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

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.

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

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 177 Lu-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 undesirable imaging time points, but the resulting impact on dosimetry accuracy is unknown. We use four-time point 177 Lu 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 combination 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 hours post-therapy (p.t.) following the first cycle of 177 Lu-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 177 Lu-DOTATATE and elucidate the uncertainty associated with non-ideal conditions.

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.

Impact of cyclic changes in pharmacokinetics and absorbed dose in pediatric neuroblastoma patients receiving [177Lu]Lu-DOTATATE.

PURPOSE: Recent reports personalizing the administered activity (AA) of each cycle of peptide receptor radionuclide therapy based on the predicted absorbed dose (AD) to the kidneys (dose-limiting organ) have been promising. Assuming identical renal pharmacokinetics for each cycle is pragmatic, however it may lead to over- or under-estimation of the optimal AA. Here, we investigate the influence that earlier cycles of [177Lu]Lu-DOTATATE had on the biokinetics and AD of subsequent cycles in a recent clinical trial that evaluated the safety and activity of [177Lu]Lu-DOTATATE in pediatric neuroblastoma (NBL). We investigated whether predictions based on an assumption of unchanging AD per unit AA (Gy/GBq) prove robust to cyclical changes in biokinetics. METHODS: A simulation study, based on dosimetry data from six children with NBL who received four-cycles of [177Lu]Lu-DOTATATE in the LuDO trial (ISRCTN98918118), was performed to explore the effect of variable biokinetics on AD. In the LuDO trial, AA was adapted to the patient's weight and SPECT/CT-based dosimetry was performed for the kidneys and tumour after each cycle. The largest tumour mass was selected for dosimetric analysis in each case. RESULTS: The median tumour AD per cycle was found to decrease from 15.6 Gy (range 8.12-26.4) in cycle 1 to 11.4 Gy (range 9.67-28.8), 11.3 Gy (range 2.73-32.9) and 4.3 Gy (range 0.72-20.1) in cycles 2, 3 and 4, respectively. By the fourth cycle, the median of the ratios of the delivered AD (ADD) and the predicted (or "expected") AD (ADE) (which was based on an assumption of stable biokinetics from the first cycle onwards) were 0.16 (range 0.02-0.92, p = 0.013) for the tumour and 1.08 (range 0.84-1.76, p > 0.05) for kidney. None of the patients had an objective response at 1 month follow up. CONCLUSION: This study demonstrates variability in Gy/GBq and tumour AD per cycle in children receiving four administrations of [177Lu]Lu-DOTATATE treatment for NBL. NBL is deemed a radiation sensitive tumour; therefore, dose-adaptive treatment planning schemes may be appropriate for some patients to compensate for decreasing tumour uptake as treatment progresses. Trial registration ISRCTN ISRCTN98918118. Registered 20 December 2013 (retrospectively registered).

Sequential prostate MRI reporting in men on active surveillance: initial experience of a dedicated PRECISE software program.

BACKGROUND AND OBJECTIVES: There is interest in using sequential multiparametric magnetic resonance imaging (mpMRI) to assess men on active surveillance (AS) for prostate cancer. The Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) recommendations propose standardised reporting mpMRI data for these men. This includes accurate size measurements of lesions over time, but such approach is time consuming for the radiologist and there is a strong need of dedicated tools to report serial scans in a systematic manner. We present the results from an initial validation cohort using dedicated PRECISE reporting software to allow automated comparison between sequential scans on AS. MATERIALS AND METHODS: We retrospectively analysed baseline and follow-up scans of 20 men randomised to 6 months of daily dutasteride (n = 10) or placebo (n = 10) from the MAPPED trial. Men underwent 3T mpMRI at baseline and after 6 months, and a dedicated radiologist reported the scans using both a widespread commercially-available platform (Osirix®) and a semi-automated dedicated PRECISE reporting tool (MIM®). Tumour volume by planimetry in all sequences and conspicuity on diffusion-weighted imaging were assessed. Reporting time was recorded, and we used the Wilcoxon test for statistical analysis. RESULTS: Median tumour volumes and conspicuity were similar using both approaches. The reporting time of the follow-up scan was quicker using the PRECISE reporting workflow both in the whole population (12'33″ vs 10'52″; p = 0.005) and in the dutasteride arm (15'50″ vs 12'59″; p = 0.01). A structured report including clinical and imaging data was generated according to the PRECISE recommendations and a comparison table between lesion characteristics at baseline and follow-up scans was also included. CONCLUSION: We conclude that a dedicated PRECISE reporting tool for sequential scans in men on AS results in a significant reduction in the reporting time and allows the radiologist to easily compare scans over time. This tool will help with our understanding of the natural history of mpMRI changes during AS.

Assessment of Vascular Stent Heating with Repetitive Transcranial Magnetic Stimulation.

OBJECTIVE: A high proportion of patients with stroke do not qualify for repetitive transcranial magnetic stimulation (rTMS) clinical studies due to the presence of metallic stents. The ultimate concern is that any metal could become heated due to eddy currents. However, to date, no clinical safety data are available regarding the risk of metallic stents heating with rTMS. METHODS: We tested the safety of common rTMS protocols (1 Hz and 10 Hz) with stents used commonly in stroke, nitinol and elgiloy. In our method, stents were tested in gelled saline at 2 different locations: at the center and at the lobe of the coil. In addition, at each location, stent heating was evaluated in 3 different orientations: parallel to the long axis of coil, parallel to the short axis of the coil, and perpendicular to the plane of the coil. RESULTS: We found that stents did not heat to more than 1°C with either 1 Hz rTMS or 10 Hz rTMS in any configuration or orientation. Heating in general was greater at the lobe when the stent was oriented perpendicularly. CONCLUSIONS: Our study represents a new method for ex vivo quantification of stent heating. We have found that heating of stents was well below the Food and Drug Administration standards of 2°C. Thus, our study paves the way for in vivo testing of rTMS (≤10 Hz) in the presence of implanted magnetic resonance imaging-compatible stents in animal studies. When planning human safety studies though, geometry, orientation, and location relative to the coil would be important to consider as well.