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      Accuracy and uncertainty analysis of reduced time point imaging effect on time-integrated activity for 177Lu-DOTATATE PRRT in patients and clinically realistic simulations

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          Abstract

          Background

          Dosimetry promises many advantages for radiopharmaceutical therapies but repeat post-therapy imaging for dosimetry can burden both patients and clinics. Recent applications of reduced time point imaging for time-integrated activity (TIA) determination for internal dosimetry following 177Lu-DOTATATE peptide receptor radionuclide therapy have shown promising results that allow for the simplification of patient-specific dosimetry. However, factors such as scheduling can lead to sub-optimal imaging time points, but the resulting impact on dosimetry accuracy is still under investigation. We use four-time point 177Lu SPECT/CT data for a cohort of patients treated at our clinic to perform a comprehensive analysis of the error and variability in time-integrated activity when reduced time point methods with various combinations of sampling points are employed.

          Methods

          The study includes 28 patients with gastroenteropancreatic neuroendocrine tumors who underwent post-therapy SPECT/CT imaging at approximately 4, 24, 96, and 168 h post-therapy (p.t.) following the first cycle of 177Lu-DOTATATE. The healthy liver, left/right kidney, spleen and up to 5 index tumors were delineated for each patient. Time-activity curves were fit with either monoexponential or biexponential functions for each structure, based on the Akaike information criterion. This fitting was performed using all 4 time points as a reference and various combinations of 2 and 3 time points to determine optimal imaging schedules and associated errors. 2 commonly used methods of single time point (STP) TIA estimation are also evaluated. A simulation study was also performed with data generated by sampling curve fit parameters from log-normal distributions derived from the clinical data and adding realistic measurement noise to sampled activities. For both clinical and simulation studies, error and variability in TIA estimates were estimated with various sampling schedules.

          Results

          The optimal post-therapy imaging time period for STP estimates of TIA was found to be 3–5 days (71–126 h) p.t. for tumor and organs, with one exception of 6–8 days (144–194 h) p.t. for spleen with one STP approach. At the optimal time point, STP estimates give mean percent errors (MPE) within ± 5% and SD < 9% across all structures with largest magnitude error for kidney TIA (MPE = − 4.1%) and highest variability also for kidney TIA (SD = 8.4%). The optimal sampling schedule for 2TP estimates of TIA is 1–2 days (21–52 h) p.t. followed by 3–5 days (71–126 h) p.t. for kidney, tumor, and spleen. Using the optimal sampling schedule, the largest magnitude MPE for 2TP estimates is 1.2% for spleen and highest variability is in tumor with SD = 5.8%. The optimal sampling schedule for 3TP estimates of TIA is 1–2 days (21–52 h) p.t. followed by 3–5 days (71–126 h) p.t. and 6–8 days (144–194 h) p.t. for all structures. Using the optimal sampling schedule, the largest magnitude MPE for 3TP estimates is 2.5% for spleen and highest variability is in tumor with SD = 2.1%. Simulated patient results corroborate these findings with similar optimal sampling schedules and errors. Many sub-optimal reduced time point sampling schedules also exhibit low error and variability.

          Conclusions

          We show that reduced time point methods can be used to achieve acceptable average TIA errors over a wide range of imaging time points and sampling schedules while maintaining low uncertainty. This information can improve the feasibility of dosimetry for 177Lu-DOTATATE and elucidate the uncertainty associated with non-ideal conditions.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s13550-023-01007-z.

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          Most cited references26

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          Phase 3 Trial of (177)Lu-Dotatate for Midgut Neuroendocrine Tumors.

          Background Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 ((177)Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors. Methods We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either (177)Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) ((177)Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here. Results At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the (177)Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the (177)Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the (177)Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the (177)Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame. Conclusions Treatment with (177)Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the (177)Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11 .).
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            177Lu-Dotatate plus long-acting octreotide versus high‑dose long-acting octreotide in patients with midgut neuroendocrine tumours (NETTER-1): final overall survival and long-term safety results from an open-label, randomised, controlled, phase 3 trial

            The primary analysis of the phase 3 NETTER-1 trial showed significant improvement in progression-free survival with 177Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide alone in patients with advanced midgut neuroendocrine tumours. Here, we report the prespecified final analysis of overall survival and long-term safety results.
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              MIRD pamphlet no. 16: Techniques for quantitative radiopharmaceutical biodistribution data acquisition and analysis for use in human radiation dose estimates.

              This report describes recommended techniques for radiopharmaceutical biodistribution data acquisition and analysis in human subjects to estimate radiation absorbed dose using the Medical Internal Radiation Dose (MIRD) schema. The document has been prepared in a format to address two audiences: individuals with a primary interest in designing clinical trials who are not experts in dosimetry and individuals with extensive experience with dosimetry-based protocols and calculational methodology. For the first group, the general concepts involved in biodistribution data acquisition are presented, with guidance provided for the number of measurements (data points) required. For those with expertise in dosimetry, highlighted sections, examples and appendices have been included to provide calculational details, as well as references, for the techniques involved. This document is intended also to serve as a guide for the investigator in choosing the appropriate methodologies when acquiring and preparing product data for review by national regulatory agencies. The emphasis is on planar imaging techniques commonly available in most nuclear medicine departments and laboratories. The measurement of the biodistribution of radiopharmaceuticals is an important aspect in calculating absorbed dose from internally deposited radionuclides. Three phases are presented: data collection, data analysis and data processing. In the first phase, data collection, the identification of source regions, the determination of their appropriate temporal sampling and the acquisition of data are discussed. In the second phase, quantitative measurement techniques involving imaging by planar scintillation camera, SPECT and PET for the calculation of activity in source regions as a function of time are discussed. In addition, nonimaging measurement techniques, including external radiation monitoring, tissue-sample counting (blood and biopsy) and excreta counting are also considered. The third phase, data processing, involves curve-fitting techniques to integrate the source time-activity curves (determining the area under these curves). For some applications, compartmental modeling procedures may be used. Last, appendices are included that provide a table of symbols and definitions, a checklist for study protocol design, example formats for quantitative imaging protocols, temporal sampling error analysis techniques and selected calculational examples. The utilization of the presented approach should aid in the standardization of protocol design for collecting kinetic data and in the calculation of absorbed dose estimates.
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                Author and article information

                Contributors
                aviator@umich.edu
                Journal
                EJNMMI Res
                EJNMMI Res
                EJNMMI Research
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                2191-219X
                12 June 2023
                12 June 2023
                2023
                : 13
                : 57
                Affiliations
                [1 ]GRID grid.214458.e, ISNI 0000000086837370, Department of Radiology, , University of Michigan, ; 1301 Catherine, 2276 Medical Science I/5610, Ann Arbor, MI 48109 USA
                [2 ]GRID grid.254444.7, ISNI 0000 0001 1456 7807, Department of Radiation Oncology, , Wayne State University, ; Detroit, MI USA
                [3 ]MIM Software Inc, Cleveland, OH USA
                Author information
                http://orcid.org/0000-0001-6531-5431
                Article
                1007
                10.1186/s13550-023-01007-z
                10260735
                37306783
                605f5cda-6c5c-48a4-8a20-be34ccdfd1ed
                © The Author(s) 2023

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 18 April 2023
                : 1 June 2023
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: R01CA240706
                Award Recipient :
                Categories
                Original Research
                Custom metadata
                © Springer-Verlag GmbH Germany, part of Springer Nature 2023

                Radiology & Imaging
                177lu,radionuclide therapy,dosimetry,single time point,reduced time point
                Radiology & Imaging
                177lu, radionuclide therapy, dosimetry, single time point, reduced time point

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