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Method Article
This method estimates the absorbed dose of different structures for peptide-receptor-radionuclide-therapy (PRRT) with the possibility of avoiding organ overlap on 2D-projections. Serial whole-body planar images permit estimation of mean absorbed doses along the whole body, while the hybrid approach, combining planar images and 3D-SPECT/CT image, overcomes the limitations of structure overlapping.
Peptide-receptor-radionuclide-therapy (PPRT) is a targeted therapy that combines a short-range energy radionuclide with a substrate with high specificity for cancer cell receptors. After injection, the radiotracer is distributed throughout the entire body, with a higher uptake in tissues where targeted receptors are overexpressed. The use of beta/gamma radionuclide emitters enables therapy imaging (beta-emission) and post-therapy imaging (gamma-emission) to be performed at the same time. Post-treatment sequential images permit absorbed dose calculation based on local uptake and wash-in/wash-out kinetics. We implemented a hybrid method that combines information derived from both 2D and 3D images. Serial whole-body images and blood samples are acquired to estimate the absorbed dose to different organs at risk and to lesions disseminated throughout the body. A single 3D-SPECT/CT image, limited to the abdominal region, overcomes projection overlap on planar images of different structures such as the intestines and kidneys. The hybrid 2D+3D-SPECT/CT method combines the effective half-life information derived from 2D planar images with the local uptake distribution derived from 3D images. We implemented this methodology to estimate the absorbed dose for patients undergoing PRRT with 177Lu-PSMA-617. The methodology could, however, be implemented with other beta-gamma radiotracers. To date, 10 patients have been enrolled into the dosimetry study with 177Lu-PSMA-617 combined with drug protectors for kidneys and salivary glands (mannitol and glutamate tablets, respectively). The median ratio between kidney uptake at 24 h evaluated on planar images and 3D-SPECT/CT is 0.45 (range:0.32-1.23). The comparison between hybrid and full 3D approach has been tested on one patient, resulting in a 1.6% underestimation with respect to full 3D (2D: 0.829 mGy/MBq, hybrid: 0.315 mGy/MBq, 3D: 0.320 mGy/MBq). Treatment safety has been confirmed, with a mean absorbed dose of 0.73 mGy/MBq (range:0.26-1.07) for kidneys, 0.56 mGy/MBq (0.33-2.63) for the parotid glands and 0.63 mGy/MBq (0.23-1.20) for submandibular glands, values in accordance with previously published data.
Among peptide-receptor radionuclide therapies, 177Lu-PSMA-617 PRRT combines a short-range beta emitter 177Lu (1.9 mm maximum range in water, half-life 6.71 days) with a prostate-specific membrane antigen (PSMA) ligand. The overexpression of PSMA in 90-100% of local prostate cancer lesions and metastatic disease (lymph node and bone) is the key to this therapy. However, PSMA receptors are also expressed in different healthy tissues where high uptake is often observed during treatments. The main organs at risk are the kidneys, red marrow, salivary and lachrymal glands. The dose to these organs may reduce maximum injectable activity, impairing the therapeutic ratio.
Our institute (IRST IRCCS) activated a protocol with the aim of increasing the therapeutic ratio between lesions and healthy tissues, providing drug protectors combined with 177Lu-PSMA-617 therapy. Mannitol, polyglutamate folate tablets combined with externally applied ice packs and N-acetylaspartylglutammate acid eye drops are used for kidneys, salivary and lachrymal gland preservation, respectively1. Post-infusion dosimetric studies are required to estimate the effective half-life (i.e., combination of physical and biological half-life) and absorbed dose for different structures of interest localized throughout the body (e.g., kidneys, salivary glands, disseminated lesions). This scenario requires whole body information obtained by acquiring sequential post-infusion whole-body planar images2. However, the overlap of high uptake structures (e.g., transient intestine uptake above the kidneys) requires 3D information capable of discriminating between different local uptakes that are blended on 2D projections. We implemented a hybrid method capable of providing a dosimetric evaluation of the entire body thanks to 2D planar images2, maintaining 3D information on a selected region (e.g., abdominal region). This method combines the activity distribution provided by 3D SPECT/CT images with the effective half-life calculated from planar images. Information obtained from other non-overlapping structures (e.g., salivary glands) are derived from planar image study only. The blood sample method used for red marrow evaluation is described in another section.
The advantage of the hybrid approach is that the entire body can be scanned, whereas a full 3D SPECT/CT method limits cranio-caudal image extension, which may make it impossible to study structures that are distant from each other. However, the low image resolution of planar imaging and the need to implement an overlap correction using a single 3D SPECT/CT acquisition represent the main drawbacks.
In order to test the safety and efficacy of PRRT therapies, it is important to compare single institution data with data previously published by other groups. The majority of published data with 177Lu-PSMA-617 are based on planar images. Thus, the described method could also be useful for the standardization of the methodologies used. Finally, it is worthy of note that the implementation of the methodology requires a high degree of collaboration between different professional figures involved (i.e., physicians, physicists, medical radiology technicians, nurses).
The dosimetry procedure was performed according to the treatment protocol "Radiometabolic Therapy (RMT) with 177Lu-PSMA-617 in advanced castration resistant prostate cancer (CRPC): efficacy and toxicity evaluation" (EUDRACT/RSO number: 2016-002732-32) (Figure 1). Selected patients underwent dosimetry evaluation based on performance status. All patients signed informed consent. Prior to treatment delivery, each patient underwent a 68Ga-PSMA-11 PET/CT whole body scan.
NOTE: It is important to underline that some steps are linked specifically to the scanner used.
1. Pre-infusion Imaging: Transmission and Blank Image Acquisition
NOTE: In this first image acquisition the patient's water equivalent thickness is evaluated. This value is used for attenuation correction of counts derived from 2D planar images acquired post 177Lu-PSMA-617 injection.
2. Post-infusion Image Acquisition: Planar Image
NOTE: Planar post-image acquisitions are used for effective half-life and mean absorbed dose evaluation of different structures.
3. Post-infusion Image Acquisition: 3D SPECT/CT
NOTE: On day 2 (16-24 h post infusion) a 3D image acquisition is performed, together with the planar image acquisition. The 3D SPECT/CT image focuses on the abdominal region and enables organ overlap (e.g., kidneys or intestinal loops) to be avoided on anterior/posterior projections.
4. Image Analysis
NOTE: Scatter, attenuation, and background corrections are implemented. Single organ and lesion mass are considered for absorbed dose evaluation. ROI and VOI are contoured on planar and 3D images.
5. Blood Sample Measurements
NOTE: Blood sample measurements are performed on High Purity Germanium (HPGe) detector for red marrow dose estimation.
6. Dosimetry evaluation
NOTE: The analysis is performed with a dedicated dosimetry software based on MIRD publications4,5,6,7,8. For each considered structure, effective half-life is evaluated on sequential 2D whole body images by bi- or mono-exponential curve fitting of time-activity curves. 3D SPECT/CT imaging is used to resolve the problem of high uptake intestine overlap on kidney structure by scaling the time-activity curves derived from planar images. Mean absorbed dose is then calculated for each structure mass. For red marrow dose evaluation, blood samples measurements are used and scaled to the patient's weight.
Dosimetry was performed for 10 patients (7 undergoing first treatment cycle, 3 second cycle). Blood samples were acquired from all but 3 patients. One patient voided the bladder before the first post-infusion image acquisition. Injected activity was 5.5 GBq for 5 patients and 4.4 GBq for 5 patients.
With regard to curve fitting, mono or bi-exponential curve fitting was used for organ time-activity-curves. Bi-exponential cu...
The method described enables whole body dosimetry to be performed for PRRT therapies and is a valid compromise between 2D whole-body and 3D dosimetry information in that it provides valuable information without significantly increasing image acquisition load. The method is also useful for the evaluation of the absorbed dose of overlapping structures and provides information on the structures lying outside the 3D SPCET/CT limited field of view.
The implementation of the methodology requires a h...
The authors have nothing to disclose.
Our thanks go to the professional figures involved in the protocol (i.e., physicians, physicists and nurses) and to the patients who agreed to take part in the study. We are also grateful to the medical radiology technicians of the Nuclear Medicine Unit for their help with protocol implementation: Valentina Mautone, Maria Caternicchia, Monia Pancisi, Daniela Fichera and Delia Bevilacqua. The authors acknowledge Alessandro Savini and Simone Marzoni for their help in the video recording. The work was partially supported by AIRC (Italian Association for Cancer Research, grant number: L2P1367 - L2P1520). The work was partially financed by the Italian Minister of Health.
Name | Company | Catalog Number | Comments |
177Lu EndolucinBeta | ITG - Isotopen Technologien München AG, Lichtenbergstrasse 1, 85748 Garching, Germany, info@itm.ag | Radiotracer 177Lu for therapy purpuse | |
Biograph mCT Flow PET/CT | Siemens Healthineers, Erlangen, Germany | PET/CT scanner | |
C-Thru 57Co planar flood - Model MED3709 | Eckert & Ziegler, Strahlen- und Medizintechnik AG, Robert-Rössle-Str. 10, 13125 Berlin, Germany, info@ezag.de | Calibration/planar source | |
Cylindrical phantom with spheric insert | Data Spectrum Corporation, 1605 East Club Boulevard, Durham NC 27704-3406, US, info@spect.com | Phantom for SPECT/CT calibration | |
Discovery NM/CT 670 SPECT/CT | International General Electric, General Electric Medical System, Haifa, Israel | SPECT/CT scanner | |
GalliaPharm 68Ge/68Ga Generator | Eckert & Ziegler, Strahlen- und Medizintechnik AG, Robert-Rössle-Str. 10, 13125 Berlin, Germany, info@ezag.de | 68Ge/68Ga Generator of 68Ga for imaging purposes | |
GammaVision v 6.08 | Ortec, Ametek - Advanced Measurement Technology, 801 South Illinois Avenue, Oak Ridge, Tennessee 37830, US, ortec.info@ametek.com | Gamma Spectorscopy software | |
High Purity Germanium HPGe, model GEM30P4-70 | Ortec, Ametek - Advanced Measurement Technology, 801 South Illinois Avenue, Oak Ridge, Tennessee 37830, US, ortec.info@ametek.com | Gamma spectometer | |
MimVista Software | MIM Software INC, Cleveland, OH 44122, US | Workstation | |
OLINDA/EXM v 1.1 | RADAR - RAdiation Dose Assessment Resource, West End Ave, Nashville, TN 37235, US (now commercially available as OLINDA/EXM v 2.0, Hermes Medical Solutions, Strandbergsgatan 16, 112 51 Stockholm, Sweden, info@hermesmedical.com) | Dosimetry software | |
PSMA 11 | ABX advanced biochemical compounds - Biomedizinische,Heinrich-Gläser-Straße 10-14, 01454 Radeberg, Germania, info@abx.de | Carrier for 68Ga radiotracer | |
PSMA 617 | Endocyte Inc. (Headquarters), 3000 Kent Avenue, West Lafayette, IN 47906 | Carrier for 177Lu radiotracer | |
Xeleris4.0 | International General Electric, General Electric Medical System, Haifa, Israel | Workstation |
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