Time-integrated Activity Coefficients Research Articles

A simulation-based method to determine optimal sampling schedules for dosimetry in radioligand therapy

AimFor dosimetry in radioligand therapy, the time-integrated activity coefficients (TIACs) for organs at risk and for tumour lesions have to be determined. The used sampling scheme affects the TIACs and therefore the calculated absorbed doses. The aim of this work was to develop a general and flexible method, which analyses numerous clinically applicable sampling schedules using true time-activity curves (TACs) of virtual patients. MethodNine virtual patients with true TACs of the tumours were created using a physiologically-based pharmacokinetic (PBPK) model and individual biokinetic data of five patients with neuroendocrine tumours and four with meningioma. 111In-DOTATATE was used for pre-therapeutic dosimetry. In total, 15,120 sampling schemes, each consisting of 4 time points, were investigated. Gaussian noise of different levels was added to the corresponding true time-activity points. A bi-exponential function was used to fit the simulated time-activity data. For each investigated sampling schedule, 1000 replications were performed. Patient-specific and population-specific optimal sampling schedules were determined using the relative root-mean-square error (rRMSE). Furthermore, the fractions of TIACs a˜ deviating >5% (fΔa˜>5%) and >10% (fΔa˜>10%) from the true TIAC a˜true were used for additional evaluations e.g. to investigate the effect of varying single time points. ResultsAlmost all patient-specific and all population-specific optimal sampling schedules have t4≥96h for all noise levels. Changing the latest time point from the population-specific optimal time to e.g. 48h leads to a median increase of fΔa˜>10% from 0.1% to 88% for the lowest investigated noise level. Using the determined population-specific optimal schedules, results in more accurate and precise results than established schedules from the literature. ConclusionA method of determining the optimal sampling schedule for dosimetry, which considers clinical working hours and measurement uncertainties, has been developed and applied. The simulation study shows that optimised sampling schedules result in high accuracy and precision of the determined TIACs.

Biodistribution, pharmacokinetics, and organ-level dosimetry for 188Re-AHDD-Lipiodol radioembolization based on quantitative post-treatment SPECT/CT scans

BackgroundRhenium-188-labelled-Lipiodol radioembolization is a safe and cost-effective treatment for primary liver cancer. In order to determine correlations between treatment doses and patient response to therapy, accurate patient-specific dosimetry is required. Up to date, the reported dosimetry of 188Re-Lipiodol has been based on whole-body (WB) planar imaging only, which has limited quantitative accuracy. The aim of the present study is to determine the in vivo pharmacokinetics, bio-distribution, and organ-level dosimetry of 188Re-AHDD-Lipiodol radioembolization using a combination of post-treatment planar and quantitative SPECT/CT images. Furthermore, based on the analysis of the pharmacokinetic data, a practical and relatively simple imaging and dosimetry method that could be implemented in clinics for 188Re-AHDD-Lipiodol radioembolization is proposed.Thirteen patients with histologically proven hepatocellular carcinoma underwent 188Re-AHDD-Lipiodol radioembolization. A series of 2–3 WB planar images and one SPECT/CT scan were acquired over 48 h after the treatment. The time-integrated activity coefficients (TIACs, also known as residence-times) and absorbed doses of tumors and organs at risk (OARs) were determined using a hybrid WB/SPECT imaging method.ResultsWhole-body imaging showed that 188Re-AHDD-Lipiodol accumulated mostly in the tumor and liver tissue but a non-negligible amount of the pharmaceutical was also observed in the stomach, lungs, salivary glands, spleen, kidneys, and urinary bladder. On average, the measured effective half-life of 188Re-AHDD-Lipiodol was 12.5 ± 1.9 h in tumor. The effective half-life in the liver and lungs (the two organs at risk) was 12.6 ± 1.7 h and 12.0 ± 1.9 h, respectively. The presence of 188Re in other organs was probably due to the chemical separation and subsequent release of the free radionuclide from Lipiodol.The average doses per injected activity in the tumor, liver, and lungs were 23.5 ± 40.8 mGy/MBq, 2.12 ± 1.78 mGy/MBq, and 0.11 ± 0.05 mGy/MBq, respectively. The proposed imaging and dosimetry method, consisting of a single SPECT/CT for activity determination followed by 188Re-AHDD-Lipiodol clearance with the liver effective half-life of 12.6 h, resulted in TIACs estimates (and hence, doses) mostly within ± 20% from the reference TIACs (estimated using three WB images and one SPECT/CT).ConclusionsThe large inter-patient variability of the absorbed doses in tumors and normal tissue in 188Re-HDD-Lipiodol radioembolization patients emphasizes the importance of patient-specific dosimetry calculations based on quantitative post-treatment SPECT/CT imaging.

First in-human radiation dosimetry of the gastrin-releasing peptide (GRP) receptor antagonist 68Ga-NODAGA-MJ9

BackgroundGastrin-releasing peptide receptor antagonists have promise in theranostics of several highly incident tumours, including prostate and breast. This study presents the first human dosimetry of 68Ga-NODAGA-MJ9 in the first five consecutive patients with recurrent prostate cancer included in a dual-tracer positron emission tomography (PET) protocol. Five male patients with biochemical relapse of prostate adenocarcinoma underwent four whole-body time-of-flight PET/CT scans within 2 h after tracer injection. To be used as input in OLINDA/EXM 2.0, time-integrated activity coefficients were derived from manually drawn regions of interest over the following body regions: brain, thyroid, lungs, heart, liver, gallbladder, spleen, stomach, kidneys, adrenals, red marrow, pancreas, intestines, urinary bladder and whole body. Organ absorbed doses and effective dose (ED) were calculated with OLINDA/EXM 2.0 using the NURBS voxelized phantoms adjusted to the ICRP-89 organ masses and ICRP103 tissue-weighting factors. Additional absorbed dose estimations were performed with OLINDA/EXM 1.1 to be comparable with similar previous publications.ResultsThe body regions receiving the highest absorbed doses were the pancreas, the urinary bladder wall, the small intestine and the kidneys (260, 69.8, 38.8 and 34.8 μGy/MBq respectively). The ED considering a 30-min urinary voiding cycle was 17.6 μSv/MBq in male patients. The increment of voiding time interval produced a significant increase of absorbed doses in bladder, prostate and testes, as well as an increase of ED. ED also increased if calculated with OLINDA/EXM 1.1. These results have been discussed in view of similar publications on bombesin analogues or on other commonly used theranostic peptides.ConclusionsThe pancreas is the most irradiated organ after the injection of 68Ga-NODAGA-MJ9, followed by the urinary bladder wall, the small intestine and the kidneys. ED is in the same range of other common 68Ga-labelled peptides. Differences with similarly published studies on bombesin analogues exist, and are mainly dependent on the methodology used for absorbed dose calculations.Trial registrationClinicaltrial.Gov identifier: NCT02111954, posted on 11/042014.

323. Evaluation of confidence intervals of time-integrated activity curve in molecular radiotherapy based on Monte Carlo method

Purpose In molecular radiotherapy (MRT) calculating biokinetic parameters plays a crucial role to assess the absorbed dose to lesions or organs at risk. The assessment of the time-integrated activity curve is affected by fitting model, number of acquired points and sampling timing. The main purpose of this work was to introduce a methodology which is able to estimate the error associated to Time-Integrated Activity Coefficient (TIAC). Methods The Monte Carlo method is implemented in matlab and relied on the generation of a large number of data-set based on root mean square error (RMSE) associated to the fit model. Biokinetic data (time acquisition window of about 50 h) of 35 patients affected by metastatic differentiated thyroid cancer and administered with two different radionuclides (123I and 131I) were analysed, by fitting all data sets. Two classes of data sets were considered: Low Number of Points (LNP) and High Number of Points (HNP) time-activity data, consisting of 4 and 20 points respectively. The correlation between RMSE and bandwidths was also investigated. Results The bandwidths assessed ([mean-lower, mean-upper]) was [−14.3, +17.1]% for LNP and [−9.3, +10.6]% for HNP. The RMSE is demonstrated to be correlated to the bandwidths with two different power laws for LNP and HNP. For LNP the R2 was 0.98 and 0.97 for lower and upper band respectively while for HNP the R2 was 0.94 and 0.97 for lower and upper band. Conclusion The method is very simple to be implemented and it has the advantage of high flexibility when there is need to impose physical constraints to the fitting. As expected, the bandwidths decrease when considering data with a larger number of points. Moreover, having our data similar time window acquisition, the RMSE itself has been observed as a good predictor of the bandwidths as computed with the present method.

A dosimetry procedure for organs-at-risk in 177Lu peptide receptor radionuclide therapy of patients with neuroendocrine tumours

PurposePeptide receptor radionuclide therapy with 177Lu-DOTATATE has become a standard treatment modality in neuroendocrine tumours (NETs). No consensus has yet been reached however regarding the absorbed dose threshold for lesion response, the absorbed dose limit to organs-at-risk, and the optimal fractionation and activity to be administered. This is partly due to a lack of uniform and comparable dosimetry protocols. The present article details the development of an organ-at-risk dosimetry procedure, which could be implemented and used routinely in a clinical context. MethodsForty-seven patients with NETs underwent 177Lu-DOTATATE therapy. Three SPECT/CT images were acquired at 4, 24 and 144–192 h post-injection. Three blood samples were obtained together with the SPECT/CT acquisitions and 2 additional samples were obtained around 30 min and 1 h post-injection. A bi-exponential fit was used to compute the source organ time-integrated activity coefficients. Coefficients were introduced into OLINDA/EXM software to compute organ-at-risk absorbed doses. Median values for all patients were computed for absorbed dose coefficient D/A0 and for late effective half-life T1/2eff for kidneys, spleen and red marrow. ResultsDosimetry resulted in a median[interquartile range] of 0.78[0.35], 1.07[0.58] and 0.028[0.010] Gy/GBq for D/A0 and of 55[9], 71[9] and 52[18] h for T1/2eff for kidneys, spleen and red marrow respectively. ConclusionsA dosimetry procedure for organs-at-risk in 177Lu-DOTATATE therapy based on serial SPECT/CT images and blood samples can be implemented routinely in a clinical context with limited patient burden. The results obtained were in accordance with those of other centres.

Re-evaluation of pediatric 18F-FDG dosimetry: Cristy–Eckerman versus UF/NCI hybrid computational phantoms

Because of the concerns associated with radiation exposure at a young age, there is an increased interest in pediatric absorbed dose estimates for imaging agents. Almost all reported pediatric absorbed dose estimates, however, have been determined using adult pharmacokinetic data with radionuclide S values that take into account the anatomical differences between adults and children based upon the older Cristy–Eckerman (C–E) stylized phantoms. In this work, we use pediatric model-derived pharmacokinetics to compare absorbed dose and effective dose estimates for 18F-FDG in pediatric patients using S values generated from two different geometries of computational phantoms. Time-integrated activity coefficients of 18F-FDG in brain, lungs, heart wall, kidneys and liver, retrospectively, calculated from 35 pediatric patients at the Boston’s Children Hospital were used. The absorbed dose calculation was performed in accordance with the Medical Internal Radiation Dose method using S values generated from the University of Florida/National Cancer Institute (UF/NCI) hybrid phantoms, as well as those from C–E stylized computational phantoms. The effective dose was computed using tissue-weighting factors from ICRP Publication 60 and ICRP Publication 103 for the C–E and UF/NCI, respectively. Substantial differences in the absorbed dose estimates between UF/NCI hybrid pediatric phantoms and the C–E stylized phantoms were found for the lungs, ovaries, red bone marrow and urinary bladder wall. Large discrepancies in the calculated dose values were observed in the bone marrow; ranging between −26% to +199%. The effective doses computed by the UF/NCI hybrid phantom S values were slightly different than those seen using the C–E stylized phantoms with percent differences of −0.7%, 2.9% and 2.5% for a newborn, 1 year old and 5 year old, respectively. Differences in anatomical modeling features among computational phantoms used to perform Monte Carlo-based photon and electron transport simulations for 18F, and very likely for other radionuclides, impact internal organ dosimetry computations for pediatric nuclear medicine studies.

Evaluation of the dosimetry approaches in ablation treatment of thyroid cancer

In this study, we aimed to evaluate dosimetric approaches in ablation treatment of Differentiated Thyroid Carcinoma (DTC) without interrupting the clinical routine. Prior to therapy, 10.7 MBq 131I in average was orally given to 24 patients suffering from DTC. MIRD formalism was used for dosimetric calculations. For blood and bone marrow dosimetry, blood samples and whole‐body counts were collected at 2, 24, 72, and 120 h after I‐131 administration. For remnant tissue dosimetry, uptake measurements were performed at the same time intervals. To estimate the remnant volume, anterior and lateral planar gamma camera images were acquired with a reference source within the field of view at 24 h after I‐131 administration. Ultrasound imaging was also performed. Treatment activities determined with the fixed activity method were administered to the patients. Secondary cancer risk relative to applied therapy was evaluated for dosimetric approaches. The average dose to blood and bone marrow were determined as 0.15 ± 0.04 and 0.11 ± 0.04 Gy/GBq, respectively. The average remnant tissue dose was 0.58 ± 0.52 Gy/MBq and the corresponding required activity to ablate the remnant was approximately 1.3 GBq of 131I. A strong correlation between 24th‐hour uptake and time‐integrated activity coefficient values was obtained. Compared to fixed activity method, approximately five times higher secondary cancer risk was determined in bone marrow dosimetry, while the risk was about three times lower in lesion‐based dosimetry.

Biodistribution and Radiation Dosimetry of 124I-DPA-713, a PET Radiotracer for Macrophage-Associated Inflammation.

Whole-body PET/CT was performed using 124I-DPA-713, a radioligand for the 18-kDa translocator protein (TSPO), to determine biodistribution and radiation dosimetry. Methods: Healthy subjects aged 18-65 y underwent whole-body PET/CT either at 4, 24, and 48 h or at 24, 48, and 72 h after intravenous injection of 124I-DPA-713. Time-activity curves were generated and used to calculate organ time-integrated activity coefficients for each subject. The resulting time-integrated activity coefficients provided input data for calculation of organ absorbed doses and effective dose for each subject using OLINDA. Subjects were genotyped for the TSPO polymorphism rs6971, and plasma protein binding of 124I-DPA-713 was measured. Results: Three male and 3 female adults with a mean age of 40 ± 19 y were imaged. The mean administered activity and mass were 70.5 ± 5.1 MBq (range, 62.4-78.1 MBq) and 469 ± 34 ng (range, 416-520 ng), respectively. There were no adverse or clinically detectable pharmacologic effects in any of the 6 subjects. No changes in vital signs, laboratory values, or electrocardiograms were observed. 124I-DPA-713 cleared rapidly (4 h after injection) from the lungs, with hepatic elimination and localization to the gastrointestinal tract. The mean effective dose over the 6 subjects was 0.459 ± 0.127 mSv/MBq, with the liver being the dose-limiting organ (0.924 ± 0.501 mGy/MBq). The percentage of free radiotracer in blood was approximately 30% at 30 and 60 min after injection. Conclusion:124I-DPA-713 clears rapidly from the lungs, with predominantly hepatic elimination, and is safe and well tolerated in healthy adults.

Biokinetics, dosimetry, and radiation risk in infants after 99mTc-MAG3 scans

BackgroundRenal scans are among the most frequent exams performed on infants and toddlers. Due to the young age, this patient group can be classified as a high-risk group with a higher probability for developing stochastic radiation effects compared to adults. As there are only limited data on biokinetics and dosimetry in this patient group, the aim of this study was to reassess the dosimetry and the associated radiation risk for infants undergoing 99mTc-MAG3 renal scans based on a retrospective analysis of existing patient data.Consecutive data were collected from 20 patients younger than 20 months (14 males; 6 females) with normal renal function undergoing 99mTc-MAG3 scans. To estimate the patient-specific organ activity, a retrospective calibration was performed based on a set of two 3D-printed infant kidneys filled with known activities. Both phantoms were scanned at different positions along the anteroposterior axis inside a water phantom, providing depth- and size-dependent attenuation correction factors for planar imaging. Time-activity curves were determined by drawing kidney, bladder, and whole-body regions-of-interest for each patient, and subsequently applying the calibration factor for conversion of counts to activity. Patient-specific time-integrated activity coefficients were obtained by integrating the organ-specific time-activity curves. Absorbed and effective dose coefficients for each patient were assessed with OLINDA/EXM for the provided newborn and 1-year-old model. The risk estimation was performed individually for each of the 20 patients with the NCI Radiation Risk Assessment Tool.ResultsThe mean age of the patients was 7.0 ± 4.5 months, with a weight between 5 and 12 kg and a body size between 60 and 89 cm. The injected activities ranged from 12 to 24 MBq of 99mTc-MAG3. The patients’ organ-specific mean absorbed dose coefficients were 0.04 ± 0.03 mGy/MBq for the kidneys and 0.27 ± 0.24 mGy/MBq for the bladder. The mean effective dose coefficient was 0.02 ± 0.02 mSv/MBq. Based on the dosimetry results, an evaluation of the excess lifetime risk for the development of radiation-induced cancer showed that the group of newborns has a risk of 16.8 per 100,000 persons, which is about 12% higher in comparison with the 1-year-old group with 14.7 per 100,000 persons (all values are given as mean plus/minus one standard deviation except otherwise specified).ConclusionIn this study, we retrospectively derived new data on biokinetics and dosimetry for infants with normal kidney function after undergoing renal scans with 99mTc-MAG3. In addition, we analyzed the associated age- and gender-specific excess lifetime risk due to ionizing radiation. The radiation-associated stochastic risk increases with the organ doses, taking age- and gender-specific influences into account. Overall, the lifetime radiation risk associated with the 99mTc-MAG3 scans is very low in comparison to the general population risk for developing cancer.

Patient-specific dosimetry of 99mTc-HYNIC-Tyr3-Octreotide in children

BackgroundTechnetium-99m-hydrazinonicotinamide-Tyr3-octreotide (99mTc-HYNIC-TOC) is recognized as a promising radiopharmaceutical for diagnosing neuroendocrine tumors (NETs). However, 99mTc-HYNIC-TOC dosimetry has been investigated only for adults. As pediatric radionuclide therapies become increasingly common, similar dosimetric studies for children are urgently needed. The aim of this study is to report personalized image-based biodistributions and dosimetry evaluations for children studies performed using 99mTc-HYNIC-TOC and to compare them with those from adult subjects.Eleven children/teenage patients with suspected or diagnosed NETs were enrolled. Patient imaging included a series of 2–3 whole-body planar scans and SPECT/CT performed over 2–24 h after the 99mTc-HYNIC-TOC injections. The time-integrated activity coefficients (TIACs) were obtained from the hybrid planar/SPECT technique. Patient-specific doses were calculated using both the voxel-level and the organ-level approaches. Estimated children doses were compared with adults’ dosimetry.ResultsPathologic uptake was observed in five patients. TIACs for normal organs with significant uptakes, i.e., kidneys, spleen, and liver, were similar to adults’ TIACs. Using the voxel-level approach, the average organ doses for children were 0.024 ± 0.009, 0.032 ± 0.017, and 0.017 ± 0.007 mGy/MBq for the kidneys, spleen, and liver, respectively, which were 30% larger than adults’ doses. Similar values were obtained from the organ-level dosimetry when using OLINDA with adapted organ masses. Tumor doses were 0.010–0.024 mGy/MBq. However, cross-organ contributions were much larger in children than in adults, comprising about 15–40% of the total organ/tumor doses. No statistical differences were found between mean doses and dose distributions in patients with and without pathologic uptakes.ConclusionAlthough the children TIACs were similar to those in adults, their doses were about 30% higher. No significant correlation was found between the children’s doses and their ages. However, substantial inter-patient variability in radiotracer uptake, indicating disparity in expression of somatostatin receptor between different patients, emphasizes the importance and necessity of patient-specific dosimetry for clinical studies.

Prediction of time-integrated activity coefficients in PRRT using simulated dynamic PET and a pharmacokinetic model

PurposeTo investigate the accuracy of predicted time-integrated activity coefficients (TIACs) in peptide-receptor radionuclide therapy (PRRT) using simulated dynamic PET data and a physiologically based pharmacokinetic (PBPK) model. MethodsPBPK parameters were estimated using biokinetic data of 15 patients after injection of (152±15)MBq of 111In-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 150MBq 68Ga-DOTATATE using the true MPPs. Dynamic PET scans around 35min p.i. (P1), 4h p.i. (P2) and the combination of P1 and P2 (P3) were simulated. Each measurement was simulated with four frames of 5min 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 5.1GBq of 90Y-DOTATATE over 30min 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. ResultsFor P1 and P2 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 P3, population variabilities for all organs including the remainder further improved, except that of the tumour (v>10%). ConclusionTreatment planning of PRRT based on dynamic PET data seems possible for the kidneys, liver and spleen using a PBPK model and patient specific information.

Feasibility of reducing differences in estimated doses in nuclear medicine between a patient-specific and a reference phantom

The feasibility of reducing the differences between patient-specific internal doses and doses estimated using reference phantoms was evaluated. Relatively simple adjustments to a polygon-surface ICRP adult male reference phantom were applied to fit selected individual dimensions using the software Rhinoceros®4.0. We tested this approach on two patient-specific phantoms: the biggest and the smallest phantoms from the Helmholtz Zentrum München library. These phantoms have unrelated anatomy and large differences in body-mass-index. Three models approximating each patient’s anatomy were considered: the voxel and the polygon-surface ICRP adult male reference phantoms and the adjusted polygon-surface reference phantom. The Specific Absorbed Fractions (SAFs) for internal photon and electron sources were calculated with the Monte Carlo code EGSnrc. Employing the time-integrated activity coefficients of a radiopharmaceutical (S)-4-(3-18F-fluoropropyl)-l-glutamic acid and the calculated SAFs, organ absorbed-dose coefficients were computed following the formalism promulgated by the Committee on Medical Internal Radiation Dose. We compared the absorbed-dose coefficients between each patient-specific phantom and other models considered with emphasis on the cross-fire component. The corresponding differences for most organs were notably lower for the adjusted reference models compared to the case when reference models were employed. Overall, the proposed approach provided reliable dose estimates for both tested patient-specific models despite the pronounced differences in their anatomy. To capture the full range of inter-individual anatomic variability more patient-specific phantoms are required. The results of this test study suggest a feasibility of estimating patient-specific doses within a relative uncertainty of 25% or less using adjusted reference models, when only simple phantom scaling is applied.

New Fetal Radiation Doses for 18F-FDG Based on Human Data.

Current standard values of fetal dosimetry deriving from 18F-FDG injection in pregnant women are estimated from animal data. The present communication offers a revision of fetal dosimetry values calculated from recently published human data, in which fetal 18F-FDG uptake was directly observed in vivo. The final doses were obtained from the observed time-integrated activity coefficients and a new generation of anthropomorphic voxel-based pregnancy phantoms.

A multi species evaluation of the radiation dosimetry of [11C]erlotinib, the radiolabeled analog of a clinically utilized tyrosine kinase inhibitor

IntroductionErlotinib is a tyrosine kinase inhibitor prescribed for non-small cell lung cancer (NSCLC) patients bearing epidermal growth factor receptor mutations in the kinase domain. The objectives of this study were to (1) establish a human dosimetry profile of [11C]erlotinib and (2) assess the consistency of calculated equivalent dose across species using the same dosimetry model. MethodsSubjects examined in this multi-species study included: a stage IIIa NSCLC patient, 3 rhesus macaque monkeys, a landrace pig, and 4 athymic nude-Fox1nu mice. [11C]erlotinib PET data of the whole body were acquired dynamically for up to 120min. Regions of interest (ROIs) were manually drawn to extract PET time activity curves (TACs) from identifiable organs. TACs were used to calculate time-integrated activity coefficients (residence times) in each ROI, which were then used to calculate the equivalent dose in OLINDA. Subject data were used to predict the equivalent dose to the organs of a 73.7kg human male. ResultsIn three of four species, the liver was identified as the organ receiving the highest equivalent dose (critical organ). The mean equivalent doses per unit of injected activity to the liver based on human, monkey, and mouse data were 29.4μSv/MBq, 17.4±6.0μSv/MBq, and 5.27±0.25μSv/MBq, respectively. The critical organ based on the pig data was the gallbladder wall (20.4μSv/MBq) but the liver received a nearly identical equivalent dose (19.5μSv/MBq). Conclusions(1) When designing PET studies using [11C]erlotinib, the liver should be considered the critical organ. (2) In organs receiving the greatest equivalent dose, mouse data underestimated the dose in comparison to larger species. However, the effective dose of [11C]erlotinib to the whole body of a 73.7kg man was predicted with good consistency based on mice (3.14±0.05μSv/MBq) or the larger species (3.46±0.25μSv/MBq).

Treatment planning in PRRT based on simulated PET data and a PBPK model. Determination of accuracy using a PET noise model.

To investigate the accuracy of treatment planning in peptide-receptor radionuclide therapy (PRRT) based on simulated PET data (using a PET noise model) and a physiologicallybasedpharmacokinetic (PBPK) model. The parameters of a PBPK model were fitted to the biokinetic data of 15 patients. True mathematical phantoms of patients (MPPs) were the PBPK model with the fitted parameters. PET measurements after bolus injection of 150 MBq 68Ga-DOTATATE were simulated for the true MPPs. PET noise with typical noise levels was added to the data (i.e. c = 0.3 [low], 3, 30 and 300 [high]). Organ activity data in the kidneys, tumour, liver and spleen were simulated at 0.5, 1 and 4 h p.i. PBPK model parameters were fitted to the simulated noisy PET data to derive the PET-predicted MPPs. Therapy was simulated assuming an infusion of 3.3 GBq of 90Y-DOTATATE over 30 min. Time-integrated activity coefficients (TIACs) of simulated therapy in tumour, kidneys, liver, spleen and remainder were calculated from both, true MPPs (true TIACs) and predicted MPPs (predicted TIACs). Variability v between true TIACs and predicted TIACs were calculated and analysed. Variability ≤ 10 % was considered to be an accurate prediction. For all noise level, variabilities for thekidneys, liver, and spleen showed an accurateprediction for TIACs, e.g.c = 300: vkidney = (5 ± 2)%, vliver = (5 ± 2)%, vspleen = (4 ± 2)%. However, tumour TIAC predictions were not accurate for all noise levels, e.g.c = 0.3: vtumour = (8 ± 5)%. PET-based treatment planning with kidneys as the dose limiting organ seems possible for all reported noise levels using an adequate PBPK model and previous knowledge about the individual patient.

Investigating the Effect of Ligand Amount and Injected Therapeutic Activity: A Simulation Study for 177Lu-Labeled PSMA-Targeting Peptides.

In molecular radiotherapy with 177Lu-labeled prostate specific membrane antigen (PSMA) peptides, kidney and/or salivary glands doses limit the activity which can be administered. The aim of this work was to investigate the effect of the ligand amount and injected activity on the tumor-to-normal tissue biologically effective dose (BED) ratio for 177Lu-labeled PSMA peptides. For this retrospective study, a recently developed physiologically based pharmacokinetic model was adapted for PSMA targeting peptides. General physiological parameters were taken from the literature. Individual parameters were fitted to planar gamma camera measurements (177Lu-PSMA I&T) of five patients with metastasizing prostate cancer. Based on the estimated parameters, the pharmacokinetics of tumor, salivary glands, kidneys, total body and red marrow was simulated and time-integrated activity coefficients were calculated for different peptide amounts. Based on these simulations, the absorbed doses and BEDs for normal tissue and tumor were calculated for all activities leading to a maximal tolerable kidney BED of 10 Gy2.5/cycle, a maximal salivary gland absorbed dose of 7.5 Gy/cycle and a maximal red marrow BED of 0.25 Gy15/cycle. The fits yielded coefficients of determination > 0.85, acceptable relative standard errors and low parameter correlations. All estimated parameters were in a physiologically reasonable range. The amounts (for 25−29 nmol) and pertaining activities leading to a maximal tumor dose, considering the defined maximal tolerable doses to organs of risk, were calculated to be 272±253 nmol (452±420 μg) and 7.3±5.1 GBq. Using the actually injected amount (235±155 μg) and the same maximal tolerable doses, the potential improvement for the tumor BED was 1–3 fold. The results suggest that currently given amounts for therapy are in the appropriate order of magnitude for many lesions. However, for lesions with high binding site density or lower perfusion, optimizing the peptide amount and activity might improve the tumor-to-kidney and tumor-to-salivary glands BED ratio considerably.

Dosimetry methodology for diagnostic nuclear medicine

For diagnostic dosimetry in nuclear medicine, quantitative imaging and activity measurements of blood and urine samples are essential. This is followed by the calculation of the absorbed organ doses and the effective dose. To achieve this, a correct temporal sampling and the use of adequate procedures to integrate the time-activity curves to obtain the total number of decays in the source organs (the time-integrated activity coefficients, TIACs) are prerequisites. If the TIACs are known, a calculation of the absorbed doses is performed by applying the “MIRD formalism”: D = TIAC · A 0 · S D: the mean absorbed dose to a target from a source region. A 0 : administered activity S: mean absorbed dose per unit cumulated activity in the target region. The S-values used for diagnostics are still based on mathematical phantoms. Although, the ICRP in its publication 103 requires the use of a set of gender-specific realistic voxel phantoms, the S-values for isotopes, however, are not yet made publicly available. For diagnostics the effective dose is the main protection quantity. It is calculated using the tissue weighting factors established by the ICRP in the publications ICRP60 and ICRP103. The effective dose, however, is only intended to calculate the risk for an age-independent reference person, not the individual risk. It is a protection quantity and is related to the probability of health detriment to an adult reference person due to stochastic effects from exposure to low doses of ionizing radiation.

Time-integrated activity coefficient estimation for radionuclide therapy using PET and a pharmacokinetic model: A simulation study on the effect of sampling schedule and noise.

The aim of this study was to investigate the accuracy of PET-based treatment planning for predicting the time-integrated activity coefficients (TIACs). 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 vorgan between TIACs from both MPPs. Large variability values of one time-point protocols [e.g., FSD = 1%, 240 min p.i., vkidneys = (9 ± 6)%, and vtumor = (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%, vkidneys = (7 ± 3)%, and vtumor = (22 ± 10)%, or three measurements, e.g., FSD = 1%, vkidneys = (7 ± 3)%, and vtumor = (22 ± 9)%. (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.

Sensitivity Analysis of a Physiologically Based Pharmacokinetic Model Used for Treatment Planning in Peptide Receptor Radionuclide Therapy.

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 koff, dissociation constant KD, 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 koff has the largest effect on RD, the largest RD values were found for changed koff = 0.001 L/min: RDkidneys = (3 ± 3)%, RDtumor = (0.5 ± 4)%, RDliver = (6 ± 9)%, RDspleen = (5 ± 5)%, RDremainder = (2 ± 31)%, RDserum = (-4 ± 25)%, and RDwholebody = (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 koff.

(177)Lu-OPS201 targeting somatostatin receptors: in vivo biodistribution and dosimetry in a pig model.

Background177Lu is used in peptide receptor radionuclide therapies for the treatment of neuroendocrine tumors. Based on the recent literature, SST2 antagonists are superior to agonists in tumor uptake. The compound OPS201 is the novel somatostatin antagonist showing the highest SST2 affinity. The aim of this study was to measure the in vivo biodistribution and dosimetry of 177Lu-OPS201 in five anesthetized Danish Landrace pigs as an appropriate substitute for humans to quantitatively assess the absorbed doses for future clinical applications.Results177Lu-OPS201 was obtained with a specific activity ranging from 10 to 17 MBq/μg. Prior to administration, the radiochemical purity was measured as s > 99.7 % in all cases. After injection, fast clearance of the compound from the blood stream was observed. Less than 5 % of the injected activity was presented in blood 10 min after injection. A series of SPECT/CT and whole-body scans conducted until 10 days after intravenous injection showed uptake mostly in the liver, spine, and kidneys. There was no visible uptake in the spleen. Blood samples were taken to determine the time-activity curve in the blood. Time-activity curves and time-integrated activity coefficients were calculated for the organs showing visible uptake. Based on these data, the absorbed organ dose coefficients for a 70-kg patient were calculated with OLINDA/EXM. For humans after an injection of 5 GBq 177Lu-OPS201, the highest predicted absorbed doses are obtained for the kidneys (13.7 Gy), the osteogenic cells (3.9 Gy), the urinary bladder wall (1.8 Gy), and the liver (1.0 Gy). No metabolites of 177Lu-OPS201 were found by radio HPLC analysis. None of the absorbed doses calculated will exceed organ toxicity levels.ConclusionsThe 177Lu-OPS201 was well tolerated and caused no abnormal physiological or behavioral signs. In vivo distributions and absorbed doses of pigs are comparable to those observed in other publications. According to the biodistribution data in pigs, presented in this work, the expected radiation exposure in humans will be within the acceptable range.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-016-0204-9) contains supplementary material, which is available to authorized users.