Automated and robust organ segmentation for 3D-based internal dose calculation.

PURPOSE: In this work, we address image segmentation in the scope of dosimetry using deep learning and make three main contributions: (a) to extend and optimize the architecture of an existing convolutional neural network (CNN) in order to obtain a fast, robust and accurate computed tomography (CT)-based organ segmentation method for kidneys and livers; (b) to train the CNN with an inhomogeneous set of CT scans and validate the CNN for daily dosimetry; and (c) to evaluate dosimetry results obtained using automated organ segmentation in comparison with manual segmentation done by two independent experts. METHODS: We adapted a performant deep learning approach using CT-images to delineate organ boundaries with sufficiently high accuracy and adequate processing time. The segmented organs were consequently used as binary masks for further convolution with a point spread function to retrieve the activity values from quantitatively reconstructed SPECT images for "volumetric"/3D dosimetry. The resulting activities were used to perform dosimetry calculations with the kidneys as source organs. RESULTS: The computational expense of the algorithm was sufficient for clinical daily routine, required minimum pre-processing and performed with acceptable accuracy a Dice coefficient of [Formula: see text] for liver segmentation and of [Formula: see text] for kidney segmentation, respectively. In addition, kidney self-absorbed doses calculated using automated segmentation differed by [Formula: see text] from dosimetry performed by two medical physicists in 8 patients. CONCLUSION: The proposed approach may accelerate volumetric dosimetry of kidneys in molecular radiotherapy with 177Lu-labelled radiopharmaceuticals such as 177Lu-DOTATOC. However, even though a fully automated segmentation methodology based on CT images accelerates organ segmentation and performs with high accuracy, it does not remove the need for supervision and corrections by experts, mostly due to misalignments in the co-registration between SPECT and CT images. Trial registration EudraCT, 2016-001897-13. Registered 26.04.2016, www.clinicaltrialsregister.eu/ctr-search/search?query=2016-001897-13 .

Phase I study to assess safety, biodistribution and radiation dosimetry for 89Zr-girentuximab in patients with renal cell carcinoma.

PURPOSE: In this phase I study, we evaluated the safety, biodistribution and dosimetry of [89Zr]Zr-DFO-girentuximab (89Zr-girentuximab) PET/CT imaging in patients with suspicion of clear cell renal cell carcinoma (ccRCC). METHODS: Ten eligible patients received an intravenous administration of 37 MBq (± 10%) of 89Zr-girentuximab at mass doses of 5 mg or 10 mg. Safety was evaluated according to the NCI CTCAE (version 4.03). Biodistribution and normal organ dosimetry was performed based on PET/CT images acquired at 0.5, 4, 24, 72 and 168 h post-administration. Additionally, tumour dosimetry was performed in patients with confirmed ccRCC and visible tumour uptake on PET/CT imaging. RESULTS: 89Zr-girentuximab was administered in ten patients as per protocol. No treatment-related adverse events ≥ grade 3 were reported. 89Zr-girentuximab imaging allowed successful differentiation between ccRCC and non-ccRCC lesions in all patients, as confirmed with histological data. Dosimetry analysis using OLINDA/EXM 2.1 showed that the organs receiving the highest doses (mean ± SD) were the liver (1.86 ± 0.40 mGy/MBq), the kidneys (1.50 ± 0.22 mGy/MBq) and the heart wall (1.45 ± 0.19 mGy/MBq), with a mean whole body effective dose of 0.57 ± 0.08 mSv/MBq. Tumour dosimetry was performed in the 6 patients with histologically confirmed ccRCC resulting in a median tumour-absorbed dose of 4.03 mGy/MBq (range 1.90-11.6 mGy/MBq). CONCLUSIONS: This study demonstrates that 89Zr-girentuximab is safe and well tolerated for the administered activities and mass doses and allows quantitative assessment of 89Zr-girentuximab PET/CT imaging in patients with suspicion of ccRCC. TRIAL REGISTRATION: NCT03556046-14th of June, 2018.

Evaluation of Safety and Dosimetry of 177Lu-DOTA-ZOL for Therapy of Bone Metastases.

Palliative treatment of bone metastasis using radiolabeled bisphosphonates is a well-known concept proven to be safe and effective. A new therapeutic radiopharmaceutical for bone metastasis is 177Lu-DOTA-zoledronic acid (177Lu-DOTA-ZOL). In this study, the safety and dosimetry of a single therapeutic dose of 177Lu-DOTA-ZOL were evaluated on the basis of a series of SPECT/CT images and blood samples. Methods: Nine patients with exclusive bone metastases from metastatic castration-resistant prostate cancer (mCRPC) (70.8 ± 8.4 y) and progression under conventional therapies participated in this prospective study. After receiving 5,780 ± 329 MBq 177Lu-DOTA-ZOL, patients underwent 3-dimensional whole-body SPECT/CT imaging and venous blood sampling over 7 d. Dosimetric evaluation was performed for main organs and tumor lesions. Safety was assessed by blood biomarkers. Results:177Lu-DOTA-ZOL showed fast uptake and high retention in bone lesions and fast clearance from the bloodstream in all patients. The average retention in tumor lesions was 0.02% injected activity per gram at 6 h after injection and approximately 0.01% at 170 h after injection. In this cohort, the average absorbed doses in bone tumor lesions, kidneys, red bone marrow, and bone surfaces were 4.21, 0.17, 0.36, and 1.19 Gy/GBq, respectively. The red marrow was found to be the dose-limiting organ for all patients. A median maximum tolerated injected activity of 6.0 GBq may exceed the defined threshold of 2 Gy for the red bone marrow in individual patients (4/8). Conclusion:177Lu-DOTA-ZOL is safe and has a favorable therapeutic index compared with other radiopharmaceuticals used in the treatment of osteoblastic bone metastases. Personalized dosimetry, however, should be considered to avoid severe hematotoxicity for individual patients.

Biodistribution and dosimetry of a single dose of albumin-binding ligand [177Lu]Lu-PSMA-ALB-56 in patients with mCRPC.

INTRODUCTION: PSMA-targeted radionuclide therapy with lutetium-177 has emerged as an effective treatment option for metastatic, castration-resistant prostate cancer (mCRPC). Recently, the concept of modifying PSMA radioligands with an albumin-binding entity was demonstrated as a promising measure to increase the tumor uptake in preclinical experiments. The aim of this study was to translate the concept to a clinical setting and evaluate the safety and dosimetry of [177Lu]Lu-PSMA-ALB-56, a novel PSMA radioligand with albumin-binding properties. METHODS: Ten patients (71.8 ± 8.2 years) with mCRPC received an activity of 3360 ± 393 MBq (120-160 µg) [177Lu]Lu-PSMA-ALB-56 followed by whole-body SPECT/CT imaging over 7 days. Volumes of interest were defined on the SPECT/CT images for dosimetric evaluation for healthy tissue and tumor lesions. General safety and therapeutic efficacy were assessed by measuring blood biomarkers. RESULTS: [177Lu]Lu-PSMA-ALB-56 was well tolerated, and no severe adverse events were observed. SPECT images revealed longer circulation of [177Lu]Lu-PSMA-ALB-56 in the blood with the highest uptake in tumor lesions at 48 h post injection. Compared with published data for other therapeutic PSMA radioligands (e.g. PSMA-617 and PSMA I&T), normalized absorbed doses of [177Lu]Lu-PSMA-ALB-56 were up to 2.3-fold higher in tumor lesions (6.64 ± 6.92 Gy/GBq) and similar in salivary glands (0.87 ± 0.43 Gy/GBq). Doses to the kidneys and red marrow (2.54 ± 0.94 Gy/GBq and 0.29 ± 0.07 Gy/GBq, respectively) were increased. CONCLUSION: Our data demonstrated that the concept of albumin-binding PSMA-radioligands is feasible and leads to increased tumor doses. After further optimization of the ligand design, the therapeutic outcomes may be improved for patients with prostate cancer.

Effect of Tumor Perfusion and Receptor Density on Tumor Control Probability in 177Lu-DOTATATE Therapy: An In Silico Analysis for Standard and Optimized Treatment.

The aim of this work was to determine a minimal tumor perfusion and receptor density for 177Lu-DOTATATE therapy using physiologically based pharmacokinetic (PBPK) modeling considering, first, a desired tumor control probability (TCP) of 99% and, second, a maximal tolerated biologically effective dose (BEDmax) for organs at risk (OARs) in the treatment of neuroendocrine tumors and meningioma. Methods: A recently developed PBPK model was used. Nine virtual patients (i.e., individualized PBPK models) were used to perform simulations of pharmacokinetics for different combinations of perfusion (0.001-0.1 mL/g/min) and receptor density (1-100 nmol/L). The TCP for each combination was determined for 3 different treatment strategies: a standard treatment (4 cycles of 7.4 GBq and 105 nmol), a treatment maximizing the number of cycles based on BEDmax for red marrow and kidneys, and a treatment having 4 cycles with optimized ligand amount and activity. The red marrow and the kidneys (BEDmax of 2 Gy15 and 40 Gy2.5, respectively) were assumed to be OARs. Additionally, the influence of varying glomerular filtration rates, kidney somatostatin receptor densities, tumor volumes, and release rates was investigated. Results: To achieve a TCP of at least 99% in the standard treatment, a minimal tumor perfusion of 0.036 ± 0.023 mL/g/min and receptor density of 34 ± 20 nmol/L were determined for the 9 virtual patients. With optimization of the number of cycles, the minimum values for perfusion and receptor density were considerably lower, at 0.022 ± 0.012 mL/g/min and 21 ± 11 nmol/L, respectively. However, even better results (perfusion, 0.018 ± 0.009 mL/g/min; receptor density, 18 ± 10 nmol/L) were obtained for strategy 3. The release rate of 177Lu (or labeled metabolites) from tumor cells had the strongest effect on the minimal perfusion and receptor density for standard and optimized treatments. Conclusion: PBPK modeling and simulations represent an elegant approach to individually determine the minimal tumor perfusion and minimal receptor density required to achieve an adequate TCP. This computational method can be used in the radiopharmaceutical development process for ligand and target selection for specific types of tumors. In addition, this method could be used to optimize clinical trials.

FAPI-74 PET/CT Using Either 18F-AlF or Cold-Kit 68Ga Labeling: Biodistribution, Radiation Dosimetry, and Tumor Delineation in Lung Cancer Patients.

68Ga-fibroblast activation protein inhibitors (FAPIs) 2, 4, and 46 have already been proposed as promising PET tracers. However, the short half-life of 68Ga (68 min) creates problems with manufacture and delivery. 18F (half-life, 110 min) labeling would result in a more practical large-scale production, and a cold-kit formulation would improve the spontaneous availability. The NOTA chelator ligand FAPI-74 can be labeled with both 18F-AlF and 68Ga. Here, we describe the in vivo evaluation of 18F-FAPI-74 and a proof of mechanism for 68Ga-FAPI-74 labeled at ambient temperature. Methods: In 10 patients with lung cancer, PET scans were acquired at 10 min, 1 h, and 3 h after administration of 259 ± 26 MBq of 18F-FAPI-74. Physiologic biodistribution and tumor uptake were semiquantitatively evaluated on the basis of SUV at each time point. Absorbed doses were evaluated using OLINDA/EXM, version 1.1, and QDOSE dosimetry software with the dose calculator IDAC-Dose, version 2.1. Identical methods were used to evaluate one examination after injection of 263 MBq of 68Ga-FAPI-74. Results: The highest contrast was achieved in primary tumors, lymph nodes, and distant metastases at 1 h after injection, with an SUVmax of more than 10. The effective dose per a 100-MBq administered activity of 18F-FAPI-74 was 1.4 ± 0.2 mSv, and for 68Ga-FAPI-74 it was 1.6 mSv. Thus, the radiation burden of a diagnostic 18F-FAPI-74 PET scan is even lower than that of PET scans with 18F-FDG and other 18F tracers; 68Ga-FAPI-74 is comparable to other 68Ga ligands. FAPI PET/CT supported target volume definition for guiding radiotherapy. Conclusion: The high contrast and low radiation burden of FAPI-74 PET/CT favor multiple clinical applications. Centralized large-scale production of 18F-FAPI-74 or decentralized cold-kit labeling of 68Ga-FAPI-74 allows flexible routine use.

Performance assessment of the ALBIRA II pre-clinical SPECT S102 system for 99mTc imaging.

OBJECTIVE: The performance characteristics of the SPECT sub-system S102 of the ALBIRA II PET/SPECT/CT are analyzed for the 80 mm field of view (FOV) to evaluate the potential in-vivo imaging in rats, based on measurements of the system response for the commonly used Technetium-99 m (99mTc) in small animal imaging. METHODS: The ALBIRA II tri-modal µPET/SPECT/CT pre-clinical system (Bruker BioSpin, Ettlingen, Germany) was used. The SPECT modality is made up of two opposite gamma cameras (Version S102) with Sodium doped Cesium Iodide (CsI(Na)) single continuous crystal detectors coupled to position-sensitive photomultipliers (PSPMTs). Imaging was performed with the NEMA NU-4 image quality phantom (Data Spectrum Corporation, Durham, USA). Measurements were performed with a starting activity concentration of 4.76 MBq/mL 99mTc. An energy window of 20% at 140 keV was selected in this study. The system offers a 20 mm, 40 mm, 60 mm and an 80 mm field of view (FOV) and in this study the 80 mm FOV was used for all the acquisitions. The data were reconstructed with an ordered subset expectation maximization (OSEM) algorithm. Sensitivity, spatial resolution, count rate linearity, convergence of the algorithm and the recovery coefficients (RC) were analyzed. All analyses were performed with PMOD and MATLAB software. RESULTS: The sensitivities measured at the center of the 80 mm FOV with the point source were 23.1 ± 0.3 cps/MBq (single pinhole SPH) and 105.6 ± 5.5 cps/MBq (multi pinhole MPH). The values for the axial, tangential and radial full width at half maximum (FWHM) were 2.51, 2.54, and 2.55 mm with SPH and 2.35, 2.44 and 2.32 mm with MPH, respectively. The corresponding RC values for the 5 mm, 4 mm, 3 mm and 2 mm rods were 0.60 ± 0.28, 0.61 ± 0.24, 0.29 ± 0.11 and 0.20 ± 0.06 with SPH and 0.56 ± 0.20, 0.50 ± 0.18, 0.38 ± 0.09 and 0.23 ± 0.06 with MPH. To obtain quantitative imaging data, the image reconstructions should be performed with 12 iterations. CONCLUSION: The ALBIRA II preclinical SPECT sub-system S102 has a favorable sensitivity and spatial resolution for the 80 mm FOV setting for both the SPH and MPH configurations and is a valuable tool for small animal imaging.

MITIGATE-NeoBOMB1, a Phase I/IIa Study to Evaluate Safety, Pharmacokinetics, and Preliminary Imaging of 68Ga-NeoBOMB1, a Gastrin-Releasing Peptide Receptor Antagonist, in GIST Patients.

Gastrin-releasing peptide receptors (GRPRs) are potential molecular imaging targets in a variety of tumors. Recently, a 68Ga-labeled antagonist to GRPRs, NeoBOMB1, was developed for PET. We report on the outcome of a phase I/IIa clinical trial (EudraCT 2016-002053-38) within the EU-FP7 project Closed-loop Molecular Environment for Minimally Invasive Treatment of Patients with Metastatic Gastrointestinal Stromal Tumors ('MITIGATE') (grant agreement no. 602306) in patients with oligometastatic gastrointestinal stromal tumors (GIST). Methods: The main objectives were evaluation of safety, biodistribution, dosimetry, and preliminary tumor targeting of 68Ga-NeoBOMB1 in patients with advanced tyrosine-kinase inhibitors-treated GIST using PET/CT. Six patients with histologically confirmed GIST and unresectable primary lesion or metastases undergoing an extended protocol for detailed pharmacokinetic analysis were included. 68Ga-NeoBOMB1 was prepared using a kit procedure with a licensed 68Ge/68Ga generator. 68Ga-NeoBOMB1 (3 MBq/kg of body weight) was injected intravenously, and safety parameters were assessed. PET/CT included dynamic imaging at 5, 11, and 19 min as well as static imaging at 1, 2, and 3-4 h after injection for dosimetry calculations. Venous blood samples and urine were collected for pharmacokinetic analysis. Tumor targeting was assessed on a per-lesion and per-patient basis. Results:68Ga-NeoBOMB1 (50 µg) was prepared with high radiochemical purity (yield > 97%). Patients received 174 ± 28 MBq of the radiotracer, which was well tolerated in all patients over a follow-up period of 4 wk. Dosimetry calculations revealed a mean effective dose of 0.029 ± 0.06 mSv/MBq, with the highest organ dose to the pancreas (0.274 ± 0.099 mSv/MBq). Mean plasma half-life was 27.3 min with primarily renal clearance (mean 25.7% ± 5.4% of injected dose 4 h after injection). Plasma metabolite analyses revealed high stability; metabolites were detected only in the urine. In 3 patients, a significant uptake with increasing maximum SUVs (SUVmax at 2 h after injection: 4.3-25.9) over time was found in tumor lesions. Conclusion: This phase I/IIa study provides safety data for 68Ga-NeoBOMB1, a promising radiopharmaceutical for targeting GRPR-expressing tumors. Safety profiles and pharmacokinetics are suitable for PET imaging, and absorbed dose estimates are comparable to those of other 68Ga-labeled radiopharmaceuticals used in clinical routine.

Modelling the internalisation process of prostate cancer cells for PSMA-specific ligands.

INTRODUCTION: In prostate-specific membrane antigen (PSMA)-targeting radioligand therapy, small molecules are regularly internalised by the tumour cells. To determine the effectiveness of these ligands, the internalised fraction over time is derived from cell studies. Parameters, such as the ligand concentration and the number of cells, are experiment-specific and therefore a comparison between ligands is difficult. A more objective approach that allows better comparison is desirable. Therefore, the aim of this work was to develop a compartmental model that fully describes all relevant pharmacokinetic interactions of PSMA-specific ligands with prostate cancer cells. METHODS: Internalisation studies were performed using the lymph node carcinoma of the prostate cell line LNCaP C4-2 and the prostatic carcinoma cell line PC-3. A new protocol was established for the determination of the PSMA-binding specificity by surface plasmon resonance (SPR). The experimental data in combination with parameters from literature were used for the modelling approach. RESULTS: A compartmental model which includes the relevant physiological mechanisms was developed. The basic model structure and some parameters originate from the literature. The PSMA-specific association and dissociation rates of Ga-PSMA-11 were measured using surface plasmon resonance technology. The ligand-induced internalisation and PSMA synthesis rates were estimated by fitting the developed model to experimental data obtained using LNCaP C4-2 cells. For all [68Ga]Ga-PSMA-11 concentrations and including four various incubation times, the ligand-induced internalisation was determined to be (3.6 ±â€¯0.1) % min-1. CONCLUSIONS: The presented approach is a prerequisite for better estimation and thus comparison of important ligand-cell interaction parameters, by combining SPR measurements, cell experiments and mathematical modelling. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT: A compartmental model was developed for evaluation and comparison of PSMA-binding small molecules. A SPR protocol was established for the determination of PSMA-binding specificity.

Treatment planning algorithm for peptide receptor radionuclide therapy considering multiple tumor lesions and organs at risk.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) has shown promising results in the treatment of tumors with high expression of somatostatin receptors such as neuroendocrine tumors (NETs) and meningioma. However, PRRT potentially produces high renal and red marrow (RM) toxicity, the kidneys usually being the dose-limiting organ. Previously, it was shown that an improved therapeutic index can be achieved by choosing an optimal combination of injected activity and peptide molar amount. The aim of this work was to develop a clinically applicable algorithm for treatment planning in PRRT. To demonstrate the applicability and possible advantages of the algorithm thus developed, an in silico clinical trial applying the algorithm to 177 Lu-DOTATATE therapy in nine virtual patients was conducted. METHODS: An algorithm for treatment planning in PRRT was developed, which simultaneously considers multiple tumor lesions, maximum tolerated biologically effective doses (BEDs) for multiple organs at risk (OARs) and a maximum achievable molar activity. The algorithm, subject to the abovementioned constraints, aims at maximizing the total number of killed tumor cells in the considered lesions/metastases. An in silico clinical trial was conducted with nine virtual patients. For each virtual patient, simulations increasing the molar dose of 177 Lu-DOTATATE from 2 to 2048 nmol by factors of 25 were performed. Maximum tolerated BEDs per cycle for the kidneys (10 Gy2.5 ) and for the RM (0.5 Gy15 ) were defined based on a planned total treatment of four cycles. A maximum achievable molar activity of 420 MBq/nmol was assumed. Optimal combinations of molar dose and activity were determined by applying the developed algorithm. For comparison, simulations for a typical plan with 177 Lu-DOTATATE (7.4 GBq, 265 nmol) were performed and BEDs for the OARs and for individual tumor lesions were calculated. Furthermore, to determine treatment efficacy, overall tumor control probability (oTCP) values after a four-cycle treatment were estimated for the optimal and typical plans. RESULTS: The conducted in silico clinical trial yielded optimal molar doses and activities ranging from 24 to 512 nmol and from 6 to 30 GBq, respectively. Tumor BEDs ranged from 2 to 107 Gy10 and from 1 to 65 Gy10 for the optimal and typical plans, respectively. The estimated oTCP values showed that the optimal plans may produce adequate tumor control in six of the nine virtual patients after four cycles of 177 Lu-DOTATATE while the typical plan may be sufficient in only two virtual patients. CONCLUSIONS: The algorithm presented can derive plans with higher tumor control than the typically delivered plan. Therefore, we propose this algorithm for clinical validation and possibly future implementation in treatment planning in molecular radiotherapy.