FL and MZL.

Advances in Delivery of Selective Internal Radiation Therapy (SIRT): Economic and Logistical Effects of Same-Stay Work-Up and Procedure in the Treatment of Unresectable Liver Tumors in England.

INTRODUCTION: Selective internal radiation therapy (SIRT) is a targeted method of treatment for unresectable liver tumors in which radiation therapy is directly delivered to the tumor(s) via the hepatic vasculature. Successful outcomes with SIRT are dependent on the specific vasculature of the liver and tumor, and the patient therefore needs to attend a "work-up" to map the hepatic vasculature prior to the SIRT procedure. Recent advances in SIRT delivery have enabled same-day or same-stay work-up and procedure, requiring only one hospital visit rather than two. We aimed to evaluate the economic, travel time, and transport-related environmental impact of a new brachytherapy device delivery program, the order-map-treat (OMT) program, in patients with unresectable hepatocellular carcinoma (HCC) in England. METHODS: A healthcare resource group (HRG)-based analysis of costs from a national payer (Department of Health and Social Care, DHSC) perspective was conducted assuming that, with OMT, patients would have to attend hospital only once for both the SIRT work-up and procedure versus twice without OMT. Patient travel time and CO2 emissions were then estimated by identifying the SIRT center closest to the centroid of each clinical commissioning group (CCG) and calculating straight-line distances with a "detour index" to capture the effect of indirect routes via road or rail. RESULTS: It was estimated that 856 patients per annum would be eligible for SIRT treatment for unresectable HCC in England. OMT would be anticipated to save GBP 2842 per patient versus performing SIRT without OMT. Furthermore, across all patients with HCC eligible for SIRT in England, OMT would avoid 74,500 km of travel, 2299 h of travel time, and 13.9 metric tons of patient transport-related CO2 emissions annually. CONCLUSION: OMT reduces the number of hospital visits required for SIRT by 50%, resulting in financial savings from the DHSC perspective, time savings from the patient perspective, and reduced CO2 emissions arising from patient transport.

Utilizing 3D Slicer to incorporate tomographic images into GATE Monte Carlo simulation for personalized dosimetry in yttrium-90 radioembolization.

PURPOSE: Monte Carlo (MC) simulation is an important technique that can help design advanced and challenging experimental setups. GATE (Geant4 application for tomographic emission) is a useful simulation toolkit for applications in nuclear medicine. Transarterial radioembolization is a treatment for liver cancer, where microspheres embedded with yttrium-90 (90 Y) are administered intra-arterially to the tumor. Personalized dosimetry for this treatment may provide higher dosimetry accuracy compared to the conventional partition model (PM) calculation. However, incorporation of three-dimensional tomographic input data into MC simulation is an intricate process. In this article, 3D Slicer, free and open-source software, was utilized for the incorporation of patient tomographic images into GATE to demonstrate the feasibility of personalized dosimetry in hepatic radioembolization with 90 Y. METHODS: In this article, the steps involved in importing, segmenting, and registering tomographic images using 3D Slicer were thoroughly described, before importing them into GATE for MC simulation. The absorbed doses estimated using GATE were then compared with that of PM. SlicerRT, a 3D Slicer extension, was then used to visualize the isodose from the MC simulation. RESULTS: A workflow diagram consisting of all the steps taken in the utilization of 3D Slicer for personalized dosimetry in 90 Y radioembolization has been presented in this article. In comparison to the MC simulation, the absorbed doses to the tumor and normal liver were overestimated by PM by 105.55% and 20.23%, respectively, whereas for lungs, the absorbed dose estimated by PM was underestimated by 25.32%. These values were supported by the isodose distribution obtained via SlicerRT, suggesting the presence of beta particles outside the volumes of interest. These findings demonstrate the importance of personalized dosimetry for a more accurate absorbed dose estimation compared to PM. CONCLUSION: The methodology provided in this study can assist users (especially students or researchers who are new to MC simulation) in navigating intricate steps required in the importation of tomographic data for MC simulation. These steps can also be utilized for other radiation therapy related applications, not necessarily limited to internal dosimetry.

Assessment of clinical studies evaluating combinations of immune checkpoint inhibitors with locoregional treatments in solid tumors.

In the last decade, immunotherapy with immune checkpoint inhibitors (ICIs) has changed the therapeutic algorithm of cancer patients. ICIs combined with other therapeutic options, such as chemo- and targeted therapies, generate impressive results in cancer patients. Locoregional treatments (LRTs) play an important role in the management of various solid tumors (e.g., hepatocellular carcinoma (HCC), neuroendocrine tumors, etc.), and this therapeutic approach may enhance the activity of the immune response to tumor cells destroying primary tumors and leading to the release of several soluble molecules. This systematic review was performed to identify studies reporting objective response rate (ORR) and survival information in patients with solid tumors treated with ICIs plus LRTs. In the present work, fourteen studies were included, and the majority of them (five studies) enrolled patients with hepatocellular carcinoma (HCC), whereas the others included patients with different diseases. The highest ORRs were seen in HCC (67%, Y-90 RE plus ipilimumab and nivolumab) and melanoma (38%, dendritic cells with mRNA plus ipilimumab) patients. ORRs were not observed in liver metastases from melanoma and colorectal cancer. These data suggest that combination of ICIs and LRTs is feasible and more active in primary tumors (particularly HCC) than metastases with a synergistic effect on antitumor immunity. However, further studies are needed to better select patients, schedules, and setting of treatments.

Validation of a commercial software dose calculation for Y-90 microspheres.

PURPOSE: Several new commercial software packages have become available that can calculate the tumor and normal tissue dose distributions from post-treatment PET-CT scans for Y-90 microsphere treatments of liver lesions. This work seeks to validate the MIM SurePlan Liver Y90 software by comparing its results to a previously developed Monte Carlo derived voxel dose kernel calculation method. METHODS: We analyzed 10 patients who had treatments for metastatic liver cancer and created contours on post Y-90 treatment PET-CT images. We then performed dose calculations using three methods and compared the results. The first two methods calculated the dose using MIM SurePlan Liver Y90's LDM (Local Deposition Method) and the VSV (Voxel S Value) algorithms. The third method calculated the dose using a publicly available Fluka Monte Carlo-derived dose kernel (MCK) calculation (used as ground truth). We investigated 3D Gamma passing rates and several dosimetric parameters. RESULTS: A total of 3%/3 mm 3D gamma passing rates averaged 99.3% for the VSV and 78.9% for LDM. Compared to the MCK distribution, the differences for combined target GTV V70Gy and normal liver and/or lobe mean doses were small. Larger differences were seen in GTV mean doses and D95, likely due to large dose gradients in the treated regions combined with differences in dose kernel, dose grid and finite volume effects. CONCLUSIONS: The MIM SurePlan Liver Y90 VSV algorithm agreed well with the MCK calculation for patients treated with Y-90 microspheres based on the gamma analysis and several dosimetric parameters. Larger dosimetric differences in lesion mean doses and D95 suggests that these metrics are less robust to changes in calculation grid location and finite volume effects for small lesions.

Relevance of artefacts in99mTc-MAA SPECT scans on pre-therapy patient-specific90Y TARE internal dosimetry: a GATE Monte Carlo study.

Objective.The direct Monte Carlo (MC) simulation of radiation transport exploiting morphological and functional tomographic imaging as input data is considered the gold standard for internal dosimetry in nuclear medicine, and it is increasingly used in studies regarding trans-arterial radio-embolization (TARE). However, artefacts affecting the functional scans, such as reconstruction artefacts and motion blurring, decrease the accuracy in defining the radionuclide distribution in the simulations and consequently lead to errors in absorbed dose estimations. In this study, the relevance of such artefacts in patient-specific three-dimensional MC dosimetry was investigated in three cases of90Y TARE.Approach.The pre-therapy99mTc MacroAggregate Albumin (Tc-MAA) SPECTs and CTs of patients were used as input for simulations performed with the GEANT4-based toolkit GATE. Several pre-simulation SPECT-masking techniques were implemented, with the aim of zeroing the decay probability in air, in lungs, or in the whole volume outside the liver.Main results.Increments in absorbed dose up to about +40% with respect to the native-SPECT simulations were found in liver-related volumes of interest (VOIs), depending on the masking procedure adopted. Regarding lungs-related VOIs, decrements in absorbed doses in right lung as high as -90% were retrieved.Significance.These results highlight the relevant influence of SPECT artefacts, if not properly treated, on dosimetric outcomes for90Y TARE cases. Well-designed SPECT-masking techniques appear to be a promising way to correct for such misestimations.

Optimized cocktail of 90Y/177Lu for radionuclide therapy of neuroendocrine tumors of various sizes: a simulation study.

BACKGROUND AND OBJECTIVES: There is significant interest and potential in the treatment of neuroendocrine tumors via peptide receptor radionuclide therapy (PRRT) using one or both of 90Y and 177Lu-labeled peptides. Given the presence of different tumor sizes in patients and differing radionuclide dose delivery properties, the present study aims to use Monte Carlo simulations to estimate S-values to spherical tumors of various sizes with 90Y and 177Lu separately and in combination. The goal is to determine ratios of 90Y to 177Lu that result in the largest absorbed doses per decay of the radionuclides and the most suitable dose profiles to treat tumors of specific sizes. MATERIAL AND METHODS: Particle transfer calculations and simulations were performed using the Monte Carlo GATE simulation software. Spherical tumors of different sizes, ranging from 0.5 to 20 mm in radius, were designed. Activities of 177Lu and 90Y, individually and in combination, were homogeneously placed within the total volume of the tumors. We determined the S-values to the tumors, and to the external volume outside of the tumors (cross-dose) which was used to approximate background tissue. The dose profiles were obtained for each of the different tumor sizes, and the uniformity of dose within each tumor was calculated. RESULTS: For all tumor sizes, the self-dose and cross-dose per decay from 90Y were higher than that from 177Lu. We observed that 177Lu had the most uniform dose distribution within tumors with radii less than 5 mm. For tumors greater than 5 mm in radius, a ratio of 25% 90Y to 75% 177Lu resulted in the most uniform doses. When the ratio of 177Lu to 90Y was smaller, the uniformity improved more with increasing tumor size. The cross-dose stayed approximately constant for tumors larger than 15 mm for all ratios of 177Lu to 90Y. Finally, as the size of the tumor increased, differences in the S-values between different ratios of 177Lu to 90Y decreased. CONCLUSION: Our work showed that to achieve a more uniform dose distribution within the tumor, 177Lu alone is more effective for small tumors. For medium and large tumors, a ratio of 90Y to 177Lu with more or less 177Lu, respectively, is recommended.

Tumour-to-normal tissue (T/N) dosimetry ratios role in assessment of 90Y selective internal radiation therapy (SIRT).

OBJECTIVE: The purpose of our work is to assess the role of tumour-to-normal tissue (T/N) dosimetry ratios for predicting response in patients undergoing locoregional therapy to the liver with 90Y microspheres. METHODS: A total of 39 patients (7 female:32 male, mean age 68.3 ± 7.6 years), underwent positron emission tomography (PET)/CT imaging after treatment with 90Y microspheres. For attenuation correction and localization of the 90Y microspheres, the low-dose, non-diagnostic CT images from PET/CT were used. The acquisition took 15 min and the reconstruction matrix size was 200 × 200 × 75 mm and voxel size of 4.07 × 4.07 × 3.00 mm. For dosimetry calculations, the local deposition method with known activity of 90Y was used. For each patient, regions of interest for tumour(s) and whole liver were manually created; the normal tissue region of interest was created automatically. mRECIST criteria on MRI done at 1 month post-treatment and subsequently every 3 months after 90Y treatment, were used to assess response. RESULTS: For 39 patients, the mean liver, tumour and normal tissue doses (mean ± SD) were, 55.17 ± 26.04 Gy, 911.87 ± 866.54 Gy and 47.79 ± 20.47 Gy, respectively. Among these patients, 31 (79%) showed complete response (CR) and 8 (21%) showed progression of disease (PD). For patients with CR, the mean T/N dose ratio obtained was 24.91 (range 3.09-80.12) and for patients with PD, the mean T/N dose ratio was significantly lower, at 6.69 (range 0.36-14.75). CONCLUSION: Our data show that patients with CR have a statistically higher T/N dose ratio than those with PD. Because, the number of PD cases was limited and partial volume effect was not considered, further investigation is warranted. ADVANCES IN KNOWLEDGE: T/N dosimetry ratios can be used for assessing response in patients undergoing locoregional therapy to the liver with 90Y microspheres.

Radioembolization Dosimetry with Total-Body 90Y PET.

Transarterial radioembolization (TARE) is a locoregional radiopharmaceutical therapy based on the delivery of radioactive 90Y microspheres to liver tumors. The importance of personalized dosimetry to make TARE safer and more effective has been demonstrated in recent clinical studies, stressing the need for quantification of the dose-response relationship to ultimately optimize the administered activity before treatment and image it after treatment. 90Y dosimetric studies are challenging because of the lack of accurate and precise methods but are best realized with PET combined with Monte Carlo simulations and other image modalities to calculate a segmental dose distribution. The aim of this study was to assess the suitability of imaging 90Y PET patients with the total-body PET/CT uEXPLORER and to investigate possible improvements in TARE 90Y PET-based dosimetry. The uEXPLORER is the first commercially available ultra-high-resolution (171 cps/kBq) total-body digital PET/CT device with a 194-cm axial PET field of view that enables the whole body to be scanned at a single bed position. Methods: Two PET/CT scanners were evaluated in this study: the Biograph mCT and the total-body uEXPLORER. Images of a National Electrical Manufacturers Association (NEMA) image-quality phantom and 2 patients were reconstructed using our standard clinical oncology protocol. A late portal phase contrast-enhanced CT scan was used to contour the liver segments and create corresponding volumes of interest. To calculate the absorbed dose, Monte Carlo simulations were performed using Geant4 Application for Tomographic Emission (GATE). The absorbed dose and dose-volume histograms were calculated for all 6 spheres (diameters ranging from 10 to 37 mm) of the NEMA phantom, the liver segments, and the entire liver. Differences between the phantom doses and an analytic ground truth were quantified through the root mean squared error. Results: The uEXPLORER showed a higher signal-to-noise ratio at 10- and 13-mm diameters, consistent with its high spatial resolution and system sensitivity. The total liver-absorbed dose showed excellent agreement between the uEXPLORER and the mCT for both patients, with differences lower than 0.2%. Larger differences of up to 60% were observed when comparing the liver segment doses. All dose-volume histograms were in good agreement, with narrower tails for the uEXPLORER in all segments, indicating lower image noise. Conclusion: This patient study is compelling for the use of total-body 90Y PET for liver dosimetry. The uEXPLORER scanner showed a better signal-to-noise ratio than mCT, especially in lower-count regions of interest, which is expected to improve dose quantification and tumor dosimetry.

Pre- and post-treatment image-based dosimetry in90Y-microsphere radioembolization using the TOPAS Monte Carlo toolkit.

Objective. To evaluate the pre-treatment and post-treatment imaging-based dosimetry of patients treated with 90Y-microspheres, including accurate estimations of dose to tumor, healthy liver and lung. To do so, the Monte Carlo (MC) TOPAS platform is in this work extended towards its utilization in radionuclide therapy.Approach. Five patients treated at the Massachusetts General Hospital were selected for this study. All patients had data for both pre-treatment SPECT-CT imaging using 99mTc-MAA as a surrogate of the 90Y-microspheres treatment and SPECT-CT imaging immediately after the 90Y activity administration. Pre- and post-treatment doses were computed with TOPAS using the SPECT images to localize the source positions and the CT images to account for tissue inhomoegeneities. We compared our results with analytical calculations following the voxel-based MIRD scheme.Main results. TOPAS results largely agreed with the MIRD-based calculations in soft tissue regions: the average difference in mean dose to the liver was 0.14 Gy GBq-1(2.6%). However, dose distributions in the lung differed considerably: absolute differences in mean doses to the lung ranged from 1.2 to 6.3 Gy GBq-1and relative differences from 153% to 231%. We also found large differences in the intra-hepatic dose distributions between pre- and post-treatment imaging, but only limited differences in the pulmonary dose.Significance. Doses to lung were found to be higher using TOPAS with respect to analytical calculations which may significantly underestimate dose to the lung, suggesting the use of MC methods for 90Y dosimetry. According to our results, pre-treatment imaging may still be representative of dose to lung in these treatments.

Treatment response assessment following transarterial radioembolization for hepatocellular carcinoma.

Transarterial radioembolization with yttrium-90 microspheres is an established therapy for hepatocellular carcinoma. Post-procedural imaging is important for the assessment of both treatment response and procedural complications. A variety of challenging treatment-specific imaging phenomena complicate imaging assessment, such as changes in tumoral size, tumoral and peritumoral enhancement, and extrahepatic complications. A review of the procedural steps, emerging variations, and timelines for post-treatment tumoral and extra-tumoral imaging changes are presented, which may aid the reporting radiologist in the interpretation of post-procedural imaging. Furthermore, a description of post-procedural complications and their significance is provided.

Cost-utility analysis of selective internal radiation therapy with Y-90 resin microspheres in hepatocellular carcinoma.

Background: The study assessed the cost-utility of selective internal radiation therapy (SIRT) with Y-90 resin microspheres versus sorafenib in UK patients with unresectable hepatocellular carcinoma ineligible for transarterial chemoembolization. Materials & methods: A lifetime partitioned survival model was developed for patients with low tumor burden (≤25%) and good liver function (albumin-bilirubin grade 1). Efficacy, safety and quality of life data were from a European Phase III randomized controlled trial and published studies. Resource use was from registries and clinical surveys. Results: Discounted quality-adjusted life-years were 1.982 and 1.381, and discounted total costs were £29,143 and 30,927, for SIRT and sorafenib, respectively. Conclusion: SIRT has the potential to be a dominant (more efficacious/less costly) or cost-effective alternative to sorafenib in patients with unresectable hepatocellular carcinoma.

Metabolic activity assessment by 18 F-fluorodeoxyglucose positron emission tomography in patients with hepatocellular carcinoma undergoing Yttrium-90 transarterial radioembolization.

BACKGROUND AND AIM: 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) is a functional image technique that can inform clinical decisions related to prognosis. We investigated the predictive role of 18 F-fluorodeoxyglucose PET/CT in patients with hepatocellular carcinoma (HCC) undergoing Yttrium-90 (Y-90) transarterial radioembolization (TARE). METHODS: Patients with HCC treated with TARE and pre-TARE PET/CT scan were recruited between 2009 and 2013. Maximum standardized uptake value and tumor-to-non-tumorous liver uptake ratio (TLR) were measured. Tumor response was evaluated in accordance with modified RECIST criteria at 3-month intervals after Y-90 TARE. RESULTS: Forty patients were included in the final analysis. The median age was 56.5 years and male predominant. Disease control in treated lesion was achieved in 82.5% (n = 33) of patients. During median 18.3-month follow-up, 27.5% (n = 11) of patients achieved progression-free survival. The cutoff of TLR, which was related to the median value, did not affect disease control rate, progression-free survival, and overall survival in patients with Y-90 TARE. CONCLUSIONS: The TLR-based stratification may be a simple method, but our study did not show the usefulness in predicting prognosis in HCC patients with Y-90 TARE. Further studies with large number of patients are needed.

Dosimetric characterization of a novel 90Y source for use in the conformal superficial brachytherapy device.

PURPOSE: To characterize the dose distribution in water of a novel beta-emitting brachytherapy source for use in a Conformal Superficial Brachytherapy (CSBT) device. METHODS AND MATERIALS: Yttrium-90 (90Y) sources were designed for use with a uniquely designed CSBT device. Depth dose and planar dose measurements were performed for bare sources and sources housed within a 3D printed source holder. Monte Carlo simulated dose rate distributions were compared to film-based measurements. Gamma analysis was performed to compare simulated and measured dose rates from seven 90Y sources placed simultaneously using the CSBT device. RESULTS: The film-based maximum measured surface dose rate for a bare source in contact with the surface was 3.35 × 10-7 cGy s-1 Bq-1. When placed in the source holder, the maximum measured dose rate was 1.41 × 10-7 cGy s-1 Bq-1. The Monte Carlo simulated depth dose rates were within 10% or 0.02 cm of the measured dose rates for each depth of measurement. The maximum film surface dose rate measured using a seven-source configuration within the CSBT device was 1.78 × 10-7 cGy s-1 Bq-1. Measured and simulated dose rate distribution of the seven-source configuration were compared by gamma analysis and yielded a passing rate of 94.08%. The gamma criteria were 3% for dose-difference and 0.07056 cm for distance-to-agreement. The estimated measured dose rate uncertainty was 5.34%. CONCLUSIONS: 90Y is a unique source that can be optimally designed for a customized CSBT device. The rapid dose falloff provided a high dose gradient, ideal for treatment of superficial lesions. The dose rate uncertainty of the 90Y-based CSBT device was within acceptable brachytherapy standards and warrants further investigation.

Algorithms and Analyses for Joint Spectral Image Reconstruction in Y-90 Bremsstrahlung SPECT.

Quantitative yttrium-90 (Y-90) SPECT imaging is challenging due to the nature of Y-90, an almost pure beta emitter that is associated with a continuous spectrum of bremsstrahlung photons that have a relatively low yield. This paper proposes joint spectral reconstruction (JSR), a novel bremsstrahlung SPECT reconstruction method that uses multiple narrow acquisition windows with accurate multi-band forward modeling to cover a wide range of the energy spectrum. Theoretical analyses using Fisher information and Monte-Carlo (MC) simulation with a digital phantom show that the proposed JSR model with multiple acquisition windows has better performance in terms of covariance (precision) than previous methods using multi-band forward modeling with a single acquisition window, or using a single-band forward modeling with a single acquisition window. We also propose an energy-window subset (ES) algorithm for JSR to achieve fast empirical convergence and maximum-likelihood based initialization for all reconstruction methods to improve quantification accuracy in early iterations. For both MC simulation with a digital phantom and experimental study with a physical multi-sphere phantom, our proposed JSR-ES, a fast algorithm for JSR with ES, yielded higher recovery coefficients (RCs) on hot spheres over all iterations and sphere sizes than all the other evaluated methods, due to fast empirical convergence. In experimental study, for the smallest hot sphere (diameter 1.6cm), at the 20th iteration the increase in RCs with JSR-ES was 66 and 31% compared with single wide and narrow band forward models, respectively. JSR-ES also yielded lower residual count error (RCE) on a cold sphere over all iterations than other methods for MC simulation with known scatter, but led to greater RCE compared with single narrow band forward model at higher iterations for experimental study when using estimated scatter.

Early metabolic response assessment of breast cancer liver metastases: 4-week posttreatment FDG PET predicts survival after 90Y microsphere radioembolization.

AIM: To evaluate the feasibility of early metabolic response assessment with 18F-FDG PET/CT in patients with breast cancer liver metastases 4 weeks after radioembolization with Yttrium-90 labeled microspheres. METHODS: 25 patients (mean age 58y, range 40-74) with advanced stage liver metastases of breast cancer were treated with 1.9 ± 0.4 GBq of 90Y-microspheres in the salvage setting and underwent 18F-FDG PET/CT at baseline and 4 weeks post-radioembolization. 14 patients (56 %) had an excessive hepatic tumor burden (> 50 % of total liver volume), 21 patients (84 %) had extrahepatic disease. Liver lesions with the highest SUVmax were selected as target lesions and a cut-off was set at 50 % reduction to separate responders from non-responders. The predictive impact of metabolic response on overall survival (OS) was investigated along with other prognostic factors. RESULTS: The median OS in this highly advanced metastatic cohort was 7 months (95 % CI, 5-9). All patients had a reduction in SUVmax (mean ΔSUVmax: -49 ± 26 %) at 4 weeks post-treatment. Patients with > 50 % SUVmax reduction survived longer (median OS 13 mo, 95 % CI 8-18) than the remaining patients (median OS 4 mo, 95 % CI 2-6; p = 0.001). From all investigated baseline factors including age, performance status, and presence of extra-hepatic disease, only the hepatic tumor burden had a significant impact on OS (p = 0.02). CONCLUSIONS: This is the first preliminary evidence in breast cancer that early post-radioembolization molecular response assessment of treated liver metastases - as early as 4 weeks posttreatment - may predict survival. If confirmed by larger series, FDG PET/CT could be considered for early response-adapted treatment modifications.