Transarterial Radioembolization for Management of Hepatocellular Carcinoma.

Transarterial radioembolization (TARE) with Yttrium-90 (Y90) is a growing area of study due to its benefits in early-, intermediate-, and late-stage hepatocellular carcinoma. Treatment intent, including curative therapy, bridging to transplant, and downstaging disease, informs treatment approach and dosimetry goals. Radiation lobectomy (RL) and radiation segmentectomy (RS) are the 2 main forms of Y90 administration which have shown improved survival outcomes with the development of personalized dosimetry. RS aims to achieve complete pathological necrosis with dose escalation and RL aims for local disease control as well as induction of contralateral lobe hypertrophy to improve hepatic reserve. Furthermore, TARE has been validated in head-to-head comparison to other locoregional and systemic therapies. Lastly, early potential exists for combination therapy between TARE and immune checkpoint inhibitors for advanced stage disease.

MIDOS: a novel stochastic model towards a treatment planning system for microsphere dosimetry in liver tumors.

PURPOSE: Transarterial radioembolization (TARE) procedures treat liver tumors by injecting radioactive microspheres into the hepatic artery. Currently, there is a critical need to optimize TARE towards a personalized dosimetry approach. To this aim, we present a novel microsphere dosimetry (MIDOS) stochastic model to estimate the activity delivered to the tumor(s), normal liver, and lung. METHODS: MIDOS incorporates adult male/female liver computational phantoms with the hepatic arterial, hepatic portal venous, and hepatic venous vascular trees. Tumors can be placed in both models at user discretion. The perfusion of microspheres follows cluster patterns, and a Markov chain approach was applied to microsphere navigation, with the terminal location of microspheres determined to be in either normal hepatic parenchyma, hepatic tumor, or lung. A tumor uptake model was implemented to determine if microspheres get lodged in the tumor, and a probability was included in determining the shunt of microspheres to the lung. A sensitivity analysis of the model parameters was performed, and radiation segmentectomy/lobectomy procedures were simulated over a wide range of activity perfused. Then, the impact of using different microspheres, i.e., SIR-Sphere®, TheraSphere®, and QuiremSphere®, on the tumor-to-normal ratio (TNR), lung shunt fraction (LSF), and mean absorbed dose was analyzed. RESULTS: Highly vascularized tumors translated into increased TNR. Treatment results (TNR and LSF) were significantly more variable for microspheres with high particle load. In our scenarios with 1.5 GBq perfusion, TNR was maximum for TheraSphere® at calibration time in segmentectomy/lobar technique, for SIR-Sphere® at 1-3 days post-calibration, and regarding QuiremSphere® at 3 days post-calibration. CONCLUSION: This novel approach is a decisive step towards developing a personalized dosimetry framework for TARE. MIDOS assists in making clinical decisions in TARE treatment planning by assessing various delivery parameters and simulating different tumor uptakes. MIDOS offers evaluation of treatment outcomes, such as TNR and LSF, and quantitative scenario-specific decisions.

90Y post-radioembolization clinical assessment with whole-body Biograph Vision Quadra PET/CT: image quality, tumor, liver and lung dosimetry.

PURPOSE: Evaluation of 90Y liver radioembolization post-treatment clinical data using a whole-body Biograph Vision Quadra PET/CT to investigate the potential of protocol optimization in terms of scan time and dosimetry. METHODS: 17 patients with hepatocellular carcinoma with median (IQR) injected activity 2393 (1348-3298) MBq were included. Pre-treatment dosimetry plan was based on 99mTc-MAA SPECT/CT with Simplicit90Y™ and post-treatment validation with Quadra using Simplicit90Y™ and HERMIA independently. Regarding the image analysis, mean and peak SNR, the coefficient of variation (COV) and lesion-to-background ratio (LBR) were evaluated. For the post-treatment dosimetry validation, the mean tumor, whole liver and lung absorbed dose evaluation was performed using Simplicit90Y and HERMES. Images were reconstructed with 20-, 15-, 10-, 5- and 1- min sinograms with 2, 4, 6 and 8 iterations. Wilcoxon signed rank test was used to show statistical significance (p < 0.05). RESULTS: There was no difference of statistical significance between 20- and 5- min reconstructed times for the peak SNR, COV and LBR. In addition, there was no difference of statistical significance between 20- and 1- min reconstructed times for all dosimetry metrics. Lung dosimetry showed consistently lower values than the expected. Tumor absorbed dose based on Simplicit90Y™ was similar to the expected while HERMES consistently underestimated significantly the measured tumor absorbed dose. Finally, there was no difference of statistical significance between expected and measured tumor, whole liver and lung dose for all reconstruction times. CONCLUSION: In this study we evaluated, in terms of image quality and dosimetry, whole-body PET clinical images of patients after having been treated with 90Y microspheres radioembolization for liver cancer. Compared to the 20-min standard scan, the simulated 5-min reconstructed images provided equal image peak SNR and noise behavior, while performing also similarly for post-treatment dosimetry of tumor, whole liver and lung absorbed doses.

Imageable Radioembolization Microspheres for Treatment of Unresectable Hepatocellular Carcinoma: Interim Results from a First-in-Human Trial.

PURPOSE: To Describe 6-Month safety, efficacy and multimodal imageability after imageable glass Yttrium-90 radioembolization for unresectable Hepatocellular Carcinoma (HCC) in a First-in Human Trial METHODS: Eye90 microspheres® (Eye90), an FDA Breakthrough Designated Device, are glass radiopaque Y-90 microspheres visible on CT and SPECT/CT. Six subjects with unresectable HCC underwent selective (≤ 2 segments) Eye90 treatment in a prospective open-label pilot trial. Key inclusion criteria included liver only HCC, ECOG ≤ 1, total lesion length ≤ 9 cm and Child-Pugh A. Prospective partition dosimetry was utilized. Safety, biochemistry, toxicity, adverse events (AE), multimodal imageability on CT and SPECT/CT and 3 and 6-month MRI local modified RECIST (mRECIST) response was evaluated. RESULTS: 6 subjects with HCC (7 lesions) were treated with Eye90 and followed to 180 days. Administration success was 100%. Eye90 CT radiopacity distribution correlated with SPECT/CT. Target lesion complete response was observed in 3 of 6 subjects (50%) and partial response in 2 (33.3%). Two subjects could not be assessed at 180 days. At 180 days, target lesion complete response was maintained in 3 subjects (50%) and partial response in 1 (16.7%). All subjects reported AEs, and 5 reported AEs related to treatment. There were no treatment related serious AEs. CONCLUSIONS: Eye90 was safe and effective in six subjects with unresectable HCC up to 6 months. Eye90 was imageable via CT and SPECT/CT with correlation between CT radiopacity and SPECT/CT radioactivity distribution. Eye90 provided previously unavailable CT based tumor targeting information.

AAPM Medical Physics Practice Guideline 14.a: Yttrium-90 microsphere radioembolization.

Radioembolization using Yttrium-90 (90 Y) microspheres is widely used to treat primary and metastatic liver tumors. The present work provides minimum practice guidelines for establishing and supporting such a program. Medical physicists play a key role in patient and staff safety during these procedures. Products currently available are identified and their properties and suppliers summarized. Appropriateness for use is the domain of the treating physician. Patient work up starts with pre-treatment imaging. First, a mapping study using Technetium-99m (Tc-99m ) is carried out to quantify the lung shunt fraction (LSF) and to characterize the vascular supply of the liver. An MRI, CT, or a PET-CT scan is used to obtain information on the tumor burden. The tumor volume, LSF, tumor histology, and other pertinent patient characteristics are used to decide the type and quantity of 90 Y to be ordered. On the day of treatment, the appropriate dose is assayed using a dose calibrator with a calibration traceable to a national standard. In the treatment suite, the care team led by an interventional radiologist delivers the dose using real-time image guidance. The treatment suite is posted as a radioactive area during the procedure and staff wear radiation dosimeters. The treatment room, patient, and staff are surveyed post-procedure. The dose delivered to the patient is determined from the ratio of pre-treatment and residual waste exposure rate measurements. Establishing such a treatment modality is a major undertaking requiring an institutional radioactive materials license amendment complying with appropriate federal and state radiation regulations and appropriate staff training commensurate with their respective role and function in the planning and delivery of the procedure. Training, documentation, and areas for potential failure modes are identified and guidance is provided to ameliorate them.

The Future of Interventions for Stage IV Colorectal Cancers.

Future options for the management of stage IV colorectal cancer are primarily focused on personalized and directed therapies. Interventions include precision cancer medicine, utilizing nanocarrier platforms for directed chemotherapy, palliative pressurized intraperitoneal aerosol chemotherapy (PIPAC), adjunctive oncolytic virotherapy, and radioembolization techniques. Comprehensive genetic profiling provides specific tumor-directed therapy based on individual genetics. Biomimetic magnetic nanoparticles as chemotherapy delivery systems may reduce systemic side effects of traditional chemotherapy by targeting tumor cells and sparing healthy cells. PIPAC is a newly emerging option for patients with peritoneal metastasis from colorectal cancer and is now being used internationally, showing promising results as a palliative therapy for colorectal cancer. Oncolytic virotherapy is another emerging potential treatment option, especially when combined with standard chemotherapy and/or radiation, as well as immunotherapy. And finally, radioembolization with yttrium-90 ( 90 Y) microspheres has shown some success in treating patients with unresectable liver metastasis from colorectal cancer via selective arterial injection.

Clinical, dosimetric, and reporting considerations for Y-90 glass microspheres in hepatocellular carcinoma: updated 2022 recommendations from an international multidisciplinary working group.

PURPOSE: In light of recently published clinical reports and trials, the TheraSphere Global Dosimetry Steering Committee (DSC) reconvened to review new data and to update previously published clinical and dosimetric recommendations for the treatment of hepatocellular carcinoma (HCC). METHODS: The TheraSphere Global DSC is comprised of health care providers across multiple disciplines involved in the treatment of HCC with yttrium-90 (Y-90) glass microsphere-based transarterial radioembolization (TARE). Literature published between January 2019 and September 2021 was reviewed, discussed, and adjudicated by the Delphi method. Recommendations included in this updated document incorporate both the results of the literature review and the expert opinion and experience of members of the committee. RESULTS: Committee discussion and consensus led to the expansion of recommendations to apply to five common clinical scenarios in patients with HCC to support more individualized efficacious treatment with Y-90 glass microspheres. Existing clinical scenarios were updated to reflect recent developments in dosimetry approaches and broader treatment paradigms evolving for patients presenting with HCC. CONCLUSION: Updated consensus recommendations are provided to guide clinical and dosimetric approaches for the use of Y-90 glass microsphere TARE in HCC, accounting for disease presentation, tumor biology, and treatment intent.

Direct comparison and reproducibility of two segmentation methods for multicompartment dosimetry: round robin study on radioembolization treatment planning in hepatocellular carcinoma.

PURPOSE: Investigate reproducibility of two segmentation methods for multicompartment dosimetry, including normal tissue absorbed dose (NTAD) and tumour absorbed dose (TAD), in hepatocellular carcinoma patients treated with yttrium-90 (90Y) glass microspheres. METHODS: TARGET was a retrospective investigation in 209 patients with < 10 tumours per lobe and at least one tumour ≥ 3 cm ± portal vein thrombosis. Dosimetry was compared using two distinct segmentation methods: anatomic (CT/MRI-based) and count threshold-based on pre-procedural 99mTc-MAA SPECT. In a round robin substudy in 20 patients with ≤ 5 unilobar tumours, the inter-observer reproducibility of eight reviewers was evaluated by computing reproducibility coefficient (RDC) of volume and absorbed dose for whole liver, whole liver normal tissue, perfused normal tissue, perfused liver, total perfused tumour, and target lesion. Intra-observer reproducibility was based on second assessments in 10 patients ≥ 2 weeks later. RESULTS: 99mTc-MAA segmentation calculated higher absorbed doses compared to anatomic segmentation (n = 209), 43.9% higher for TAD (95% limits of agreement [LoA]: - 49.0%, 306.2%) and 21.3% for NTAD (95% LoA: - 67.6%, 354.0%). For the round robin substudy (n = 20), inter-observer reproducibility was better for anatomic (RDC range: 1.17 to 3.53) than 99mTc-MAA SPECT segmentation (1.29 to 7.00) and similar between anatomic imaging modalities (CT: 1.09 to 3.56; MRI: 1.24 to 3.50). Inter-observer reproducibility was better for larger volumes. Perfused normal tissue volume RDC was 1.95 by anatomic and 3.19 by 99mTc-MAA SPECT, with corresponding absorbed dose RDC 1.46 and 1.75. Total perfused tumour volume RDC was higher, 2.92 for anatomic and 7.0 by 99mTc-MAA SPECT with corresponding absorbed dose RDC of 1.84 and 2.78. Intra-observer variability was lower for perfused NTAD (range: 14.3 to 19.7 Gy) than total perfused TAD (range: 42.8 to 121.4 Gy). CONCLUSION: Anatomic segmentation-based dosimetry, versus 99mTc-MAA segmentation, results in lower absorbed doses with superior reproducibility. Higher volume compartments, such as normal tissue versus tumour, exhibit improved reproducibility. TRIAL REGISTRATION: NCT03295006.

Fibroblast activation protein-targeted radionuclide therapy: background, opportunities, and challenges of first (pre)clinical studies.

INTRODUCTION: Fibroblast activation protein (FAP) is highly overexpressed in stromal tissue of various cancers. While FAP has been recognized as a potential diagnostic or therapeutic cancer target for decades, the surge of radiolabeled FAP-targeting molecules has the potential to revolutionize its perspective. It is presently hypothesized that FAP targeted radioligand therapy (TRT) may become a novel treatment for various types of cancer. To date, several preclinical and case series have been reported on FAP TRT using varying compounds and showing effective and tolerant results in advanced cancer patients. Here, we review the current (pre)clinical data on FAP TRT and discuss its perspective towards broader clinical implementation.  METHODS: A PubMed search was performed to identify all FAP tracers used for TRT. Both preclinical and clinical studies were included if they reported on dosimetry, treatment response or adverse events. The last search was performed on July 22 2022. In addition, a database search was performed on clinical trial registries (date 15th of July 2022) to search for prospective trials on FAP TRT. RESULTS: In total, 35 papers were identified that were related to FAP TRT. This resulted in the inclusion of the following tracers for review: FAPI-04, FAPI-46, FAP-2286, SA.FAP, ND-bisFAPI, PNT6555, TEFAPI-06/07, FAPI-C12/C16, and FSDD. CONCLUSION: To date, data was reported on more than 100 patients that were treated with different FAP targeted radionuclide therapies such as [177Lu]Lu-FAPI-04, [90Y]Y-FAPI-46, [177Lu]Lu-FAP-2286, [177Lu]Lu-DOTA.SA.FAPI and [177Lu]Lu-DOTAGA.(SA.FAPi)2. In these studies, FAP targeted radionuclide therapy has resulted in objective responses in difficult to treat end stage cancer patients with manageable adverse events. Although no prospective data is yet available, these early data encourages further research.

Phantom-based evaluation of yttrium-90 datasets using biograph vision quadra.

PURPOSE: The image quality characteristics of two NEMA phantoms with yttrium-90 (90Y) were evaluated on a long axial field-of-view (AFOV) PET/CT. The purpose was to identify the optimized reconstruction setup for the imaging of patients with hepatocellular carcinoma after 90Y radioembolization. METHODS: Two NEMA phantoms were used, where one had a 1:10 sphere to background activity concentration ratio and the second had cold background. Reconstruction parameters used are as follows: iterations 2 to 8, Gaussian filter 2- to 6-mm full-width-at-half-maximum, reconstruction matrices 440 × 440 and 220 × 220, high sensitivity (HS), and ultra-high sensitivity (UHS) modes. 50-, 40-, 30-, 20-, 10-, and 5-min acquisitions were reconstructed. The measurements included recovery coefficients (RC), signal-to-noise ratio (SNR), background variability, and lung error which measures the residual error in the corrections. Patient data were reconstructed with 20-, 10-, 5-, and 1-min time frames and evaluated in terms of SNR. RESULTS: The RC for the hot phantom was 0.36, 0.45, 0.53, 0.63, 0.68, and 0.84 for the spheres with diameters of 10, 13, 17, 22, 28, and 37 mm, respectively, for UHS 2 iterations, a 220 × 220 matrix, and 50-min acquisition. The RC values did not differ with acquisition times down to 20 min. The SNR was the highest for 2 iterations, measured 11.7, 16.6, 17.6, 19.4, 21.9, and 27.7 while the background variability was the lowest (27.59, 27.08, 27.36, 26.44, 30.11, and 33.51%). The lung error was 18%. For the patient dataset, the SNR was 19%, 20%, 24%, and 31% higher for 2 iterations compared to 4 iterations for 20-, 10-, 5-, and 1-min time frames, respectively. CONCLUSIONS: This study evaluates the NEMA image quality of a long AFOV PET/CT scanner with 90Y. It provides high RC for the smallest sphere compared to other standard AFOV scanners at shorter scan times. The maximum patient SNR was for 2 iterations, 20 min, while 5 min delivers images with acceptable SNR.

Voxel-based dosimetry predicting treatment response and related toxicity in HCC patients treated with resin-based Y90 radioembolization: a prospective, single-arm study.

BACKGROUND: There is an increasing body of evidence indicating Y90 dose thresholds for tumor response and treatment-related toxicity. These thresholds are poorly studied in resin Y90, particularly in hepatocellular carcinoma (HCC). PURPOSE: To evaluate the efficacy of prospective voxel-based dosimetry for predicting treatment response and adverse events (AEs) in patients with HCC undergoing resin-based Y90 radioembolization. MATERIALS AND METHODS: This correlative study was based on a prospective single-arm clinical trial (NCT04172714), which evaluated the efficacy of low/scout (555 MBq) activity of resin-based Y90 for treatment planning. Partition model was used with goal of tumor dose (TD) > 200 Gy and non-tumoral liver dose (NTLD) < 70 Gy for non-segmental therapies. Single compartment dose of 200 Gy was used for segmentectomies. Prescribed Y90 activity minus scout activity was administered for therapeutic Y90 followed by Y90-PET/CT. Sureplan® (MIM Software, Cleveland, OH) was used for dosimetry analysis. Treatment response was evaluated at 3 and 6 months. Receiver operating characteristic curve determined TD response threshold for objective response (OR) and complete response (CR) as well as non-tumor liver dose (NTLD) threshold that predicted AEs. RESULTS: N = 30 patients were treated with 33 tumors (19 segmental and 14 non-segmental). One patient died before the first imaging, and clinical follow-up was excluded from this analysis. Overall, 26 (81%) of the tumors had an OR and 23 (72%) had a CR. A mean TD of 253 Gy predicted an OR with 92% sensitivity and 83% specificity (area under the curve (AUC = 0.929, p < 0.001). A mean TD of 337 Gy predicted a CR with 83% sensitivity and 89% specificity (AUC = 0.845, p < 0.001). A mean NTLD of 81 and 87 Gy predicted grade 3 AEs with 100% sensitivity and 100% specificity in the non-segmental cohort at 3- and 6-month post Y90, respectively. CONCLUSION: In patients with HCC undergoing resin-based Y90, there are dose response and dose toxicity thresholds directly affecting outcomes. CLINICAL TRIAL NUMBER: NCT04172714.

Real-world data from yttrium-90 ibritumomab tiuxetan treatment of relapsed or refractory indolent B-cell non-Hodgkin's lymphoma: J3Zi Study.

Yttrium-90 ibritumomab tiuxetan (90YIT) is a radioimmunotherapy agent in which the radioisotope yttrium-90 is bound to ibritumomab via tiuxetan as a chelating agent, and is used for relapsed or refractory low-grade B-cell non-Hodgkin's lymphoma (rr-B-NHL). We conducted a joint study to evaluate the clinical outcome of 90YIT. The J3Zi study is composed of data from patients receiving 90YIT for rr-B-NHL from the top three institutions with 10 years of 90YIT treatment experience from October 2008 to May 2018 in Japan. The efficacy, prognostic factors and safety of 90YIT were retrospectively evaluated. Data from 316 patients were analyzed; the mean age was 64.6 years and the median number of prior treatments was 2. The median PFS was 3.0 years, the final OS rate was over 60%, and the median OS was not reached during the study period. Significant factors influencing PFS were sIL-2R ≤ 500 (U/mL) and no disease progression within 24 months of first treatment. Significant factors influencing OS were number of prior treatments ≤ 2 and sIL-2R ≤ 500 (U/mL). The PFS and OS rates were found to be significantly higher in the late half era (2013 to 2018) than in the early half era (2008 to 2013) during the study period. Prognosis following 90YIT treatment was improved in the late half era compared to the early half era. As treatment using 90YIT increased, administration of 90YIT shifted to the earlier treatment line. This may have contributed to the improvement of prognosis found in the late era. (UMIN000037105).

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.

Evaluation of Atlas-based auto-segmentation of liver in MR images for Yttrium-90 selective internal radiation therapy.

PURPOSE: The aim was to explore the feasibility of applying an atlas-based auto-segmentation tool, MIM Atlas Segment, for liver delineation in MR images in Y-90 selective internal radiation therapy (SIRT). MATERIALS AND METHODS: MR images of 41 liver patients treated with resin Y-90 SIRT were included: 20 patients' images were used to create an atlas, and the other 21 patients' images were used for testing. Auto-segmentation of liver in the MR images was performed with MIM Atlas Segment, and various settings for the auto-segmentation (i.e., with and without normalized deformable registration, single atlas-match and multi-atlas match, and multi-atlas match using different finalization methods) were tested. Auto-segmented liver contours were compared with physician manually-delineated contours, using Dice similarity coefficient (DSC) and mean distance to agreement (MDA). Ratio of volume (RV) and ratio of activity (RA) were calculated to further evaluate the auto-segmentation results. RESULTS: Auto-segmentations with normalized deformable registration generated better contours than those without normalized deformable registration. With normalized deformable registration, 3-atlas match using Majority Vote (MV) method generated better results than single-atlas match and 3-atlas match using STAPLE method, and generated similar results as 5-atlas match using MV method or STAPLE method. The average DSC, MDA, and RV of the contours generated with normalized deformable registration are 0.80-0.83, 0.60-0.67, and 0.91-1.00 cm, respectively. The average RA are 1.00-1.01, which indicate that the activities calculated using the auto-segmented liver contours are close to the accurate activities. CONCLUSION: The atlas-based auto-segmentation can be applied to generate initial liver contours in MR images for resin Y-90 SIRT, which can be used for activity calculations after physicians review.

Hepatocellular carcinoma radiation segmentectomy treatment intensification prior to liver transplantation increases rates of complete pathologic necrosis: an explant analysis of 75 tumors.

PURPOSE: To verify the correlation between yttrium-90 glass microsphere radiation segmentectomy treatment intensification of hepatocellular carcinoma (HCC) and complete pathologic necrosis (CPN) at liver transplantation. METHODS: A retrospective, single center, analysis of patients with HCC who received radiation segmentectomy prior to liver transplantation from 2016 to 2021 was performed. The tumor treatment intensification cohort (n = 38) was prescribed radiation segmentectomy as per response recommendations identified in a previously published baseline cohort study (n = 37). Treatment intensification and baseline cohort treatment parameters were compared for rates of CPN. Both cohorts were then combined for an overall analysis of treatment parameter correlation with CPN. RESULTS: Sixty-three patients with a combined 75 tumors were analyzed. Specific activity, dose, and treatment activity were significantly higher in the treatment intensification cohort (all p < 0.01), while particles per cubic centimeter of treated liver were not. CPN was achieved in 76% (n = 29) of tumors in the treatment intensification cohort compared to 49% (n = 18) in the baseline cohort (p = 0.013). The combined cohort CPN rate was 63% (n = 47). ROC analysis showed that specific activity ≥ 327 Bq (AUC 0.75, p < 0.001), dose ≥ 446 Gy (AUC 0.69, p = 0.005), and treatment activity ≥ 2.55 Gbq (AUC 0.71, p = 0.002) were predictive of CPN. Multivariate logistic regression demonstrated that a specific activity ≥ 327 Bq was the sole independent predictor of CPN (p = 0.013). CONCLUSION: Radiation segmentectomy treatment intensification for patients with HCC prior to liver transplantation increases rates of CPN. While dose strongly correlated with pathologic response, specific activity was the most significant independent radiation segmentectomy treatment parameter associated with CPN.

A global evaluation of advanced dosimetry in transarterial radioembolization of hepatocellular carcinoma with Yttrium-90: the TARGET study.

PURPOSE: To investigate the relationships between tumor absorbed dose (TAD) or normal tissue absorbed dose (NTAD) and clinical outcomes in hepatocellular carcinoma (HCC) treated with yttrium-90 glass microspheres. METHODS: TARGET was a retrospective investigation in 13 centers across eight countries. Key inclusion criteria: liver-dominant HCC with or without portal vein thrombosis, < 10 tumors per lobe (at least one ≥ 3 cm), Child-Pugh stage A/B7, BCLC stages A-C, and no prior intra-arterial treatment. Multi-compartment pre-treatment dosimetry was performed retrospectively. Primary endpoint was the relationship between ≥ grade 3 hyperbilirubinemia (such that > 15% of patients experienced an event) without disease progression and NTAD. Secondary endpoints included relationships between (1) objective response (OR) and TAD, (2) overall survival (OS) and TAD, and (3) alpha fetoprotein (AFP) and TAD. RESULTS: No relationship was found between NTAD and ≥ grade 3 hyperbilirubinemia, which occurred in 4.8% of the 209 patients. The mRECIST OR rate over all lesions was 61.7%; for the target (largest) lesion, 70.8%. Responders and non-responders had geometric mean total perfused TADs of 225.5 Gy and 188.3 Gy (p = 0.048). Probability of OR was higher with increasing TAD (p = 0.044). Higher TAD was associated with longer OS (HR per 100 Gy increase = 0.83, 95% CI: 0.71-0.95; p = 0.009). Increased TAD was associated with higher probability of AFP response (p = 0.046 for baseline AFP ≥ 200 ng/mL). CONCLUSION: Real-world data confirmed a significant association between TAD and OR, TAD and OS, and TAD and AFP response. No association was found between ≥ grade 3 hyperbilirubinemia and NTAD. TRIAL REGISTRATION NUMBER: NCT03295006.

Dose-response relationship after yttrium-90-radioembolization with glass microspheres in patients with neuroendocrine tumor liver metastases.

BACKGROUND: In radioembolization, response is achieved through the irradiation and damaging of tumor DNA. For hepatic metastases of neuroendocrine tumors, a dose-response relationship has not been established yet. This study assesses whether increasing tumor-absorbed doses lead to increased response rates. METHODS: We included all patients who underwent yttrium-90 (90Y) glass microspheres radioembolization in our center if both pre- and post-treatment contrast-enhanced CT and post-injection PET/CT were available. Up to five hepatic tumors and the healthy hepatic tissue were delineated, and absorbed dose was quantified using post-injection PET/CT. Response was measured according to RECIST 1.1 on patient and tumor level. Linear mixed models were used to study the relationship between absorbed dose and response on tumor level. Logistic regression analysis was used on patient level to study dose-response and hepatic dose-toxicity relationships. RESULTS: A total of 128 tumors in 26 patients (31 procedures) were included in the response analysis. While correcting for confounding by tumor volume, a significant effect of response on dose was found (p = 0.0465). Geometric mean of absorbed dose for responding tumors was 170 Gy, for stable disease 101 Gy, and for progressive disease 67 Gy. No significant dose-toxicity relationship could be identified. CONCLUSION: In patients with neuroendocrine tumor liver metastases, treated with 90Y-radioembolization, a clear dose-response relationship was found. We propose to perform 90Y-radioembolization with an absolute minimum planned tumor-absorbed dose of 150 Gy.

Phase I prospective trial of TAS-102 (trifluridine and tipiracil) and radioembolization with 90Y resin microspheres for chemo-refractory colorectal liver metastases.

BACKGROUND: Extrahepatic disease progression limits clinical efficacy of Yttrium-90 (90Y) radioembolization (TARE) for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). Trifluridine and tipiracil (TAS-102) has overall survival benefit for patients with refractory mCRC and may be a radiosensitizer. METHODS: Sequential lobar TARE using 90Y resin microspheres in combination with TAS-102 in 28-day cycles were used to treat adult patients with bilobar liver-dominant chemo-refractory mCRC according to 3 + 3 dose escalation design with a 12-patient dose expansion cohort. Study objectives were to establish safety and determine maximum tolerated dose (MTD) of TAS-102 in combination with TARE. RESULTS: A total of 21 patients (14 women, 7 men) with median age of 60 years were enrolled. No dose limiting toxicities were observed. Treatment related severe adverse events included cytopenias (10 patients, 48%) and radioembolization-induced liver disease (2 patients, 10%). Disease control rate in the liver lobes treated with TARE was 100%. Best observed radiographic responses were partial response for 4 patients (19%) and stable disease for 12 patients (57%). CONCLUSIONS: The combination of TAS-102 and TARE for patients with liver-dominant mCRC is safe and consistently achieves disease control within the liver. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02602327 (first posted 11/11/2015).

90Y-Labeled Gold Nanoparticle Depot (NPD) Combined with Anti-PD-L1 Antibodies Strongly Inhibits the Growth of 4T1 Tumors in Immunocompetent Mice and Induces an Abscopal Effect on a Distant Non-Irradiated Tumor.

The effectiveness and normal tissue toxicity of a novel nanoparticle depot (NPD) brachytherapy seed incorporating gold nanoparticles (AuNPs) labeled with ß-particle emitting, 90Y (termed a "radiation nanomedicine"), were studied for the treatment of 4T1 triple-negative murine mammary carcinoma tumors in Balb/c mice and for inducing an abscopal effect on a distant non-irradiated tumor alone or combined with anti-PD-L1 immune checkpoint antibodies. Balb/c mice with two subcutaneous 4T1 tumors─a primary tumor and a distant secondary tumor were implanted intratumorally (i.t.) in the primary tumor with NPD incorporating 3.5 MBq of 90Y-AuNPs (1 × 1014 AuNPs) or unlabeled AuNPs, alone or combined with systemically administered anti-PD-L1 antibodies (200 µg i.p. three times/week for 2 weeks) or received anti-PD-L1 antibodies alone or no treatment. The primary tumor was strongly growth-inhibited over 14 d by NPD incorporating 90Y-AuNPs but only very modestly inhibited by NPD incorporating unlabeled AuNPs. Anti-PD-L1 antibodies alone were ineffective, and combining anti-PD-L1 antibodies with NPD incorporating 90Y-AuNPs did not further inhibit the growth of the primary tumor. Secondary tumor growth was inhibited by treatment of the primary tumor with NPD incorporating 90Y-AuNPs, and growth inhibition was enhanced by anti-PD-L1 antibodies. Treatment of the primary tumor with NPD incorporating unlabeled AuNPs or anti-PD-L1 antibodies alone had no effect on secondary tumor growth. Biodistribution studies showed high uptake of 90Y in the primary tumor [516-810% implanted dose/g (%ID/g)] but very low uptake in the secondary tumor (0.033-0.16% ID/g) and in normal tissues (<0.5% ID/g) except for kidneys (5-8% ID/g). Very high radiation absorbed doses were estimated for the primary tumor (472 Gy) but very low doses in the secondary tumor (0.13 Gy). There was highdose-heterogeneity in the primary tumor with doses as high as 9964 Gy in close proximity to the NPD, decreasing rapidly with distance from the NPD. Normal organ doses were low (<1 Gy) except for kidneys (4 Gy). No normal tissue toxicity was observed, but white blood cell counts (WBC) decreased in tumor-bearing mice treated with NPD incorporating 90Y-AuNPs. Decreased WBC counts were interpreted as tumor response and not toxicity since these were higher than that in healthy non-tumor-bearing mice, and there was a direct association between WBC counts and 4T1 tumor burden. We conclude that implantation of NPD incorporating 90Y-AuNPs into a primary 4T1 tumor in Balb/c mice strongly inhibited tumor growth and combined with anti-PD-L1 antibodies induced an abscopal effect on a distant secondary tumor. This radiation nanomedicine is promising for the local treatment of triple-negative breast cancer tumors in patients, and these therapeutic effects may extend to non-irradiated lesions, especially when combined with checkpoint immunotherapy.

Realized tumor to normal ratios in hepatocellular carcinoma patients undergoing transarterial radioembolization: a retrospective evaluation.

OBJECTIVES: To determine the realized tumor to normal ratios (TNRs) in patients undergoing radiation segmentectomies (RS); determine the relationship between TNRs and particle load in transarterial radioembolization (TARE). METHODS: In total, 148 patients who underwent 184 TARE procedures for hepatocellular carcinoma were evaluated. Post treatment SPECT CT bremsstrahlung imaging was analyzed utilizing Simplicit90y™ to determine realized TNR. A model which normalized activity across all RS treatments to a level that would achieve 400 Gy by unicompartmental dosing was created to determine the affect realized TNR would have on tumor absorbed dose. RESULTS: The mean TNR in the setting of RS was 2.88 ± 1.60 and was higher for glass as compared to resin microspheres (3.07 ± 1.68 vs 2.24 ± 1.21, p = 0.01). The TNR was significantly greater in the RS as compared to the lobar deliveries (2.88 ± 1.60 vs 2.16 ± 1.12, p < 0.01). When normalizing the activity of RS treatments to the level required to achieve 400 Gy by unicompartmental calculations, there was found to be significant differences in the predicted tumor absorbed dose when separated by the median tumor dose (601.2 ± 133.3 vs 1146.9 ± 297.5, p < 0.01) or median realized TNR (1119.2 ± 341 Gy vs 635.7 ± 160.2 Gy, p < 0.01). Particle load was found to be associated with TNR on univariate (p < 0.01) and multivariate (p < 0.01) analysis. CONCLUSION: Significant TNRs are seen in RS and perhaps argue for the use of multi-compartmental dosimetry techniques in this setting and particle load may affect TNR. KEY POINTS: • Tumor to normal ratios were significantly higher in radiation segmentectomies than lobar deliveries. • Tumor to normal ratios were significantly higher when utilizing glass, as compared to resin microspheres. • When creating a model that prescribed the activity required to reach 400 Gy by MIRD, realized tumor dose varied significantly in radiation segmentectomies.