Dependence of treatment planning accuracy in peptide receptor radionuclide therapy on the sampling schedule (original) (raw)
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Cancer Biotherapy and Radiopharmaceuticals, 2016
The aim of this work was to evaluate the sensitivity of time-integrated activity coefficients (TIACs) on the erroneously chosen prior knowledge in a physiologically based pharmacokinetic (PBPK) model used for treatment planning in peptide receptor radionuclide therapy (PRRT). Parameters of the PBPK model were fitted to the biokinetic data of 15 patients after the injection of 111 In-DTPAOC. The fittings were performed using fixed parameter values taken from literature as prior knowledge (reference case, Ref). The fixed parameters were gender, physical information (e.g., body weight), dissociation rate k off , dissociation constant K D , fraction of blood flow, and spleen and liver volumes. The fittings were repeated with changed fixed parameters (Changed). The relative deviations (RDs) of TIACs calculated from Changed and Ref were analyzed for kidneys, tumor, liver, spleen, remainder, whole body, and serum. A changed k off has the largest effect on RD, the largest RD values were found for changed k off = 0.001 L/min: RD kidneys = (3-3)%, RD tumor = (0.5-4)%, RD liver = (6-9)%, RD spleen = (5-5)%, RD remainder = (2-31)%, RD serum = (-4-25)%, and RD wholebody = (3-16)%. For other changed parameters, the maximum RDs were <1%. The calculation of organ TIACs in PRRT using the PBPK model was little affected by assigning wrong prior knowledge to the evaluated patients. The calculation of bone marrow-absorbed doses could be affected by the inaccurate TIACs of serum and remainder in the case of an inadequate k off .
Medical Physics, 2016
The aim of this study was to investigate the accuracy of PET-based treatment planning for predicting the time-integrated activity coefficients (TIACs). Methods: The parameters of a physiologically based pharmacokinetic (PBPK) model were fitted to the biokinetic data of 15 patients to derive assumed true parameters and were used to construct true mathematical patient phantoms (MPPs). Biokinetics of 150 MBq 68 Ga-DOTATATE-PET was simulated with different noise levels [fractional standard deviation (FSD) 10%, 1%, 0.1%, and 0.01%], and seven combinations of measurements at 30 min, 1 h, and 4 h p.i. PBPK model parameters were fitted to the simulated noisy PET data using population-based Bayesian parameters to construct predicted MPPs. Therapy simulations were performed as 30 min infusion of 90 Y-DOTATATE of 3.3 GBq in both true and predicted MPPs. Prediction accuracy was then calculated as relative variability v organ between TIACs from both MPPs. Results: Large variability values of one time-point protocols [e.g., FSD = 1%, 240 min p.i., v kidneys = (9 ± 6)%, and v tumor = (27 ± 26)%] show inaccurate prediction. Accurate TIAC prediction of the kidneys was obtained for the case of two measurements (1 and 4 h p.i.), e.g., FSD = 1%, v kidneys = (7 ± 3)%, and v tumor = (22 ± 10)%, or three measurements, e.g., FSD = 1%, v kidneys = (7 ± 3)%, and v tumor = (22 ± 9)%. Conclusions: 68 Ga-DOTATATE-PET measurements could possibly be used to predict the TIACs of 90 Y-DOTATATE when using a PBPK model and population-based Bayesian parameters. The two time-point measurement at 1 and 4 h p.i. with a noise up to FSD = 1% allows an accurate prediction of the TIACs in kidneys.
Differences in predicted and actually absorbed doses in peptide receptor radionuclide therapy
Medical Physics, 2012
Purpose: An important assumption in dosimetry prior to radionuclide therapy is the equivalence of pretherapeutic and therapeutic biodistribution. In this study the authors investigate if this assumption is justified in sst2-receptor targeting peptide therapy, as unequal amounts of peptide and different peptides for pretherapeutic measurements and therapy are commonly used. Methods: Physiologically based pharmacokinetic models were developed. Gamma camera and serum measurements of ten patients with metastasizing neuroendocrine tumors were conducted using 111 In-DTPAOC. The most suitable model was selected using the corrected Akaike information criterion. Based on that model and the estimated individual parameters, predicted and measured 90 Y-DOTATATE excretions during therapy were compared. The residence times for the pretherapeutic (measured) and therapeutic scenarios (simulated) were calculated. Results: Predicted and measured therapeutic excretion differed in three patients by 10%, 31%, and 7%. The measured pretherapeutic and therapeutic excretion differed by 53%, 56%, and 52%. The simulated therapeutic residence times of kidney and tumor were 3.1 ± 0.6 and 2.5 ± 1.2 fold higher than the measured pretherapeutic ones. Conclusions: To avoid the introduction of unnecessary inaccuracy in dosimetry, using the same substance along with the same amount for pretherapeutic measurements and therapy is recommended.
2021
In this study, we identified the most important physiologic parameters determining the variability of the organ at risk and tumor absorbed doses (ADs) in Peptide-receptor radionuclide therapy (PRRT). Therefore, a global sensitivity analysis (GSA) with Sobol method and a physiologically-based pharmacokinetic (PBPK) model were used. A whole-body PBPK model that has been developed for treatment planning in PRRT therapy for meningioma and neuroendocrine patients was used. The physiologic parameters of interest for the GSA analysis were the parameters that have been previously estimated from the biokinetic data and were reported in the literature, i.e. the organ receptor densities Rd, organ flows f, organ release rates, and peptide binding rate. GSA with Sobol method was chosen based on its accuracy for sensitivity studies. A widely used GSA MATLAB-based toolbox (https://www.safetoolbox.info/) and an in-house program based on MATLAB software (version R2018b) were used for the analysis. The sampling method with a log-normal distribution was used to avoid any negative values of the sampled parameters. The main effects Si and total effects STi were calculated and analyzed using the GSA program and the PBPK model to identify the importance of each model parameter i for the individualization of the ADs in PRRT. To warrant the convergence of the calculated Si and STi, various numbers of model simulations up to 15000 samples were used. The inter-individual variability of tumor ADs (coefficients of variation CV up to 97.05%) was higher than that in the organ at risk (e.g. kidneys CV around 31.59%). Receptor density was identified as the most important parameters determined the ADs of tumors, e.g. [RdTU2]: Si = 0.856, STi = 0.951. The same results was found for the organ at risk where the receptor density had the highest main effect and total effect values, e.g. [RdK]: Si = 0.802, STi = 0.963. We have shown the first implementation of the GSA with the Sobol method to identify the most important parameters for the individualization of the calculated ADs in PRRT. Our results suggested an accurate measurement of the receptor densities for an accurate determination of the tumor and organ at risk ADs.
Physica Medica, 2017
To investigate the accuracy of predicted time-integrated activity coefficients (TIACs) in peptidereceptor radionuclide therapy (PRRT) using simulated dynamic PET data and a physiologically based pharmacokinetic (PBPK) model. Methods: PBPK parameters were estimated using biokinetic data of 15 patients after injection of (152 ± 15) MBq of 111 In-DTPAOC (total peptide amount (5.78 ± 0.25) nmol). True mathematical phantoms of patients (MPPs) were the PBPK model with the estimated parameters. Dynamic PET measurements were simulated as being done after bolus injection of 150 MBq 68 Ga-DOTATATE using the true MPPs. Dynamic PET scans around 35 min p.i. (P 1), 4 h p.i. (P 2) and the combination of P 1 and P 2 (P 3) were simulated. Each measurement was simulated with four frames of 5 min each and 2 bed positions. PBPK parameters were fitted to the PET data to derive the PET-predicted MPPs. Therapy was simulated assuming an infusion of 5.1 GBq of 90 Y-DOTATATE over 30 min in both true and PET-predicted MPPs. TIACs of simulated therapy were calculated, true MPPs (true TIACs) and predicted MPPs (predicted TIACs) followed by the calculation of variabilities v. Results: For P 1 and P 2 the population variabilities of kidneys, liver and spleen were acceptable (v < 10%). For the tumours and the remainders, the values were large (up to 25%). For P 3 , population variabilities for all organs including the remainder further improved, except that of the tumour (v > 10%). Conclusion: Treatment planning of PRRT based on dynamic PET data seems possible for the kidneys, liver and spleen using a PBPK model and patient specific information.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2004
The therapeutic effects of peptide receptor-based radionuclide therapy are extensively being investigated in rats bearing tumors. Both the dose to the tumor and the therapy-limiting dose to normal tissues, such as kidneys and bone marrow, are of interest for these preclinical studies. The aim of this work was to develop a generalized computational model for internal dosimetry in rats. Mature rats were dissected and the relative positions, dimensions, and weights of all of their major organs were measured. A mathematic model was set up for the rat body and its internal organs to enable Monte Carlo radiation transport calculations to determine estimates for both tumor and organ self-doses as cross-organ doses for (90)Y, (111)In, and (177)Lu. The organs and body were mostly of ellipsoid shape with the axes given as the measured length, width, and height normalized to values that, together with the measured weights, are consistent with the recommended soft-tissue and bone densities. A s...
PROCEEDINGS OF THE INTERNATIONAL CONFERENCE AND SCHOOL ON PHYSICS IN MEDICINE AND BIOSYSTEM (ICSPMB): Physics Contribution in Medicine and Biomedical Applications
This study aimed to determine the effect of the physiological parameters (PP) to the optimal administration of Lysine/Arginine for kidney protection during peptide-receptor radionuclide therapy (PRRT) using the Physiologicallybased Pharmacokinetic (PBPK) model. Modeling of PBPK was performed to describe the bio-distribution of Lysine/Arginine in three patients of Neuroendocrine Tumor. The fitted PBPK model to the bio-distribution of Lysine/Arginine recently reported in the literature was used as the basic framework for the study's analysis in this study. The investigated PPs were blood flow out of the organ to the veins (Fout), organ clearance (c), and the total number of kidneys receptor (RK). Simulations were performed to investigate the effect of the PPs to the optimal time of 90 Y-DOTATATE injection (TI), the Lysine/Arginine dose (DO), and the duration of the administered Lysine/Arginine dose (DU). In these simulations, each PP was varied to the ±SD, ±25%, ±50%, and ±75% of the mean values. The optimal values of TI, DO, and DU were determined based on the smallest AUC (Area Under the Curve) of the peptide in the proximal tubule of the kidneys organ (The smallest AUC value indicates the smallest dose). As a result, the optimal TI, DO, and DU was 31 min, 50 gr Lysine and 50 gr Arginine, and 180 min, respectively. We found that the PPs have a marginal effect on the determination of the optimal administration of the Lysine/Arginine except for the organ clearance (c) parameter which gives a significant change in the AUC value (coefficients of variation CV up to 58.32%, 95%, and 65.54 for TI, DO, and DU, respectively). According to our three patient's model, the currently-used peptide injection at minute 31 (average from three patients) after amino acid infusion and distribution of the 50 gr Lysine and 50 gr Arginine which administered over 180 minutes was suitable for clinical use. Additionally, organ clearance (c) was the most critical parameter on the bio-distribution of Lysine/Arginine.
EJNMMI Physics
Background After each cycle of [177Lu]-DOTA-TATE peptide receptor radionuclide therapy (PRRT) dosimetry is performed to enable precise calculation of the radiation-absorbed dose to tumors and normal organs. Absorbed doses are routinely calculated from three quantitative single-photon emission computed tomography (SPECT) studies corrected by computed tomography (CT) acquired at t1 = 24 h, t2 = 96 h, and t3 = 168 h after the first cycle of treatment. After following cycles, a single SPECT/CT study is performed. The aim of the present study is to assess the feasibility of a “two time point” quantitative SPECT/CT protocol after the first PRRT cycle and its impact on patient management. Quantitative SPECT/CT data of 25 consecutive patients with metastatic neuroendocrine tumors after PRRT were retrospectively analyzed. Radiation-absorbed doses calculated using the standard protocol with three SPECT/CT studies acquired at (t1, t2, t3) were compared to those obtained from three different “t...
A population-based method to determine the time-integrated activity in molecular radiotherapy
EJNMMI Physics, 2021
Background: The calculation of time-integrated activities (TIAs) for tumours and organs is required for dosimetry in molecular radiotherapy. The accuracy of the calculated TIAs is highly dependent on the chosen fit function. Selection of an adequate function is therefore of high importance. However, model (i.e. function) selection works more accurately when more biokinetic data are available than are usually obtained in a single patient. In this retrospective analysis, we therefore developed a method for population-based model selection that can be used for the determination of individual time-integrated activities (TIAs). The method is demonstrated at an example of [ 177 Lu] Lu-PSMA-I&T kidneys biokinetics. It is based on population fitting and is specifically advantageous for cases with a low number of available biokinetic data per patient. Methods: Renal biokinetics of [ 177 Lu]Lu-PSMA-I&T from thirteen patients with metastatic castration-resistant prostate cancer acquired by planar imaging were used. Twenty exponential functions were derived from various parameterizations of monoand bi-exponential functions. The parameters of the functions were fitted (with different combinations of shared and individual parameters) to the biokinetic data of all patients. The goodness of fits were assumed as acceptable based on visual inspection of the fitted curves and coefficients of variation CVs < 50%. The Akaike weight (based on the corrected Akaike Information Criterion) was used to select the fit function most supported by the data from the set of functions with acceptable goodness of fit. Results: The function A 1 βe −(1 + phys) t + A 1 (1 − β)e −(phys) t with shared parameter β was selected as the function most supported by the data with an Akaike weight of 97%. Parameters A 1 and 1 were fitted individually for every patient while parameter β was fitted as a shared parameter in the population yielding a value of 0.9632 ± 0.0037. Conclusions: The presented population-based model selection allows for a higher number of parameters of investigated fit functions which leads to better fits. It also reduces the uncertainty of the obtained Akaike weights and the selected best fit function based on them. The use of the population-determined shared parameter for future patients allows the fitting of more appropriate functions also for patients for whom only a low number of individual data are available.