A comparison of 111In-DOTATOC and 111In-DOTATATE: biodistribution and dosimetry in the same patients with metastatic neuroendocrine tumours

[Yttrium-90-DOTA-Tyr3]-octreotide (DOTATOC) and [177Lu-DOTA-Tyr3-Thr8]-octreotide (DOTATATE) are used for peptide receptor-mediated radionuclide therapy (PRMRT) in neuroendocrine tumours. No human data comparing these two compounds are available so far. We used 111In as a surrogate for 90Y and 177Lu and examined whether one of the 111In-labelled peptides had a more favourable biodistribution in patients with neuroendocrine tumours. Special emphasis was given to kidney uptake and tumour-to-kidney ratio since kidney toxicity is usually the dose-limiting factor. Five patients with metastatic neuroendocrine tumours were injected with 222MBq 111In-DOTATOC and 111In-DOTATATE within 2 weeks. Up to 48h after injection, whole-body scans were performed and blood and urine samples were collected. The mean absorbed dose was calculated for tumours, kidney, liver, spleen and bone marrow. In all cases 111In-DOTATATE showed a higher uptake (%IA) in kidney and liver. The amount of 111In-DOTATOC excreted into the urine was significantly higher than for 111In-DOTATATE. The mean absorbed dose to the red marrow was nearly identical. 111In-DOTATOC showed a higher tumour-to-kidney absorbed dose ratio in seven of nine evaluated tumours. The variability of the tumour-to-kidney ratio was high and the significance level in favour of 111In-DOTATOC was P=0.065. In five patients the pharmacokinetics of 111In-DOTATOC and 111In-DOTATATE was found to be comparable. The two peptides appear to be nearly equivalent for PRMRT in neuroendocrine tumours, with minor advantages for 111In/90Y-DOTATOC; on this basis, we shall continue to use 90Y-DOTATOC for PRMRT in patients with metastatic neuroendocrine tumour

Production of Medical Radioisotopes with High Specific Activity in Photonuclear Reactions with γ\gamma Beams of High Intensity and Large Brilliance

We study the production of radioisotopes for nuclear medicine in $(\gamma,x{\rm n}+y{\rm p})$ photonuclear reactions or ($\gamma,\gamma'$) photoexcitation reactions with high flux [($10^{13}-10^{15}$)$\gamma$/s], small diameter $\sim (100 \, \mu$m$)^2$ and small band width ($\Delta E/E \approx 10^{-3}-10^{-4}$) $\gamma$ beams produced by Compton back-scattering of laser light from relativistic brilliant electron beams. We compare them to (ion,$x$n$+ y$p) reactions with (ion=p,d,$\alpha$) from particle accelerators like cyclotrons and (n,$\gamma$) or (n,f) reactions from nuclear reactors. For photonuclear reactions with a narrow $\gamma$ beam the energy deposition in the target can be managed by using a stack of thin target foils or wires, hence avoiding direct stopping of the Compton and pair electrons (positrons). $(\gamma,\gamma')$ isomer production via specially selected $\gamma$ cascades allows to produce high specific activity in multiple excitations, where no back-pumping of the isomer to the ground state occurs. We discuss in detail many specific radioisotopes for diagnostics and therapy applications. Photonuclear reactions with $\gamma$ beams allow to produce certain radioisotopes, e.g. $^{47}$Sc, $^{44}$Ti, $^{67}$Cu, $^{103}$Pd, $^{117m}$Sn, $^{169}$Er, $^{195m}$Pt or $^{225}$Ac, with higher specific activity and/or more economically than with classical methods. This will open the way for completely new clinical applications of radioisotopes. For example $^{195m}$Pt could be used to verify the patient's response to chemotherapy with platinum compounds before a complete treatment is performed. Also innovative isotopes like $^{47}$Sc, $^{67}$Cu and $^{225}$Ac could be produced for the first time in sufficient quantities for large-scale application in targeted radionuclide therapy.Comment: submitted to Appl. Phys.

Biokinetic models for radiopharmaceuticals.

Radiopharmaceuticals administered for diagnostic or therapeutic applications in humans are selectively transported into specific organs and tissues of the body, metabolised, and finally excreted according to their biochemical and metabolic properties. Due to the presence of the radioactive label, each of the body regions containing the substance becomes an emitting source (source region), which can also irradiate the neighbouring tissues (defined as target regions). Consequently, each body organ or tissue could receive a radiation dose (absorbed dose) after administration of radiopharmaceuticals even if no activity is present in it. The absorbed dose delivered by incorporated radioactive material is called the internal dose. Direct measurements of the internal dose are not possible for evident practical reasons, so this quantity has to be calculated using a mathematical approach. Such an approach has to take into account that

Compartmental model of 18F-choline.

  The MADEIRA Project (Minimizing Activity and Dose with Enhanced Image quality by Radiopharmaceutical Administrations), cofunded by the European Commission through EURATOM Seventh Framework Programme, aims to improve the efficacy and safety of 3D functional imaging by optimizing, among others, the knowledge of the temporal variation of the radiopharmaceuticals’ uptake in and clearance from tumor and healthy tissues. With the help of compartmental modeling it is intended to optimize the time schedule for data collection, thus contributing to reduce the radiation exposures of the patients. The model will also be adopted to evaluate the organ doses to the patients. Administration of 18F-choline to screen for recurrence or metastasis in prostate cancer patients is one of the diagnostic applications under consideration in the frame of the project. PET and CT images have been acquired up to four hours after injection of 18F-choline. Additionally blood and urine samples have been collected and measured in a gamma counter. The radioactivity concentration in different organs and data of plasma and urine clearance were used to set-up a compartmental model of the biokinetics of the radiopharmaceutical. It features a central compartment (blood) exchanging with organs. The structure describes explicitly liver, kidneys, spleen, plasma and bladder as separate units with a forcing function approach. The model is presented together with an evaluation of the individual and population kinetic parameters, and a revised time schedule for data collection is proposed. This optimized time schedule will be validated in a further set of patient studies

New calculations for internal dosimetry of beta-emitting radiopharmaceuticals.

The calculation of absorbed dose from internally incorporated radionuclides is based on the so-called specific absorbed fractions (SAFs) which represent the fraction of energy emitted in a given source region that is absorbed per unit mass in a specific target organ. Until recently, photon SAFs were calculated using MIRD-type mathematical phantoms. For electrons, the energy released was assumed to be absorbed locally ('ICRP 30 approach'). For this work, photon and electron SAFs were derived with Monte Carlo simulations in the new male voxel-based reference computational phantom adopted by the ICRP and ICRU. The present results show that the assumption of electrons being locally absorbed is not always true at energies above 300-500 keV. For source/target organ pairs in close vicinity, high-energy electrons escaping from the source organ may result in cross-fire electron SAFs in the same order of magnitude as those from photons. Examples of organ absorbed doses per unit activity are given for (18)F-choline and (123)I-iodide. The impact of the new electron SAFs used for absorbed dose calculations compared with the previously used assumptions was found to be small. The organ dose coefficients for the two approaches differ by not more than 6 % for most organs. Only for irradiation of the urinary bladder wall by activity in the contents, the ICRP 30 approach presents an overestimation of approximately 40-50%

Kompartmentmodel für 18F-Cholin.

Um die Effizienz und Sicherheit von dreidimensionalen, funktionellen Bildgebungsverfahren zu optimieren, soll die zeitlichen Variation von Aufnahme und Ausscheidung des Radiopharmazeutikums im Tumor sowie im gesunden Gewebe mit Hilfe von Kompartmentmodellen untersucht werden. Die nuklearmedizinische, diagnostische Anwendung, die in dieser Studie untersucht wurde, ist die Verabreichung von 18F-Cholin für die Suche nach Rezidiven oder Metastasen bei Prostatakrebspatienten. PET- und CT-Bilder wurden bis zu vier Stunden nach Injektion von 18F-Cholin aufgenommen. Zusätzlich wurden Blut und Urinproben gesammelt und in einem Gammacounter gemessen. Die Radioaktivitätskonzentrationen in verschiedenen Organen sowie die Blut- und Urindaten wurden benutzt, um ein Kompartmentmodel der Biokinetik des Radiopharmazeutikums aufzusetzen. Es besteht aus einem zentralen Kompartment (Blut) das in Austausch mit den anderen Organen steht. Die Struktur beschreibt die Leber, die Nieren, die Milz, das Blut und die Blase als separate Einheiten. Zusammen mit dem Model werden die individuellen biokinetischen Parameter sowie die der Population vorgestellt. Ein überarbeiteter Zeitplan für die Messung von Patienten wird vorgeschlagen

Nonlinear compartmental model of ¹⁸F-choline.

INTRODUCTION: This work develops a compartmental model of (18)F-choline in order to evaluate its biokinetics and so to describe the temporal variation of the radiopharmaceuticals' uptake in and clearance from organs and tissues. METHODS: Ten patients were considered in this study. A commercially available tool for compartmental analysis (SAAM II) was used to model the values of activity concentrations in organs and tissues obtained from PET images or from measurements of collected blood and urine samples. RESULTS: A linear compartmental model of the biokinetics of the radiopharmaceutical was initially developed. It features a central compartment (blood) exchanging with organs. The structure describes explicitly liver, kidneys, spleen, blood and urinary excretion. The linear model tended to overestimate systematically the activity in the liver and in the kidney compartments in the first 20 min post-administration. A nonlinear process of kinetic saturation was considered, according to the typical Michaelis-Menten kinetics. Therefore nonlinear equations were added to describe the flux of (18)F-choline from blood to liver and from blood to kidneys. The nonlinear model showed a tendency for improvement in the description of the activity in liver and kidneys, but not for the urine. CONCLUSIONS: The simple linear model presented is not able to properly describe the biokinetics of (18)F-choline as measured in prostatic cancer patients. The introduction of nonlinear kinetics, although based on physiologically plausible assumptions, resulted in nonsignificant improvements of the model predictive power

Compartmental model of ¹⁸F-choline.

The MADEIRA Project (Minimizing Activity and Dose with Enhanced Image quality by Radiopharmaceutical Administrations), aims to improve the efficacy and safety of 3D functional imaging by optimizing, among others, the knowledge of the temporal variation of the radiopharmaceuticals' uptake in and clearance from tumor and healthy tissues. With the help of compartmental modeling it is intended to optimize the time schedule for data collection and improve the evaluation of the organ doses to the patients. Administration of 18F-choline to screen for recurrence or the occurrence of metastases in prostate cancer patients is one of the diagnostic applications under consideration in the frame of the project. PET and CT images have been acquired up to four hours after injection of 18F-choline. Additionally blood and urine samples have been collected and measured in a gamma counter. The radioactivity concentration in different organs and data of plasma clearance and elimination into urine were used to set-up a compartmental model of the biokinetics of the radiopharmaceutical. It features a central compartment (blood) exchanging with organs. The structure describes explicitly liver, kidneys, spleen, plasma and bladder as separate units with a forcing function approach. The model is presented together with an evaluation of the individual and population kinetic parameters, and a revised time schedule for data collection is proposed. This optimized time schedule will be validated in a further set of patient studies