Linear Boltzmann equation solver for voxel-level dosimetry in radiopharmaceutical therapy: Comparison with Monte Carlo and kernel convolution.

BACKGROUND: With recent interest in patient-specific dosimetry for radiopharmaceutical therapy (RPT) and selective internal radiation therapy (SIRT), an increasing number of voxel-based algorithms are being evaluated. Monte Carlo (MC) radiation transport, generally considered to be the most accurate among different methods for voxel-level absorbed dose estimation, can be computationally inefficient for routine clinical use. PURPOSE: This work demonstrates a recently implemented grid-based linear Boltzmann transport equation (LBTE) solver for fast and accurate voxel-based dosimetry in RPT and SIRT and benchmarks it against MC. METHODS: A deterministic LBTE solver (Acuros MRT) was implemented within a commercial RPT dosimetry package (Velocity 4.1). The LBTE is directly discretized using an adaptive mesh refined grid and then the coupled photon-electron radiation transport is iteratively solved inside specified volumes to estimate radiation doses from both photons and charged particles in heterogeneous media. To evaluate the performance of the LBTE solver for RPT and SIRT applications, 177 Lu SPECT/CT, 90 Y PET/CT, and 131 I SPECT/CT images of phantoms and patients were used. Multiple lesions (2-1052 mL) and normal organs were delineated for each study. Voxel dosimetry was performed with the LBTE solver, dose voxel kernel (DVK) convolution with density correction, and a validated in-house MC code using the same time-integrated activity and density maps as input to the different dose engines. The resulting dose maps, difference maps, and dose-volume-histogram (DVH) metrics were compared, to assess the voxel-level agreement. Evaluation of mean absorbed dose included comparison with structure-level estimates from OLINDA. RESULTS: In the phantom inserts/compartments, the LBTE solver versus MC and DVK convolution demonstrated good agreement with mean absorbed dose and DVH metrics agreeing to within 5% except for the D90 and D70 metrics of a very low activity concentration insert of 90 Y where the agreement was within 15%. In the patient studies (five patients imaged after 177 Lu DOTATATE RPT, five after 90 Y SIRT, and two after 131 I radioimmunotherapy), in general, there was better agreement between the LBTE solver and MC than between LBTE solver and DVK convolution for mean absorbed dose and voxel-level evaluations. Across all patients for all three radionuclides, for soft tissue structures (kidney, liver, lesions), the mean absorbed dose estimates from the LBTE solver were in good agreement with those from MC (median difference < 1%, maximum 9%) and those from DVK (median difference < 5%, maximum 9%). The LBTE and OLINDA estimates for mean absorbed dose in kidneys and liver agreed to within 10%, but differences for lesions were larger with a maximum 14% for 177 Lu, 23% for 90 Y, and 26% for 131 I. For bone regions, the agreement in mean absorbed doses between LBTE and both MC and DVK were similar (median < 11%, max 11%) while for lung the agreement between LBTE and MC (median < 1%, max 8%) was substantially better than between LBTE and DVK (median < 16%, max 33%). Voxel level estimates for soft tissue structures also showed good agreement between the LBTE solver and both MC and DVK with a median difference < 5% (maximum < 13%) for the DVH metrics with all three radionuclides. The largest difference in DVH metrics was for the D90 and D70 metric in lung and bone where the uptake was low. Here, the difference between LBTE and MC had a median value < 14% (maximum 23%) for bone and < 4% (maximum 37%) for lung, while the corresponding differences between LBTE and DVK were < 23% (maximum 31%) and < 67% (maximum 313%), respectively. For a typical patient with a matrix size of 166 × 166 × 129 (voxel size 3 × 3 × 3 mm3 ), voxel dosimetry using the LBTE solver was as fast as ∼2 min on a desktop computer. CONCLUSION: Having established good agreement between the LBTE solver and MC for RPT and SIRT applications, the LBTE solver is a viable option for voxel dosimetry that can be faster than MC. Further analysis is being performed to encompass the broad range of radionuclides and conditions encountered clinically.

Stereotactic body radiation therapy (SBRT) following Yttrium-90 (90Y) selective internal radiation therapy (SIRT): a feasibility planning study using90Y delivered dose.

Objective.90Y selective internal radiation therapy (SIRT) treatment of hepatocellular carcinoma (HCC) can potentially underdose lesions, as identified on post-therapy PET/CT imaging. This study introduces a methodology and explores the feasibility for selectively treating SIRT-underdosed HCC lesions, or lesion subvolumes, with stereotactic body radiation therapy (SBRT) following post-SIRT dosimetry.Approach. We retrospectively analyzed post-treatment PET/CT images of 20 HCC patients after90Y SIRT. Predicted tumor response from SIRT was quantified based on personalized post-therapy dosimetry and corresponding response models. Predicted non-responding tumor regions were then targeted with a hypothetical SBRT boost plan using a framework for selecting eligible tumors and tumor subregions. SBRT boost plans were compared to SBRT plans targeting all tumors irrespective of SIRT dose with the same prescription and organ-at-risk (OAR) objectives. The potential benefit of SIRT followed by a SBRT was evaluated based on OAR dose and predicted toxicity compared to the independent SBRT treatment.Main results. Following SIRT, 14/20 patients had at least one predicted non-responding tumor considered eligible for a SBRT boost. When comparing SBRT plans, 10/14 (71%) SBRTboostand 12/20 (60%) SBRTaloneplans were within OAR dose constraints. For three patients, SBRTboostplans were within OAR constraints while SBRTaloneplans were not. Across the 14 eligible patients, SBRTboostplans had significantly less dose to the healthy liver (decrease in mean dose was on average ± standard deviation, 2.09 Gy ± 1.99 Gy, ) and reduced the overall targeted PTV volume (39% ± 21%) compared with SBRTalone.Significance. A clinical methodology for treating HCC using a synergized SIRT and SBRT approach is presented, demonstrating that it could reduce normal tissue toxicity risk in a majority of our retrospectively evaluated cases. Selectively targeting SIRT underdosed HCC lesions, or lesion subvolumes, with SBRT could improve tumor control and patient outcomes post-SIRT and allow SIRT to function as a target debulking tool for cases when SBRT is not independently feasible.

A Multicenter Study on Observed Discrepancies Between Vendor-Stated and PET-Measured 90Y Activities for Both Glass and Resin Microsphere Devices.

Dosimetry-guided treatment planning in selective internal radiation therapy relies on accurate and reproducible measurement of administered activity. This 4-center, 5-PET-device study compared the manufacturer-declared 90Y activity in vials with quantitative 90Y PET/CT assessment of the same vials. We compared 90Y PET-measured activity (APET) for 56 90Y-labeled glass and 18 90Y-labeled resin microsphere vials with the calibrated activity specified by the manufacturer (AM). Additionally, the same analysis was performed for 4 90Y-chloride vials. The mean APET/AM ratio was 0.79 ± 0.04 (range, 0.71-0.89) for glass microspheres and 1.15 ± 0.06 (range, 1.05-1.25) for resin microspheres. The mean APET/AM ratio for 90Y-chloride vials was 1.00 ± 0.04 (range, 0.96-1.06). Thus, we found an average difference of 46% between glass and resin microsphere activity calibrations, whereas close agreement was found for chloride solutions. We expect that the reported discrepancies will promote further investigations to establish reliable and accurate patient dosimetry and dose-effect assessments.

Experimental validation of Monte Carlo dosimetry for therapeutic beta emitters with radiochromic film in a 3D-printed phantom.

PURPOSE: Validation of dosimetry software, such as Monte Carlo (MC) radiation transport codes used for patient-specific absorbed dose estimation, is critical prior to their use in clinical decision making. However, direct experimental validation in the clinic is generally not performed for low/medium-energy beta emitters used in radiopharmaceutical therapy (RPT) due to the challenges of measuring energy deposited by short-range particles. Our objective was to design a practical phantom geometry for radiochromic film (RF)-based absorbed dose measurements of beta-emitting radionuclides and perform experiments to directly validate our in-house developed Dose Planning Method (DPM) MC code dedicated to internal dosimetry. METHODS: The experimental setup was designed for measuring absorbed dose from beta emitters that have a range sufficiently penetrating to ∼200 µm in water as well as to capture any photon contributions to absorbed dose. Assayed 177 Lu and 90 Y liquid sources, 13-450 MBq estimated to deliver 0.5-10 Gy to the sensitive layer of the RF, were injected into the cavity of two 3D-printed half-cylinders that had been sealed with 12.7 µm or 25.4 µm thick Kapton Tape. A 3.8 × 6 cm strip of GafChromic EBT3 RF was sandwiched between the two taped half-cylinders. After 2-48 h exposures, films were retrieved and wipe tested for contamination. Absorbed dose to the RF was measured using a commercial triple-channel dosimetry optimization method and a calibration generated via 6 MV photon beam. Profiles were analyzed across the central 1 cm2 area of the RF for validation. Eleven experiments were completed with 177 Lu and nine with 90 Y both in saline and a bone equivalent solution. Depth dose curves were generated for 177 Lu and 90 Y stacking multiple RF strips between a single filled half-cylinder and an acrylic backing. All experiments were modeled in DPM to generate voxelized MC absorbed dose estimates. We extended our study to benchmark general purpose MC codes MCNP6 and EGSnrc against the experimental results as well. RESULTS: A total of 20 experiments showed that both the 3D-printed phantoms and the final absorbed dose values were reproducible. The agreement between the absorbed dose estimates from the RF measurements and DPM was on average -4.0% (range -10.9% to 3.2%) for all single film 177 Lu experiments and was on average -1.0% (range -2.7% to 0.7%) for all single film 90 Y experiments. Absorbed depth dose estimates by DPM agreed with RF on average 1.2% (range -8.0% to 15.2%) across all depths for 177 Lu and on average 4.0% (range -5.0% to 9.3%) across all depths for 90 Y. DPM absorbed dose estimates agreed with estimates from EGSnrc and MCNP across the board, within 4.7% and within 3.4% for 177 Lu and 90 Y respectively, for all geometries and across all depths. MC showed that absorbed dose to RF from betas was greater than 92% of the total (betas + other radiations) for 177 Lu, indicating measurement of dominant beta contribution with our design. CONCLUSIONS: The reproducible results with a RF insert in a simple phantom designed for liquid sources demonstrate that this is a reliable setup for experimentally validating dosimetry algorithms used in therapies with beta-emitting unsealed sources. Absorbed doses estimated with the DPM MC code showed close agreement with RF measurement and with results from two general purpose MC codes, thereby validating the use of this algorithms for clinical RPT dosimetry.

Intra- and inter-operator variability in MRI-based manual segmentation of HCC lesions and its impact on dosimetry.

PURPOSE: The aim was to quantify inter- and intra-observer variability in manually delineated hepatocellular carcinoma (HCC) lesion contours and the resulting impact on radioembolization (RE) dosimetry. METHODS: Ten patients with HCC lesions treated with Y-90 RE and imaged with post-therapy Y-90 PET/CT were selected for retrospective analysis. Three radiologists contoured 20 lesions manually on baseline multiphase contrast-enhanced MRIs, and two of the radiologists re-contoured at two additional sessions. Contours were transferred to co-registered PET/CT-based Y-90 dose maps. Volume-dependent recovery coefficients were applied for partial volume correction (PVC) when reporting mean absorbed dose. To understand how uncertainty varies with tumor size, we fit power models regressing relative uncertainty in volume and in mean absorbed dose on contour volume. Finally, we determined effects of segmentation uncertainty on tumor control probability (TCP), as calculated using logistic models developed in a previous RE study. RESULTS: The average lesion volume ranged from 1.8 to 194.5 mL, and the mean absorbed dose ranged from 23.4 to 1629.0 Gy. The mean inter-observer Dice coefficient for lesion contours was significantly less than the mean intra-observer Dice coefficient (0.79 vs. 0.85, p < 0.001). Uncertainty in segmented volume, as measured by the Coefficient of Variation (CV), ranged from 4.2 to 34.7% with an average of 17.2%. The CV in mean absorbed dose had an average value of 5.4% (range 1.2-13.1%) without PVC while it was 15.1% (range 1.5-55.2%) with PVC. Using the fitted models for uncertainty as a function of volume on our prior data, the mean change in TCP due to segmentation uncertainty alone was estimated as 16.2% (maximum 48.5%). CONCLUSIONS: Though we find relatively high inter- and intra-observer reliability overall, uncertainty in tumor contouring propagates into non-negligible uncertainty in dose metrics and outcome prediction for individual cases that should be considered in dosimetry-guided treatment.

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 Pipeline for Automated Voxel Dosimetry: Application in Patients with Multi-SPECT/CT Imaging After 177Lu-Peptide Receptor Radionuclide Therapy.

Patient-specific dosimetry in radiopharmaceutical therapy (RPT) is impeded by the lack of tools that are accurate and practical for the clinic. Our aims were to construct and test an integrated voxel-level pipeline that automates key components (organ segmentation, registration, dose-rate estimation, and curve fitting) of the RPT dosimetry process and then to use it to report patient-specific dosimetry in 177Lu-DOTATATE therapy. Methods: An integrated workflow that automates the entire dosimetry process, except tumor segmentation, was constructed. First, convolutional neural networks (CNNs) are used to automatically segment organs on the CT portion of one post-therapy SPECT/CT scan. Second, local contour intensity-based SPECT--SPECT alignment results in volume-of-interest propagation to other time points. Third, dose rate is estimated by explicit Monte Carlo (MC) radiation transport using the fast, Dose Planning Method code. Fourth, the optimal function for dose-rate fitting is automatically selected for each voxel. When reporting mean dose, we apply partial-volume correction, and uncertainty is estimated by an empiric approach of perturbing segmentations. Results: The workflow was used with 4-time-point 177Lu SPECT/CT imaging data from 20 patients with 77 neuroendocrine tumors, segmented by a radiologist. CNN-defined kidneys resulted in high Dice values (0.91-0.94) and only small differences (2%-5%) in mean dose when compared with manual segmentation. Contour intensity-based registration led to visually enhanced alignment, and the voxel-level fitting had high R 2 values. Across patients, dosimetry results were highly variable; for example, the average of the mean absorbed dose (Gy/GBq) was 3.2 (range, 0.2-10.4) for lesions, 0.49 (range, 0.24-1.02) for left kidney, 0.54 (range, 0.31-1.07) for right kidney, and 0.51 (range, 0.27-1.04) for healthy liver. Patient results further demonstrated the high variability in the number of cycles needed to deliver hypothetical threshold absorbed doses of 23 Gy to kidney and 100 Gy to tumor. The uncertainty in mean dose, attributable to variability in segmentation, averaged 6% (range, 3%-17%) for organs and 10% (range, 3%-37%) for lesions. For a typical patient, the time for the entire process was about 25 min (∼2 min manual time) on a desktop computer, including time for CNN organ segmentation, coregistration, MC dosimetry, and voxel curve fitting. Conclusion: A pipeline integrating novel tools that are fast and automated provides the capacity for clinical translation of dosimetry-guided RPT.

Pretreatment Levels of Soluble Tumor Necrosis Factor Receptor 1 and Hepatocyte Growth Factor Predict Toxicity and Overall Survival After 90Y Radioembolization: Potential Novel Application of Biomarkers for Personalized Management of Hepatotoxicity.

Liver function may be negatively affected by radiation for treatment of hepatic malignancy. Pretreatment blood cytokine levels are biomarkers for prediction of toxicity and survival after external-beam radiation therapy. We hypothesized that cytokines may also predict outcomes after radioembolization, enabling a biomarker-driven personalized approach to treatment. Methods: Pretherapy blood samples from patients enrolled on a prospective protocol evaluating 90Y radioembolization for management of intrahepatic malignancy were analyzed for 2 cytokines selected on the basis of prior studies in stereotactic body radiotherapy, soluble tumor necrosis factor receptor 1 (sTNFR1) and hepatocyte growth factor (HGF), via enzyme-linked immunosorbent assay, and key dosimetric parameters were derived from posttreatment 90Y PET/CT imaging. Toxicity was defined as a change in albumin-bilirubin score from baseline to follow-up (3-6 mo after treatment). Associations of cytokine levels, dose metrics, and baseline liver function with toxicity and overall survival were assessed. Results: Data from 43 patients treated with 90Y radioembolization for primary (48.8% [21/43]) or secondary (51.2% [22/43]) malignancy were assessed. Examined dose metrics and baseline liver function were not associated with liver toxicity; however, levels of sTNFR1 (P = 0.045) and HGF (P = 0.005) were associated with liver toxicity in univariate models. Cytokines were the only predictors of toxicity in multivariable models including dose metrics and prior liver-directed therapy. sTNFR1 (hazard ratio, 12.3; 95% CI, 3.5-42.5, P < 0.001) and HGF (hazard ratio, 7.5; 95% CI, 2.4-23.1, P < 0.001) predicted overall survival, and findings were similar when models were controlled for absorbed dose and presence of metastatic disease. Conclusion: Pretreatment cytokine levels predict liver toxicity and overall survival. These pathways can be targeted with available drugs, an advantage over previously studied dose metrics and liver function tests. Interventions directed at the TNFα-axis should be considered in future studies for prevention of liver toxicity, and HGF should be explored further to determine whether its elevation drives toxicity or indicates ongoing liver regeneration after prior injury.

DblurDoseNet: A deep residual learning network for voxel radionuclide dosimetry compensating for single-photon emission computerized tomography imaging resolution.

PURPOSE: Current methods for patient-specific voxel-level dosimetry in radionuclide therapy suffer from a trade-off between accuracy and computational efficiency. Monte Carlo (MC) radiation transport algorithms are considered the gold standard for voxel-level dosimetry but can be computationally expensive, whereas faster dose voxel kernel (DVK) convolution can be suboptimal in the presence of tissue heterogeneities. Furthermore, the accuracies of both these methods are limited by the spatial resolution of the reconstructed emission image. To overcome these limitations, this paper considers a single deep convolutional neural network (CNN) with residual learning (named DblurDoseNet) that learns to produce dose-rate maps while compensating for the limited resolution of SPECT images. METHODS: We trained our CNN using MC-generated dose-rate maps that directly corresponded to the true activity maps in virtual patient phantoms. Residual learning was applied such that our CNN learned only the difference between the true dose-rate map and DVK dose-rate map with density scaling. Our CNN consists of a 3D depth feature extractor followed by a 2D U-Net, where the input was 11 slices (3.3 cm) of a given Lu-177 SPECT/CT image and density map, and the output was the dose-rate map corresponding to the center slice. The CNN was trained with nine virtual patient phantoms and tested on five different phantoms plus 42 SPECT/CT scans of patients who underwent Lu-177 DOTATATE therapy. RESULTS: When testing on virtual patient phantoms, the lesion/organ mean dose-rate error and the normalized root mean square error (NRMSE) relative to the ground truth of the CNN method was consistently lower than DVK and MC, when applied to SPECT images. Compared to DVK/MC, the average improvement for the CNN in mean dose-rate error was 55%/53% and 66%/56%; and in NRMSE was 18%/17% and 10%/11% for lesion and kidney regions, respectively. Line profiles and dose-volume histograms demonstrated compensation for SPECT resolution effects in the CNN-generated dose-rate maps. The ensemble noise standard deviation, determined from multiple Poisson realizations, was improved by 21%/27% compared to DVK/MC. In patients, potential improvements from CNN dose-rate maps compared to DVK/MC were illustrated qualitatively, due to the absence of ground truth. The trained residual CNN took about 30 s on a single GPU (Tesla V100) to generate a 512 × $\; \times \;$ 512 × $\; \times \;$ 130 dose-rate map for a patient. CONCLUSION: The proposed residual CNN, trained using phantoms generated from patient images, has potential for real-time patient-specific dosimetry in clinical treatment planning due to its demonstrated improvement in accuracy, resolution, noise, and speed over the DVK/MC approaches.

Y-90 SIRT: evaluation of TCP variation across dosimetric models.

INTRODUCTION: Much progress has been made in implementing selective internal radiation therapy (SIRT) as a viable treatment option for hepatic malignancies. However, there is still much need for improved options for calculating the amount of activity to be administered. To make advances towards this goal, this study examines the relationship between predicted biological outcomes of liver tumors via tumor control probabilities (TCP) and parenchyma via normal tissue complication probabilities (NTCP) given variations in absorbed dose prescription methodologies. METHODS: Thirty-nine glass microsphere treatments in 35 patients with hepatocellular carcinoma or metastatic liver disease were analyzed using 99mTc-MAA SPECT/CT and 90Y PET/CT scans. Predicted biological outcomes corresponding to the single compartment (standard) model and multi-compartment (partition) dosimetry model were compared using our previously derived TCP dose-response curves over a range of 80-150 Gy prescribed absorbed dose to the perfused volume, recommended in the package insert for glass microspheres. Retrospective planning dosimetry was performed on the MAA SPECT/CT; changes from the planned infused activity due to selection of absorbed dose level and dosimetry model (standard or partition) were used to scale absorbed doses reported from 90Y PET/CT including liver parenchyma and lesions (N = 120) > 2 ml. A parameterized charting system was developed across all potential prescription options to enable a clear relationship between standard prescription vs. the partition model-based prescription. Using a previously proposed NTCP model, the change in prescribed dose from a standard model prescription of 120 Gy to the perfused volume to a 15% NTCP prescription to the normal liver was explored. RESULTS: Average TCP predictions for the partition model compared with the standard model varied from a 13% decrease to a 32% increase when the prescribed dose was varied across the range of 80-150 Gy. In the parametrized chart comparing absorbed dose prescription ranges across the standard model and partition models, a line of equivalent absorbed dose to a tumor was identified. TCP predictions on a per lesion basis varied between a 26% decrease and a 81% increase for the most commonly chosen prescription options when comparing the partition model with the standard model. NTCP model was only applicable to a subset of patients because of the small volume fraction of the liver that was targeted in most cases. CONCLUSION: Our retrospective analysis of patient imaging data shows that the choice of prescribed dose and which model to prescribe potentially contribute to a wide variation in average tumor efficacy. Biological response data should be included as one factor when looking to improve patient care in the clinic. The use of parameterized charting, such as presented here, will help direct physicians when transitioning to newer prescription methods.

Development and comprehensive commissioning of an automated brachytherapy plan checker.

PURPOSE: To present on the commissioning of an automated brachytherapy plan checker (BPC) for the evaluation of high-dose-rate brachytherapy treatment plans in support of standardized workflows and patient safety. METHODS AND MATERIALS: A BPC was developed using an applications programming interface in a commercial treatment planning system based on different inputs (e.g., regulations, professional society recommendations, and user feedback) and leveraged our experience with an in-house developed external beam plan checker. The BPC was commissioned using a comprehensive suite of test plans with known errors and anonymized clinical plans. RESULTS: During commissioning, the BPC was successfully executed on a total of 87 test plans. Commissioning tests spanned a range of treatment sites and evaluated that pass and fail states were correct. Administration settings were changed in a nonclinical database to evaluate tests involving the source and afterloader. Clinical testing of the BPC was then performed in parallel with a manual review process before clinical implementation. CONCLUSIONS: To commission the BPC for clinical use, a comprehensive suite of test plans was developed and used to ensure the BPC correctly detected and reported errors. A summary of the test plans is presented to help guide users developing similar automated tools. The BPC represents a process-improvement initiative designed to reduce errors and improve safety for brachytherapy patients. By using a comprehensive test suite for commissioning, tests are available for periodic quality assurance and after software upgrades.

Prediction of Tumor Control in 90Y Radioembolization by Logit Models with PET/CT-Based Dose Metrics.

The aim of this work was to develop models for tumor control probability (TCP) in radioembolization with 90Y PET/CT-derived radiobiologic dose metrics. Methods: Patients with primary liver cancer or liver metastases who underwent radioembolization with glass microspheres were imaged with 90Y PET/CT for voxel-level dosimetry to determine lesion absorbed dose (AD) metrics, biological effective dose (BED) metrics, equivalent uniform dose, and equivalent uniform BED for 28 treatments (89 lesions). The lesion dose-shrinkage correlation was assessed on the basis of RECIST and, when available, modified RECIST (mRECIST) at first follow-up. For a subset with mRECIST, logit regression TCP models were fit via maximum likelihood to relate lesion-level binary response to the dose metrics. As an exploratory analysis, the nontumoral liver dose-toxicity relationship was also evaluated. Results: Lesion dose-shrinkage analysis showed that there were no significant differences between model parameters for primary and metastatic subgroups and that correlation coefficients were superior with mRECIST. Therefore, subsequent TCP analysis was performed for the combined group using mRECIST only. The overall lesion-level mRECIST response rate was 57%. The AD and BED metrics yielding 50% TCP were 292 and 441 Gy, respectively. All dose metrics considered for TCP modeling, including mean AD, were significantly associated with the probability of response, with high areas under the curve (0.87-0.90, P < 0.0001) and high sensitivity (>0.75) and specificity (>0.83) calculated using a threshold corresponding to 50% TCP. Because nonuniform AD deposition by microspheres cannot be determined by PET at a microscopic scale, radiosensitivity values extracted here by fitting models to clinical response data were substantially lower than reported for in vitro cell cultures or for external-beam radiotherapy clinical studies. There was no correlation between nontumoral liver AD and toxicity measures. Conclusion: Despite the heterogeneous patient cohort, logistic regression TCP models showed a strong association between various dose metrics and the probability of response. The performance of mean AD was comparable to that of radiobiologic dose metrics that involve more complex calculations. These results demonstrate the importance of considering TCP in treatment planning for radioembolization.

Transarterial Radioembolization for Hepatocellular Carcinoma and Hepatic Metastases: Clinical Aspects and Dosimetry Models.

Transarterial radioembolization (TARE) with Yttrium-90 (90Y) microspheres is a liver-directed therapy for primary and metastatic disease. This manuscript provides a review of the clinical literature on TARE indications and efficacy with overviews of patient-selection and toxicity. Current dosimetry models used in practice are safe, relatively simple, and easy for clinicians to use. Planning currently relies on the imperfect surrogate, 99mTc macroaggregated albumin. Post-therapy quantitative imaging (90Y SPECT/CT or 90Y PET/CT) of microspheres can be used to calculate the macroscopic in vivo absorbed dose distribution. Similar to the evolution of other brachytherapy dose calculations, TARE is moving toward more patient-specific dosimetry that includes calculating and reporting nonuniform dose distributions throughout tumors and normal uninvolved liver.

Assessing Spatial Concordance Between Theranostic Pairs Using Phantom and Patient-Specific Acceptance Criteria: Application to 99mTc-MAA SPECT/90Y-Microsphere PET.

PURPOSE: Predictive 3-dimensional dosimetry requires spatial concordance between diagnostic and therapeutic activity distributions. We assess similarity between theranostic pairs (99mTc-macroaggregated albumin [MAA] single photon emission computed tomography [SPECT] and 90Y microsphere positron emission tomography [PET]) in patients using criteria that account for spatial resolution differences and misregistration. METHODS AND MATERIALS: Phantom-based acceptance criteria were determined using a liver phantom filled with 99mTc and 90YCl3 and scanned with SPECT/computed tomography [CT] and PET/CT, respectively. Gaussian blurring was applied to PET to match 99mTc phantom scan image quality. After rigid registration between SPECT/CT and PET/CT, perturbations up to ±3 voxels were applied to determine the similarity metric (SM) sensitivity. 99mTc-MAA SPECT/CT and 90Y microsphere PET/CT image pairs/patients (n = 23) were processed analogously. SMs calculated included the Pearson correlation coefficient (ρr), Lin's concordance correlation coefficient (ρc), Spearman's rank correlation coefficient (ρs), the mean squared difference, and the Dice similarity coefficient (DSC). Patient-specific acceptance criteria were determined by evaluating the SMs of the blurred PET compared with itself misregistered. RESULTS: After transforming PET to SPECT resolution, high similarity was found in phantom, with ρc, ρr, ρs > 0.98 ± 0.01, a mean squared difference of (4.1 ± 0.3) × 10-4 and DSC > 0.85 ± 0.01 for investigated thresholds (5%, 30%, and 50%). SMs for patients varied from poor to good. A small percentage (13%-30%) of patient scans were acceptable using phantom-based acceptance criteria. The percentage increased slightly (17%-35%) using patient-specific acceptance criteria. DSC for most patients were substantially lower (average 0.95 vs 0.61 for 5% threshold) than phantom values. CONCLUSIONS: At best, 35% of patients had an SM within the acceptance criteria established to account for imaging-related effects impacting spatial concordance between 99mTc-MAA SPECT and 90Y PET. Additional clinical factors should be evaluated in the future. The procedure of accounting for image-related effects when assessing spatial concordance can be applied to other theranostic pairs.

Silicon Photomultipliers for Deep Tissue Cerenkov Emission Detection During External Beam Radiotherapy.

Cerenkov Emission (CE) during external beam radiation therapy (EBRT) from a linear accelerator (Linac) has been demonstrated as a useful tool for radiotherapy quality assurance and potentially other applications for online tracking of tumors during treatment delivery. However, some of the current challenges that are impacting the potential of CE are related to the limited detection sensitivity and the lack of flexible tools to fit into an already complex treatment delivery environment. Silicon photomultiplier (SiPM) solid-state devices are new promising tools for low light detection due to their extreme sensitivity that mirrors photomultiplier tubes and yet have a form factor that is similar to silicon photodiodes, allowing for improved flexibility in device design that may help in the process of wider clinical applicability. In this work, we assess the feasibility of using SiPMs to detect CE during EBRT from a Linac and contrast their performance with commercially available silicon photodiodes (PDs). We demonstrate the feasibility of the SiPM based probes for standard dosimetry measurements. We also demonstrate that CE optical signals can be detected from tissue depths about five times greater than that for standard probes based on PDs, making our SiPM probe an enabling technology of CE measurements, particularly for deep tissue applications.

Dose volume histogram-based optimization of image reconstruction parameters for quantitative 90 Y-PET imaging.

PURPOSE: 90 Y-microsphere radioembolization or selective internal radiation therapy is increasingly being used as a treatment option for tumors that are not candidates for surgery and external beam radiation therapy. Recently, volumetric 90 Y-dosimetry techniques have been implemented to explore tumor dose-response on the basis of 3D 90 Y-activity distribution from PET imaging. Despite being a theranostic study, the optimization of quantitative 90 Y-PET image reconstruction still uses the mean activity concentration recovery coefficient (RC) as the objective function, which is more relevant to diagnostic and detection tasks than is to dosimetry. The aim of this study was to optimize 90 Y-PET image reconstruction by minimizing errors in volumetric dosimetry via the dose volume histogram (DVH). We propose a joint optimization of the number of equivalent iterations (the product of the iterations and subsets) and the postreconstruction filtration (FWHM) to improve the accuracy of voxel-level 90 Y dosimetry. METHODS: A modified NEMA IEC phantom was used to emulate clinically relevant 90 Y-PET imaging conditions through various combinations of acquisition durations, activity concentrations, sphere-to-background ratios, and sphere diameters. PET data were acquired in list mode for 300 min in a single-bed position; we then rebinned the list mode PET data to 60, 45, 30, 15, and 5 min per bed, with 10 different realizations. Errors in the DVH were calculated as root mean square errors (RMSE) of the differences in the image-based DVH and the expected DVH. The new optimization approach was tested in a phantom study, and the results were compared with the more commonly used objective function of the mean activity concentration RC. RESULTS: In a wide range of clinically relevant imaging conditions, using 36 equivalent iterations with a 5.2-mm filtration resulted in decreased systematic errors in volumetric 90 Y dosimetry, quantified as image-based DVH, in 90 Y-PET images reconstructed using the ordered subset expectation maximization (OSEM) iterative reconstruction algorithm with time of flight (TOF) and point spread function (PSF) modeling. Our proposed objective function of minimizing errors in DVH, which allows for joint optimization of 90 Y-PET iterations and filtration for volumetric quantification of the 90 Y dose, was shown to be superior to conventional RC-based optimization approaches for image-based absorbed dose quantification. CONCLUSION: Our proposed objective function of minimizing errors in DVH, which allows for joint optimization of iterations and filtration to reduce errors in the PET-based volumetric quantification 90 Y dose, is relevant to dosimetry in therapy procedures. The proposed optimization method using DVH as the objective function could be applied to any imaging modality used to assess voxel-level quantitative information.

Impact of 90Y PET gradient-based tumor segmentation on voxel-level dosimetry in liver radioembolization.

BACKGROUND: The purpose was to validate 90Y PET gradient-based tumor segmentation in phantoms and to evaluate the impact of the segmentation method on reported tumor absorbed dose (AD) and biological effective dose (BED) in 90Y microsphere radioembolization (RE) patients. A semi-automated gradient-based method was applied to phantoms and patient tumors on the 90Y PET with the initial bounding volume for gradient detection determined from a registered diagnostic CT or MR; this PET-based segmentation (PS) was compared with radiologist-defined morphologic segmentation (MS) on CT or MRI. AD and BED volume histogram metrics (D90, D70, mean) were calculated using both segmentations and concordance/correlations were investigated. Spatial concordance was assessed using Dice similarity coefficient (DSC) and mean distance to agreement (MDA). PS was repeated to assess intra-observer variability. RESULTS: In phantoms, PS demonstrated high accuracy in lesion volumes (within 15%), AD metrics (within 11%), high spatial concordance relative to morphologic segmentation (DSC > 0.86 and MDA < 1.5 mm), and low intra-observer variability (DSC > 0.99, MDA < 0.2 mm, AD/BED metrics within 2%). For patients (58 lesions), spatial concordance between PS and MS was degraded compared to in-phantom (average DSC = 0.54, average MDA = 4.8 mm); the average mean tumor AD was 226 ± 153 and 197 ± 138 Gy, respectively for PS and MS. For patient AD metrics, the best Pearson correlation (r) and concordance correlation coefficient (ccc) between segmentation methods was found for mean AD (r = 0.94, ccc = 0.92), but worsened as the metric approached the minimum dose (for D90, r = 0.77, ccc = 0.69); BED metrics exhibited a similar trend. Patient PS showed low intra-observer variability (average DSC = 0.81, average MDA = 2.2 mm, average AD/BED metrics within 3.0%). CONCLUSIONS: 90Y PET gradient-based segmentation led to accurate/robust results in phantoms, and showed high concordance with MS for reporting mean tumor AD/BED in patients. However, tumor coverage metrics such as D90 exhibited worse concordance between segmentation methods, highlighting the need to standardize segmentation methods when reporting AD/BED metrics from post-therapy 90Y PET. Estimated differences in reported AD/BED metrics due to segmentation method will be useful for interpreting RE dosimetry results in the literature including tumor response data.

Hepatocellular Carcinoma Tumor Dose Response After 90Y-radioembolization With Glass Microspheres Using 90Y-SPECT/CT-Based Voxel Dosimetry.

PURPOSE: To investigate hepatocellular carcinoma tumor dose-response characteristics based on voxel-level absorbed doses (D) and biological effective doses (BED) using quantitative 90Y-single-photon emission computed tomography (SPECT)/computed tomography (CT) after 90Y-radioembilization with glass microspheres. We also investigated the relationship between normal liver D and toxicities. METHODS AND MATERIALS: 90Y-radioembolization activity distributions for 34 patients were based on quantitative 90Y-bremsstrahlung SPECT/CT. D maps were generated using a local-deposition algorithm. Contrast-enhanced CT or magnetic resonance imaging scans of the liver were registered to 90Y-SPECT/CT, and all tumors larger than 2.5 cm diameter (53 tumors) were segmented. Tumor mean D and BED (Dmean and BEDmean) and dose volume coverage from 0% to 100% in 10% steps (D0-D100 and BED0-BED100) were extracted. Tumor response was evaluated on follow-up using World Health Organization (WHO), Response Evaluation Criteria in Solid Tumors (RECIST), and modified RECIST (mRECIST) criteria. Differences in dose metrics for responders and nonresponders were assessed using the Mann-Whitney U test. A univariate logistic regression model was used to determine tumor dose metrics that correlated with tumor response. Correlations among tumor size, tumor Dmean, and tumor dose heterogeneity (defined as the coefficient of variation) were assessed. RESULTS: The objective response rates were 14 of 53, 15 of 53, and 30 of 53 for WHO, RECIST, and mRECIST criteria, respectively. WHO and RECIST response statuses did not correlate with D or BED. For mRECIST responders and nonresponders, D and BED were significantly different for Dmean, D20 to D80, BEDmean, and BED0 to BED80. Threshold doses (and the 95% confidence interval) for 50% probability of mRECIST response (D50%) were 160 Gy (123-196 Gy) for Dmean and 214 Gy (146-280 Gy) for BEDmean. Tumor dose heterogeneity significantly correlated with tumor volume. No statistically significant association between Dmean to normal liver and complications related to bilirubin, albumin, or ascites was observed. CONCLUSIONS: Hepatocellular carcinoma tumor dose-response curves after 90Y-radioembolization with glass microspheres showed Dmean of 160 Gy and BEDmean of 214 Gy for D50% with a positive predictive value of ∼70% and a negative predictive value of ∼62%. No complications were observed in our patient cohort for normal liver Dmean less than 44 Gy.

The value of 99mTc-MAA SPECT/CT for lung shunt estimation in 90Y radioembolization: a phantom and patient study.

BACKGROUND: A major toxicity concern in radioembolization therapy of hepatic malignancies is radiation-induced pneumonitis and sclerosis due to hepatopulmonary shunting of 90Y microspheres. Currently, 99mTc macroaggregated albumin (99mTc-MAA) imaging is used to estimate the lung shunt fraction (LSF) prior to treatment. The aim of this study was to evaluate the accuracy/precision of LSF estimated from 99mTc planar and SPECT/CT phantom imaging, and within this context, to compare the corresponding LSF and lung-absorbed dose values from 99mTc-MAA patient studies. Additionally, LSFs from pre- and post-therapy imaging were compared. RESULTS: A liver/lung torso phantom filled with 99mTc to achieve three lung shunt values was scanned by planar and SPECT/CT imaging with repeat acquisitions to assess accuracy and precision. To facilitate processing of patient data, a workflow that relies on SPECT and CT-based auto-contouring to define liver and lung volumes for the LSF calculation was implemented. Planar imaging-based LSF estimates for 40 patients, obtained from their medical records, were retrospectively compared with SPECT/CT imaging-based calculations with attenuation and scatter correction. Additionally, in a subset of 20 patients, the pre-therapy estimates were compared with 90Y PET/CT-based measurements. In the phantom study, improved accuracy in LSF estimation was achieved using SPECT/CT with attenuation and scatter correction (within 13% of the true value) compared with planar imaging (up to 44% overestimation). The results in patients showed a similar trend with planar imaging significantly overestimating LSF compared to SPECT/CT. There was no correlation between lung shunt estimates and the delay between 99mTc-MAA administration and scanning, but off-target extra hepatic uptake tended to be more likely in patients with a longer delay. The mean lung absorbed dose predictions for the 28 patients who underwent therapy was 9.3 Gy (range 1.3-29.4) for planar imaging and 3.2 Gy (range 0.4-13.4) for SPECT/CT. For the patients with post-therapy imaging, the mean LSF from 90Y PET/CT was 1.0%, (range 0.3-2.8). This value was not significantly different from the mean LSF estimate from 99mTc-MAA SPECT/CT (mean 1.0%, range 0.4-1.6; p = 0.968), but was significantly lower than the mean LSF estimate based on planar imaging (mean 4.1%, range 1.2-15.0; p = 0.0002). CONCLUSIONS: The improved accuracy demonstrated by the phantom study, agreement with 90Y PET/CT in patient studies, and the practicality of using auto-contouring for liver/lung definition suggests that 99mTc-MAA SPECT/CT with scatter and attenuation corrections should be used for lung shunt estimation prior to radioembolization.

The impact of a high-definition multileaf collimator for spine SBRT.

PURPOSE: Advanced radiotherapy delivery systems designed for high-dose, high-precision treatments often come equipped with high-definition multi-leaf collimators (HD-MLC) aimed at more finely shaping radiation dose to the target. In this work, we study the effect of a high definition MLC on spine stereotactic body radiation therapy (SBRT) treatment plan quality and plan deliverability. METHODS AND MATERIALS: Seventeen spine SBRT cases were planned with VMAT using a standard definition MLC (M120), HD-MLC, and HD-MLC with an added objective to reduce monitor units (MU). M120 plans were converted into plans deliverable on an HD-MLC using in-house software. Plan quality and plan deliverability as measured by portal dosimetry were compared among the three types of plans. RESULTS: Only minor differences were noted in plan quality between the M120 and HD-MLC plans. Plans generated with the HD-MLC tended to have better spinal cord sparing (3% reduction in maximum cord dose). HD-MLC plans on average had 12% more MU and 55% greater modulation complexity as defined by an in-house metric. HD-MLC plans also had significantly degraded deliverability. Of the VMAT arcs measured, 94% had lower gamma passing metrics when using the HD-MLC. CONCLUSION: Modest improvements in plan quality were noted when switching from M120 to HD-MLC at the expense of significantly less accurate deliverability in some cases.