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.

Monte Carlo-derived 99m Tc uptake quantification with commercial planar MBI: Tumor and breast activity concentrations.

BACKGROUND: Current molecular breast imaging (MBI) images are limited to qualitative evaluation, not absolute measurement, of 99m Tc uptake in benign and malignant breast tissues. PURPOSE: This work assesses the accuracy of previously-published and newly-proposed tumor and normal breast tissue 99m Tc uptake MBI measurements using simulations of a commercial dual-headed planar MBI system under typical clinical and acquisition protocols. METHODS: Quantification techniques were tested in over 4000 simulated acquisitions of spherical and ellipsoid tumors with clinically relevant uptake conditions using a validated Monte Carlo application of the GE Discovery NM750b system. The evaluated techniques consisted of four tumor total activity methodologies (two single-detector-based and two geometric-mean-based), two tumor MBI volume methodologies (diameter-based and ROI-based), and two normal tissue activity concentration methodologies (single-detector-based and geometric-mean-based). The most accurate of these techniques were then used to estimate tumor activity concentrations and tumor to normal tissue relative activity concentrations (RC). RESULTS: Single-detector techniques for tumor total activity quantification achieved mean (standard deviation) relative errors of 0.2% (4.3%) and 1.6% (4.4%) when using the near and far detector images, respectively and were more accurate and precise than the measured 8.1% (5.8%) errors of a previously published geometric-mean technique. Using these activity estimates and the true tumor volumes resulted in tumor activity concentration and RC errors within 10% of simulated values. The precision of tumor activity concentration and RC when using only MBI measurements were largely driven by the errors in estimating tumor MBI volume using planar images (± 30% inter-quartile range). CONCLUSIONS: Planar MBI images were shown to accurately and reliably be used to estimate tumor total activities and normal tissue activity concentrations in this simulation study. However, volumetric tumor uptake measurements (i.e., absolute and relative concentrations) are limited by inaccuracies in MBI volume estimation using two-dimensional images, highlighting the need for either tomographic MBI acquisitions or anatomical volume estimates for accurate three-dimensional tumor uptake estimates.

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.

Accuracy and Safety of Scout Dose Resin Yttrium-90 Microspheres for Radioembolization Therapy Treatment Planning: A Prospective Single-Arm Clinical Trial.

PURPOSE: To compare the accuracy and safety of 0.56 GBq resin yttrium-90 (90Y) (scout90Y) microspheres with those of technetium-99m macroaggregated albumin (MAA) in predicting the therapeutic 90Y (Rx90Y) dose for patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This prospective single-arm clinical trial (Clinicaltrials.gov: NCT04172714) recruited patients with HCC. Patients underwent same-day mapping with MAA and scout90Y. Rx90Y activity was administered 3 days after mapping. Using paired t test and Pearson correlation, the tumor-to-normal ratio (TNR), lung shunt fraction (LSF), predicted mean tumor dose (TD), and nontumoral liver dose (NTLD) by MAA and scout90Y were compared with those by Rx90Y. Bland-Altman plots compared the level of agreement between the TNR and LSF of scout90Y and MAA with that of Rx90Y. The safety of scout90Y was evaluated by examining the discrepancy in extrahepatic activity between MAA and scout90Y. RESULTS: Thirty patients were treated using 19 segmental and 14 nonsegmental (ie, 2 contiguous segments or nonsegmental) therapies. MAA had weak LSF, moderate TNR, and moderate TD linear correlation with Rx90Y. Scout90Y had a moderate LSF, strong TNR, strong TD, and very strong NTLD in correlation with those of Rx90Y. Furthermore, the TNR and LSF of scout90Y had a stronger agreement with those of Rx90Y than with those of MAA. In the nonsegmental subgroup, MAA had no significant correlation with the TD and NTLD of Rx90Y, whereas scout90Y had a very strong correlation with both of these factors. In the segmental subgroup, both MAA and scout90Y had a strong linear correlation with the TD and NTLD of Rx90Y. CONCLUSIONS: Compared with MAA, scout90Y is a more accurate surrogate for Rx90Y biodistribution for nonsegmental therapies.

Functional tumor diameter measurement with molecular breast imaging: development and clinical application.

Purpose: Molecular breast imaging (MBI) is used clinically to visualize the uptake of99mTc-sestamibi in breast cancers. Here, we use Monte Carlo simulations to develop a methodology to estimate tumor diameter in focal lesions and explore a semi-automatic implementation for clinical data.Methods: A validated Monte Carlo simulation of the GE Discovery NM 750b was used to simulate >75,000 unique spherical/ellipsoidal tumor, normal breast, and image acquisition conditions. Subsets of this data were used to 1) characterize the dependence of the full-width at half-maximum (FWHM) of a tumor profile on tumor, normal breast, and acquisition conditions, 2) develop a methodology to estimate tumor diameters, and 3) quantify the diameter accuracy in a broad range of clinical conditions. Finally, the methodology was implemented in patient images and compared to diameter estimates from physician contours on MBI, mammography, and ultrasound imaging.Results: Tumor profile FWHM was determined be linearly dependent on tumor diameter but independent of other factors such as tumor shape, uptake, and distance from the detector. A linear regression was used to calculate tumor diameter from the FWHM estimated from a background-corrected profile across a tumor extracted from a median-filtered single-detector MBI image, i.e., diameter = 1.2 mm + 1.2 × FWHM, for FWHM ≥ 13 mm. Across a variety of simulated clinical conditions, the mean error of the methodology was 0.2 mm (accuracy), with >50% of cases estimated within 1-pixel width of the truth (precision). In patient images, the semi-automatic methodology provided the longest diameter in 94% (60/64) of cases. The estimated true diameters, for oval lesions with homogeneous uptake, differed by ± 5 mm from physician measurements.Conclusion: This work demonstrates the feasibility of accurately quantifying tumor diameter in clinical MBI, and to our knowledge, is the first to explore its implementation and application in patient data.

Single-Photon Emission Computed Tomographic Reverse Lymphatic Mapping for Groin Vascularized Lymph Node Transplant Planning.

BACKGROUND: Superficial inguinal (groin) vascularized lymph node transplantation is the most common option for the treatment of lymphedema, particularly in combination with free abdominal flap breast reconstruction. This study examines the utility of single-photon emission computed tomographic (SPECT/CT) lymphoscintigraphy for lower extremity reverse lymphatic mapping in presurgical planning for groin vascularized lymph node transplantation and appraises the physiologic lymphatic drainage to the superficial inguinal lymph nodes. METHODS: All patients who underwent bilateral lower extremity SPECT/CT reverse lymphatic mapping over a 5-year period were included. Retrospective case note analysis was performed to collect demographic, surgical, and outcomes data. RESULTS: The study included 84 patients; 56 of these subsequently underwent groin vascularized lymph node transplantation (58 flaps). Fifty-four of these flaps were combined with free abdominal flaps for breast reconstruction (55 flaps). Using SPECT/CT reverse lymphatic mapping investigation of 168 inguinal regions, drainage to at least one superficial inguinal region was visualized in 38.1 percent of patients; in 13.1 percent, drainage was visualized to both superficial inguinal regions. Using this information for presurgical planning, groin vascularized lymph node flap harvest was performed from the contralateral side in 57 of 58 cases (98.3 percent) using intraoperative gamma probe guidance, and no patient developed donor lower extremity lymphedema during follow-up (mean ± SD, 34.5 ± 15.4 months). CONCLUSIONS: The authors' use of presurgical SPECT/CT reverse lymphatic mapping together with limited flap dissection and intraoperative gamma probe guidance resulted in no clinical cases of iatrogenic donor lower extremity lymphedema. The high incidence of drainage from the lower extremity to the superficial inguinal region mandates the use of reverse lymphatic mapping when performing groin vascularized lymph node transplantation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Factors modulating 99m Tc-MAA planar lung dosimetry for 90 Y radioembolization.

PURPOSE: To investigate the accuracy and biases of predicted lung shunt fraction (LSF) and lung dose (LD) calculations via 99m Tc-macro-aggregated albumin (99m Tc-MAA) planar imaging for treatment planning of 90 Y-microsphere radioembolization. METHODS AND MATERIALS: LSFs in 52 planning and LDs in 44 treatment procedures were retrospectively calculated, in consecutive radioembolization patients over a 2 year interval, using 99m Tc-MAA planar and SPECT/CT imaging. For each procedure, multiple planar LSFs and LDs were calculated using different: (1) contours, (2) views, (3) liver 99m Tc-MAA shine-through compensations, and (4) lung mass estimations. The accuracy of each planar-based LSF and LD methodology was determined by calculating the median (range) absolute difference from SPECT/CT-based LSF and LD values, which have been demonstrated in phantom and patient studies to more accurately and reliably quantify the true LSF and LD values. RESULTS: Standard-of-care LSF using geometric mean of lung and liver contours had median (range) absolute over-estimation of 4.4 percentage points (pp) (0.9 to 11.9 pp) from SPECT/CT LSF. Using anterior views only decreased LSF errors (2.4 pp median, -1.1 to +5.7 pp range). Planar LD over-estimations decreased when using single-view versus geometric-mean LSF (1.3 vs. 2.6 Gy median and 7.2 vs. 18.5 Gy maximum using 1000 g lung mass) but increased when using patient-specific versus standard-man lung mass (2.4 vs. 1.3 Gy median and 11.8 vs. 7.2 Gy maximum using single-view LSF). CONCLUSIONS: Calculating planar LSF from lung and liver contours of a single view and planar LD using that same LSF and 1000 g lung mass was found to improve accuracy and minimize bias in planar lung dosimetry.

Organ-level internal dosimetry for intra-hepatic-arterial administration of 99m Tc-macroaggregated albumin.

PURPOSE: There are no published data on organ doses following intra-hepatic-arterial administration of 99m Tc-macroaggregated-albumin (IHA 99m Tc-MAA) routinely used in 90 Y-radioembolization treatment planning to assess intra- and extra-hepatic depositions and calculate lung-shunt-fraction (LSF). We propose a method to model the organ doses following IHA 99m Tc-MAA that incorporates three in vivo constituent biodistributions, the 99m Tc-MAA that escape the liver due to LSF, and the 99m Tc-MAA dissociation fraction (DF). METHODS: The potential in vivo biodistributions for IHA 99m Tc-MAA are: Liver-Only MAA with all activity sequestered in the liver (LSF = 0&DF = 0), Intravenous MAA with all activity transferred intravenously as 99m Tc-MAA (LSF = 1&DF = 0), and Intravenous Pertechnetate with all activity is transferred intravenously as 99m Tc-pertechnetate (LSF = 0&DF = 1). Organ doses for Liver-Only MAA were determined using OLINDA/EXM 2.2, where liver was modeled as the source organ containing 99m Tc-MAA, while those for Intravenous MAA and Intravenous Pertechnetate were from ICRP 128. Organ doses for the general case can be determined as a weighted-linear-combination of the three constituent biodistributions depending on the LSF and DF. The maximum-dose scenario was modeled by selecting the highest dose rate for each organ amongst the three constituent cases. RESULTS: For Liver-Only MAA, the liver as source organ received the highest dose at 98.6 and 126 mGy/GBq for the adult male and adult female phantoms, respectively; all remaining organs received <27 and <32 mGy/GBq. For Intravenous MAA, the lung as source organ received the highest dose at 66 and 97 mGy/GBq; all remaining organs received <16 and <21 mGy/GBq. The organ with the highest dose for Intravenous Pertechnetate was the upper-large-intestinal wall at 56 and 73 mGy/GBq; all remaining organs received <26 and <34 mGy/GBq. The liver and lung doses for the maximum-dose scenario with 5 mCi (185 MBq) 99m Tc-MAA were estimated at 18.2 and 12.2 mGy, and 23.3 and 17.9 mGy, for the adult male and adult female phantoms, respectively. CONCLUSION: Organ dose estimates following IHA 99m Tc-MAA based on constituent biodistribution models and patient-specific LSF and DF values have been derived. Liver and lung were the organs with highest dose, receiving at most 15-25 mGy in the maximum-dose scenario, following 5 mCi IHA 99m Tc-MAA.

The American Brachytherapy Society consensus statement for permanent implant brachytherapy using Yttrium-90 microsphere radioembolization for liver tumors.

PURPOSE: To develop a multidisciplinary consensus for high quality multidisciplinary implementation of brachytherapy using Yttrium-90 (90Y) microspheres transarterial radioembolization (90Y TARE) for primary and metastatic cancers in the liver. METHODS AND MATERIALS: Members of the American Brachytherapy Society (ABS) and colleagues with multidisciplinary expertise in liver tumor therapy formulated guidelines for 90Y TARE for unresectable primary liver malignancies and unresectable metastatic cancer to the liver. The consensus is provided on the most recent literature and clinical experience. RESULTS: The ABS strongly recommends the use of 90Y microsphere brachytherapy for the definitive/palliative treatment of unresectable liver cancer when recommended by the multidisciplinary team. A quality management program must be implemented at the start of 90Y TARE program development and follow-up data should be tracked for efficacy and toxicity. Patient-specific dosimetry optimized for treatment intent is recommended when conducting 90Y TARE. Implementation in patients on systemic therapy should account for factors that may enhance treatment related toxicity without delaying treatment inappropriately. Further management and salvage therapy options including retreatment with 90Y TARE should be carefully considered. CONCLUSIONS: ABS consensus for implementing a safe 90Y TARE program for liver cancer in the multidisciplinary setting is presented. It builds on previous guidelines to include recommendations for appropriate implementation based on current literature and practices in experienced centers. Practitioners and cooperative groups are encouraged to use this document as a guide to formulate their clinical practices and to adopt the most recent dose reporting policies that are critical for a unified outcome analysis of future effectiveness studies.

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.

A prospective, multicenter, open-label, single-arm clinical trial design to evaluate the safety and efficacy of 90Y resin microspheres for the treatment of unresectable HCC: the DOORwaY90 (Duration Of Objective Response with arterial Ytrrium-90) study.

BACKGROUND: Selective internal radiation therapy (SIRT) with yttrium-90 (90Y) resin microspheres is an established locoregional treatment option for unresectable hepatocellular carcinoma (HCC), which delivers a lethal dose of radiation to hepatic tumors, while sparing surrounding healthy tissue. DOORwaY90 is a prospective, multicenter, open-label, single arm study, designed to evaluate the safety and effectiveness of 90Y resin microspheres as first-line treatment in patients with unresectable/unablatable HCC. It is unique in that it is the first study with resin microspheres to utilize a personalized 90Y dosimetry approach, and independent review for treatment planning and response assessment. METHODS: Eligibility criteria include unresectable/unablatable HCC, Barcelona Clinic Liver Cancer stage A, B1, B2, or C with a maximal single tumor diameter of ≤ 8 cm, and a sum of maximal tumor diameters of ≤ 12 cm, and at least one tumor ≥ 2 cm (long axis) per localized, modified Response Evaluation Criteria in Solid Tumors. Partition model dosimetry is used to determine the optimal dose; the target mean dose to tumor is ≥ 150 Gy. Patients are assessed at baseline and at regular intervals up until 12 months of treatment for response rates, safety, and quality of life (QoL). Post-treatment dosimetry is used to assess dose delivered to tumor and consider if retreatment is necessary. The co-primary endpoints are best objective response rate and duration of response. Secondary endpoints include grade ≥ 3 toxicity, QoL, and incidence of liver resection and transplantation post SIRT. Target recruitment is 100 patients. DISCUSSION: The results of this trial should provide further information on the potential use of SIRT with 90Y resin microspheres as first-line therapy for unresectable HCC. TRIAL REGISTRATION: Clinicaltrials.gov; NCT04736121; date of 1st registration, January 27, 2021, https://clinicaltrials.gov/ct2/show/NCT04736121 .

Precision dosimetry in yttrium-90 radioembolization through CT imaging of radiopaque microspheres in a rabbit liver model.

PURPOSE: To perform precision dosimetry in yttrium-90 radioembolization through CT imaging of radiopaque microspheres in a rabbit liver model and to compare extracted dose metrics to those produced from conventional PET-based dosimetry. MATERIALS AND METHODS: A CT calibration phantom was designed containing posts with nominal microsphere concentrations of 0.5 mg/mL, 5.0 mg/mL, and 25.0 mg/mL. The mean Hounsfield unit was extracted from the post volumes to generate a calibration curve to relate Hounsfield units to microsphere concentration. A nominal bolus of 40 mg of microspheres was administered to the livers of eight rabbits, followed by PET/CT imaging. A CT-based activity distribution was calculated through the application of the calibration curve to the CT liver volume. Post-treatment dosimetry was performed through the convolution of yttrium-90 dose-voxel kernels and the PET- and CT-based cumulated activity distributions. The mean dose to the liver in PET- and CT-based dose distributions was compared through linear regression, ANOVA, and Bland-Altman analysis. RESULTS: A linear least-squares fit to the average Hounsfield unit and microsphere concentration data from the calibration phantom confirmed a strong correlation (r2 > 0.999) with a slope of 14.13 HU/mg/mL. A poor correlation was found between the mean dose derived from CT and PET (r2 = 0.374), while the ANOVA analysis revealed statistically significant differences (p < 10-12) between the MIRD-derived mean dose and the PET- and CT-derived mean dose. Bland-Altman analysis predicted an offset of 15.0 Gy between the mean dose in CT and PET. The dose within the liver was shown to be more heterogeneous in CT than in PET with an average coefficient of variation equal to 1.99 and 1.02, respectively. CONCLUSION: The benefits of a CT-based approach to post-treatment dosimetry in yttrium-90 radioembolization include improved visualization of the dose distribution, reduced partial volume effects, a better representation of dose heterogeneity, and the mitigation of respiratory motion effects. Post-treatment CT imaging of radiopaque microspheres in yttrium-90 radioembolization provides the means to perform precision dosimetry and extract accurate dose metrics used to refine the understanding of the dose-response relationship, which could ultimately improve future patient outcomes.

A Prospective Comparative Study of Using Ultrasonography, 4D-CT and Parathyroid Dual-Phase Scintigraphy with SPECT in Patients with Primary Hyperparathyroidism.

Thirty-one consecutive patients were included in this study who were planned for parathyroidectomy due to primary hyperparathyroidism. They were studied with US, 4D-CT and dual-phase scintigraphy including SPECT/CT, and possible adenomas were identified in each imaging modality. Imaging data were quantified with US, CT and SPECT. Parathyroidectomies were performed as minimally invasive according to preoperative imaging findings. A total of 16 adenomas were found in 15 patients, and the surgery was negative in four patients. The imaging results were compared with each other and correlated to histology findings and blood biochemistry (S-Ca and P-PTH). Quantitative SPECT found a strong correlation between the quantification methods-Conjugate Gradient with Attenuation and Scatter Correction with a zone map (CGZAS) and Conjugate Gradient with Attenuation and Scatter Correction (CGAS)-measured as SUVmax and kBq/mL. However, a statistically significant correlation between the quantitative parameters (CGZAS and CGAS) and serum biomarkers (S-PTH and S-Ca) was not observed. The sensitivities of the imaging methods were calculated using histopathology as a gold standard. SPECT/CT demonstrated 93% sensitivity, 4D-CT 93% sensitivity and ultrasonography 73% sensitivity. The imaging methods were compared with each other using parathyroid regions because findings and locations varied between the modalities. Our prospective study supports that quantitative SPECT/CT is useful for presurgical assessment of primary hyperparathyroidism.

A Prospective Phase II Study of Safety and Efficacy of Sorafenib Followed by 90Y Glass Microspheres for Patients with Advanced or Metastatic Hepatocellular Carcinoma.

PURPOSE: The most common cause of death in advanced/metastatic hepatocellular carcinoma (HCC) is liver failure due to tumor progression. While retrospective studies and meta-analyses of systemic therapy combined with liver-directed therapy have been performed, prospective studies of safety/efficacy of antiangiogenesis followed by intra-arterial therapies are lacking. We tested our hypothesis that sorafenib followed by yttrium 90 glass microspheres (90Y GMs) is safe and that survival outcomes may improve by controlling hepatic tumors. METHODS: We enrolled 38 Child-Pugh A patients with advanced/metastatic HCC. In sum, 34 received sorafenib, followed after 4 weeks by 90Y GMs. Analysis of safety and survival outcomes was performed to assess adverse events, median progression-free survival, and overall survival. RESULTS: A total of 34 patients were evaluable: 14 (41.2%) with chronic hepatitis, nine (26.5%) with vascular invasion, and eleven (32.4%) with extrahepatic diseases. Safety analysis revealed that the combination therapy was well tolerated. Grade III-IV adverse events comprised fatigue (n=3), diarrhea (n=2), nausea (n=1), vomiting (n=2), hypertension (n=4), thrombocytopenia (n=1), hyperbilirubinemia (n=1), proteinuria (n=1), hyponatremia (n=1), and elevated alanine or aspartate aminotransferase (n=5). Median progression-free and overall survival were 10.4 months (95% CI 5.8-14.4) and 13.2 months (95% CI 7.9-18.9), respectively. Twelve patients (35.3%) achieved partial responses and 16 (47.0%) stable disease. Median duration of sorafenib was 20 (3-90) weeks, and average dose was 622 (466-800) mg daily. Dosimetry showed similar mean doses between planned and delivered calculations to normal liver and tumor:normal liver uptake ratio, with no significant correlation with adverse events at 3 and 6 months post-90Y treatment. CONCLUSION: This is the first prospective study to evaluate sorafenib followed by 90Y in patients with advanced HCC. The study validated our hypothesis of safety with encouraging efficacy signals of the sequencing treatment, and provides proof of concept for future combination modalities for patients with advanced or metastatic HCC. CLINICAL TRIAL REGISTRATION NUMBER: NCT01900002.

Reassessment of the lung dose limits for radioembolization.

Radioembolization, also known as selective internal radiation therapy (SIRT), is an established treatment for the management of patients with unresectable liver tumors. Advances in liver dosimetry and new knowledge about tumor dose-response relationships have helped promote the well-tolerated use of higher prescribed doses, consequently transitioning radioembolization from palliative to curative therapy. Lung dosimetry, unfortunately, has not seen the same advances in dose calculation methodology and renewed consensus in dose limits as normal liver and tumor dosimetry. Therefore, the efficacy of curative radioembolization may be compromised in patients where the current lung dose calculations unnecessarily limit the administered activity. The field is thus at a stage where a systematic review and update of lung dose limits is necessary to advance the clinical practice of radioembolization. This work summarizes the historical context and literature for origins of the current lung dose limits following radioembolization, that is, the 25-year-old, single institution, small patient cohort series that helped establish the lung shunt fraction and dose limits. Newer clinical evidence based on larger patient cohorts that challenges the historical data on lung dose limits are then discussed. We conclude by revisiting the rationale for current lung dose limits and by proposing a staged approach to advance the field of lung dosimetry and thus the practice of radioembolization as a whole.

Monte Carlo simulation of pixelated CZT detector with Geant4: validation of clinical molecular breast imaging system.

Purpose. Molecular breast imaging (MBI) of99mTc-sestamibi with dual-headed, pixelated, cadmium-zinc-telluride (CZT) detectors is increasingly used in breast cancer care for screening/detecting lesions, monitoring response to therapy, and predicting risk of cancer. MBI as a truly quantitative tool in these applications, however, is limited due the lack of absolute99mTc-sestamibi uptake quantification. To help advance the field of quantitative MBI, we have developed a Monte Carlo simulation application of the GE Discovery NM 750b system.Methods. Our simulation consists of a two-step process using the Geant4 toolkit to model the detector and source geometry and to track photon interactions and a MATLAB script to model the charge transport within the pixelated CZT detector. Simulated detector and detector response model parameters were selected to match measured and simulated standard performance characteristics using various99mTc point-, line-, and film-sources in air. The final model parameters were verified by comparing the count profiles, energy spectra, and region of interest counts between simulated and measured images of a breast phantom with two spherical lesions in 5 cm thick medium of air or water.Results. Final performance characteristics with99mTc sources in air were: (1) energy resolution: 6.1% measured versus 5.9% simulated photopeak full-width at half-maximum (FWHM), (2) spatial resolution: mean error between measured and simulated FWHM of 0.08 mm across 4.4-14.0 mm FWHM range, and (3) sensitivity: 572 cpm/µCi measured versus 567 cpm/µCi simulated (<1% error). Good agreement was observed in the breast phantom line profiles through the spherical lesions and overall energy spectra, with <5% difference in sphere counts between simulated and measured data.Conclusion. A pixelated CZT charge transport and induction model was successfully implemented and validated to simulate imaging with the GE Discovery NM 750b system. This work will enable investigations improving MBI image quality and developing algorithms for uptake quantification.

Post-administration dosimetry in yttrium-90 radioembolization through micro-CT imaging of radiopaque microspheres in a porcine renal model.

The purpose of this study is to perform post-administration dosimetry in yttrium-90 radioembolization through micro-CT imaging of radiopaque microsphere distributions in a porcine renal model and explore the impact of spatial resolution of an imaging system on the extraction of specific dose metrics. Following the administration of radiopaque microspheres to the kidney of a hybrid farm pig, the kidney was explanted and imaged with micro-CT. To produce an activity distribution, 400 MBq of yttrium-90 activity was distributed throughout segmented voxels of the embolized vasculature based on an established linear relationship between microsphere concentration and CT voxel value. This distribution was down-sampled to coarser isotropic grids ranging in voxel size from 2.5 to 15 mm to emulate nominal resolutions comparable to those found in yttrium-90 PET and Bremsstrahlung SPECT imaging. Dose distributions were calculated through the convolution of activity distributions with dose-voxel kernels generated using the GATE Monte Carlo toolkit. Contours were computed to represent normal tissue and target volumes. Dose-volume histograms, dose metrics, and dose profiles were compared to a ground truth dose distribution computed with GATE. The mean dose to the target for all studied voxel sizes was found to be within 5.7% of the ground truth mean dose.D70was shown to be strongly correlated with image voxel size of the dose distribution (r2 = 0.90).D70is cited in the literature as an important dose metric and its dependence on voxel size suggests higher resolution dose distributions may provide new perspectives on dose-response relationships in yttrium-90 radioembolization. This study demonstrates that dose distributions with large voxels incorrectly homogenize the dose by attributing escalated doses to normal tissues and reduced doses in high-dose target regions. High-resolution micro-CT imaging of radiopaque microsphere distributions can provide increased confidence in characterizing the absorbed dose heterogeneity in yttrium-90 radioembolization.