A Novel Time–Activity Information-Sharing Approach Using Nonlinear Mixed Models for Patient-Specific Dosimetry with Reduced Imaging Time Points: Application in SPECT/CT After ¹⁷⁷Lu-DOTATATE

Abstract

Multiple time point SPECT/CT imaging for dosimetry is burdensome for patients and lacks statistical efficiency. A novel method for joint kidney time-activity estimation based on a statistical mixed model, a prior cohort of patients with complete time-activity data, and only one or two imaging points for new patients was compared to previously proposed single time point methods in virtual and clinical patient data. Methods: Data were available for ten patients with neuroendocrine tumors treated with Lu-177 DOTATATE and imaged up to four times between days 0 and 7 using SPECT/CT. Mixed models using one or two time points were evaluated retrospectively in the clinical cohort, using the multiple time point fit as the reference. Timeactivity data for 250 virtual patients were generated using parameter values from the clinical cohort. Mixed models were fit using one (~96h) and two (4h, ~96h) time points for each virtual patient combined with complete data for the other patients in each data set. Time-integrated activities (TIAs) calculated from mixed model fits and other reduced time point methods were compared to known values. Results: All mixed models and single time point methods performed well overall, achieving mean bias <7% in the virtual cohort. Mixed models exhibited lower bias, greater precision, and substantially fewer outliers compared to single time point methods. For clinical patients, one and two time point mixed models resulted in more accurate TIA estimates for 94% (17/18) and 72% (13/18) of kidneys, respectively, but should be further validated in a larger cohort. In virtual patients, mixed models resulted in more than a two-fold reduction in the proportion of kidneys with |bias| > 10% (6% vs. 15%). Conclusions: Mixed models based on a historical cohort of patients with complete time-activity data and new patients with only one or two SPECT/CT scans demonstrate less bias on average and significantly fewer outliers when estimating kidney TIA, compared with popular reduced time point methods. Use of mixed models allows for reduction of the imaging burden while maintaining accuracy, which is crucial for clinical implementation of dosimetry-based treatment.

EANM dosimetry committee recommendations for dosimetry of 177Lu-labelled somatostatin-receptor- and PSMA-targeting ligands

“…It is generally not recommended to routinely perform absorbed dose calculations based on a single time point. However, as shown in recent publications on [177Lu]Lu-SSRT and [177Lu]Lu-PSMA therapies [139][140][141][142], it is possible if the pharmacokinetics has previously been characterised across a population, and the effective half-life in the organ of interest does not vary widely from patient to patient. The uncertainty associated with such techniques is governed by the distribution and representativeness of the population data.…”

Patient-specific dosimetry adapted to variable number of SPECT/CT time-points per cycle for $$^{177}$$Lu-DOTATATE therapy

“…Dosimetric workflow Several authors proposed methods to estimate absorbed doses from a low number of acquisitions [ 15 – 17 , 19 – 22 ] by using an approximation of time-integrated activity from mono-exponential model [ 16 , 17 ] or a bi-exponential model [ 20 ] or by exploiting a priori information about pharmacokinetic properties (e.g., pharmacokinetic parameters are homogeneous between patients). In this study, the tri-exponential model was chosen to take into account patients’ physiology and seems to be better than the mono-exponential model [ 41 ].…”

“…On the one hand, some works try to reduce the number of acquisitions by selecting the appropriate time-points and/or the type of acquisition (planar and/or SPECT/CT) so that the error from the original workflow is as small as possible [ 13 , 14 ]. Others proposed workflows reduced to a single SPECT/CT acquisition from the second cycle [ 15 – 20 ], based on an approximation of the time-integrated activity or a priori information: use of pharmacokinetics obtained in a previous cycle [ 21 ] or from other patients [ 22 ]. In most published studies, the TAC is modelled with mono-exponential function that considers only one global decrease phase and not the three physiological phases: one uptake phase and two clearance phases (rapid- and long-term).…”

Bestimmung der zeitintegrierten Aktivität mit einem Messwert und einem PBPK-Modell im Rahmen der NLME-Modellierung

“…Zusätzlich wurden die TIACs mit den gleichen Modellen und nur jeweils genau einem der 5 Messzeitpunkte berechnet. Die relativen Abweichungen (RA) (Median, min, max) zwischen den aus nur einem Messzeitpunkt berechneten TIACs und den Referenz-TIACs wurden analysiert und mit den Ergebnissen von Devasia et al 1 verglichen.…”

“…T4=48 h wurde als der Zeitpunkt mit den niedrigsten medianen RA ermittelt: RA_Tumor=(2, -16, 21)%, RA_Nieren=(5, 0, 18)%, RA_Leber=(0, -13, 11)%, RA_Milz=(9, -11, 16)%, RA_GK=(2, -3, 7)% und RA_Serum=(4, -23, 25)%. Die hier erhaltenen Ergebnisse für die RA der TIACs waren im Vergleich zur Methode von Devasia et al 1 ähnlich für die Nieren, aber um einen Faktor 2–17 besser für Tumoren.…”