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Purpose: Peptide receptor radionuclide therapy in patients with neuroendocrine tumours has yielded promising results. This prospective study investigated the feasibility of dosimetry of the kidneys and bone marrow during therapy and its impact on efficacy and outcome., Methods: The study group comprised 200 consecutive patients with metastasized somatostatin receptor-positive neuroendocrine tumours progressing on standard therapy or not suitable for other therapeutic options. A treatment cycle consisted of 7.4 GBq 177 Lu-DOTA-octreotate with co-infusion of a mixed amino acid solution, and cycles were repeated until the absorbed dose to the kidneys reached 23 Gy or there were other reasons for stopping therapy. The Ki-67 index was ≤2% in 47 patients (23.5%), 3-20% in 121 (60.5%) and >20% in 16 (8%)., Results: In 123 patients (61.5%) the absorbed dose to the kidneys reached 23 Gy with three to nine cycles during first-line therapy; in no patient was a dose to the bone marrow of 2 Gy reached. The best responses (according to RECIST 1.1) were a complete response (CR) in 1 patient (0.5%), a partial response (PR) in 47 (23.5%), stable disease (SD) in 135 (67.5%) and progressive disease (PD) in 7 (3.5%). Median progression-free survival was 27 months (95% CI 22-30 months) in all patients, 33 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 15 months in those in whom it did not. Median overall survival (OS) was 43 months (95% CI 39-53 months) in all patients, 54 months in those in whom the absorbed dose to the kidneys reached 23 Gy and 25 months in those in whom it did not. Median OS was 60 months in patients with a best response of PR or CR, 42 months in those with SD and 16 months in those with PD. Three patients (1.5%) developed acute leukaemia, 1 patient (0.5%) chronic leukaemia (unconfirmed) and 30 patients (15%) grade 3 or 4 bone marrow toxicity. Eight patients (4%) developed grade 2 kidney toxicity and one patient (0.5%) grade 4 kidney toxicity., Conclusions: Dosimetry-based therapy with 177 Lu-DOTA-octreotate is feasible. Patients in whom the absorbed dose to the kidneys reached 23 Gy had a longer OS than those in whom it did not. Patients with CR/PR had a longer OS than those with SD. Bone marrow dosimetry did not predict toxicity.

Unlabelled: Quantitative imaging and dosimetry are crucial for individualized treatment during peptide receptor radionuclide therapy (PRRT). (177)Lu-DOTATATE and (68)Ga-DOTATOC/(68)Ga-DOTATATE are used, respectively, for PRRT and PET examinations targeting somatostatin receptors (SSTRs) in patients affected by neuroendocrine tumors. The aim of the study was to quantitatively and qualitatively compare the performance of (68)Ga-DOTATOC and (68)Ga-DOTATATE in the context of subsequent PRRT with (177)Lu-DOTATATE under standardized conditions in the same patient as well as to investigate the sufficiency of standardized uptake value (SUV) for estimation of SSTR expression., Methods: Ten patients with metastatic neuroendocrine tumors underwent one 45-min dynamic and 3 whole-body PET/CT examinations at 1, 2, and 3 h after injection with both tracers. The number of detected lesions, SUVs in lesions and normal tissue, total functional tumor volume, and SSTR volume (functional tumor volume multiplied by mean SUV) were investigated for each time point. Net uptake rate (Ki) was calculated according to the Patlak method for 3 tumors per patient., Results: There were no significant differences in lesion count, lesion SUV, Ki, functional tumor volume, or SSTR volume between (68)Ga-DOTATOC and (68)Ga-DOTATATE at any time point. The detection rate was similar, although with differences for single lesions in occasional patients. For healthy organs, marginally higher uptake of (68)Ga-DOTATATE was observed in kidneys, bone marrow, and liver at 1 h. (68)Ga-DOTATOC uptake was higher in mediastinal blood pool at the 1-h time point (P = 0.018). The tumor-to-liver ratio was marginally higher for (68)Ga-DOTATOC at the 3-h time point (P = 0.037). Blood clearance was fast and similar for both tracers. SUV did not correlate with Ki linearly and achieved saturation for a Ki of greater than 0.2 mL/cm(3)/min, corresponding to an SUV of more than 25., Conclusion: (68)Ga-DOTATOC and (68)Ga-DOTATATE are suited equally well for staging and patient selection for PRRT with (177)Lu-DOTATATE. However, the slight difference in the healthy organ distribution and excretion may render (68)Ga-DOTATATE preferable. SUV did not correlate linearly with Ki and thus may not reflect the SSTR density accurately at its higher values, whereas Ki might be the outcome measure of choice for quantification of SSTR density and assessment of treatment outcome.

Unlabelled: (68)Ga-DOTATOC and (68)Ga-DOTATATE are 2 radiolabeled somatostatin analogs for in vivo diagnosis of neuroendocrine tumors with PET. The aim of the present work was to measure their comparative biodistribution and radiation dosimetry., Methods: Ten patients diagnosed with neuroendocrine tumors were included. Each patient underwent a 45-min dynamic and 3 whole-body PET/CT scans at 1, 2, and 3 h after injection of each tracer on consecutive days. Absorbed doses were calculated using OLINDA/EXM 1.1., Results: Data from 9 patients could be included in the analysis. Of the major organs, the highest uptake at 1, 2, and 3 h after injection was observed in the spleen, followed by kidneys and liver. For both tracers, the highest absorbed organ doses were seen in the spleen and urinary bladder wall, followed by kidney, adrenals, and liver. The absorbed doses to the liver and gallbladder wall were slightly but significantly higher for (68)Ga-DOTATATE. The total effective dose was 0.021 ± 0.003 mSv/MBq for both tracers., Conclusion: The effective dose for a typical 100-MBq administration of (68)Ga-DOTATATE and (68)Ga-DOTATOC is 2.1 mSv for both tracers. Therefore, from a radiation dosimetry point of view, there is no preference for either tracer for PET/CT evaluation of somatostatin receptor-expressing tumors.

Unlabelled: The organs at risk in radionuclide therapy with (177)Lu-octreotate are the bone marrow and the kidneys. The primary aim of this study was to develop an individualized dosimetry protocol for the bone marrow. The secondary aim was to identify those patients, undergoing fractionated therapy with 7.4 GBq/cycle, who first reached an accumulated dose of either 2 Gy to the bone marrow or 23 Gy to the kidneys., Methods: Two hundred patients with metastatic neuroendocrine tumors with high somatostatin receptor expression were included. After the administration of 7.4 GBq of (177)Lu-octreotate, blood samples were drawn 6 times within the first 24 h. In 50 patients, additional blood samples were obtained at 96 and 168 h. Moreover, urine was collected from 30 patients during the first 24 h. Planar whole-body and SPECT/CT images over the abdomen were acquired at 24, 96, and 168 h after the infusion. Calculation of the absorbed radiation dose to the bone marrow was based on blood and urinary activity curves combined with organ-based analysis of the whole-body images. The absorbed dose to the kidney was calculated from the pharmacokinetic data obtained from SPECT/CT., Results: For a single cycle of 7.4 GBq, the absorbed dose to the bone marrow and the kidney ranged from 0.05 to 0.4 Gy and from 2 to 10 Gy, respectively. In 197 of 200 patients, the kidneys accumulated an absorbed dose of 23 Gy before the bone marrow reached 2 Gy. Between 2 and 10 cycles of (177)Lu-octreotate could be administered before the upper dose limit for the individual patient was reached., Conclusion: A method based on repeated whole-body imaging in combination with blood and urinary activity data over time was developed to determine the absorbed dose to the bone marrow. The dose-limiting organ was the kidney in 197 of 200 patients. In 50% of the patients, more than 4 cycles of 7.4 GBq of (177)Lu-octreotate could be administered, whereas 20% of the subjects were treated with fewer than 4 cycles. Individualized absorbed dose calculation is essential to optimize the therapy.

Aims: Fractionated (177)Lu-DOTA-octreotate therapy has been reported to be an effective treatment option for patients with generalized neuroendocrine tumors. In our clinic, full individual dosimetry is performed during the first therapy cycle, while dosimetry at later cycles is based on the 24 h uptake measurement assuming an unchanged effective half-life. Our aim was to evaluate this assumption and the variation in the 24 h uptake during therapy., Patients: Thirty patients, 13 women and 17 men, were included in the study., Methods: During the first therapy cycle the (177)Lu-concentration was measured with SPECT/CT over the abdomen at 24 h, 96 h and 168 h after infusion. The effective half-life was determined for the kidneys, liver and spleen. The procedure was repeated at cycle 4 or 5., Results: The median ratio between the effective half-lives of the latter and the first cycle was 0.97 and 1.01 for the right and left kidney, with a range of 0.89-1.01 (1st-3rd quartile) and 0.93-1.05, respectively., Discussion: The mean value of the ratios was slightly lower than one, indicating a tendency towards increased activity elimination during therapy. In individual patients, significant changes were found for all organs, often when a large tumor burden reduction occurred during treatment. Possible contributing factors appeared to be larger amounts of non-tumor bound tracer, improved organ function (kidneys), decrease of vessel obstruction (spleen), less scatter from large tumors and reduction of small metastases (liver and spleen)., Conclusion: With most patients it is safe to estimate absorbed doses to kidneys, liver and spleen from 24 h activity concentration assuming an unchanged effective half-life during therapy. Patients with risk factors for kidney dysfunction need to be monitored in more detail. Simplified dosimetry based on the assumption of unchanged effective half-life can function as guidance to the number of therapy cycles an individual patient can tolerate.

Objectives: The aim of this pilot study was to explore the impact of peptide mass on binding of [(68)Ga]-DOTATOC to neuroendocrine tumour somatostatin receptors in vivo using a tracer of variable specific radioactivity (SRA) and to show the logistic feasibility of sequential PET scans in the same patient., Material and Methods: Nine patients with gastroenteropancreatic neuroendocrine tumours were included. Six of them underwent three sequential PET-CT examinations with intravenous injections of [(68)Ga]-DOTATOC proceeded by 0, 50 and 250 or 500 microg of octreotide, administered 10 min before the tracer. Three patients were examined by dynamic and static PET/CT for pharmacokinetic and dosimetric calculations. The [(68)Ga]-DOTATOC synthesis included preconcentration and purification of the generator eluate and microwave heating in a semi-automated in-house procedure., Results: [(68)Ga]-DOTATOC synthesis and quality control were accomplished within 30 min and radiochemical purity was >95%. The tracer accumulation in the tumours varied and depended on the total amount of the administered peptide. In five of six patients, the highest tumour-to-normal tissue ratio was found when 50 microg of octreotide was preadministered. One patient showed a continuously increasing tumour uptake. Dosimetrically, a large variation in organ doses was found (kidney: 0.086-0.168 mSv/MBq; liver: 0.026-0.096 mSv/MBq; spleen: 0.046-0.226 mSv/MBq). The effective dose (0.015, 0.0067 and 0.0042 mSv/MBq) was correlated to the total amount of decays., Discussion: Three sequential PET-CT examinations using (68)Ga-based tracer was carried out in 1 day. The use of high SRA [(68)Ga]-DOTATOC and unlabelled octreotide indicates an optimal mass leading to better image contrast. [(68)Ga]-DOTATOC-PET-CT employing variable SRA may be utilised for accurate quantification of tumour uptake with subsequent dosimetry for personalized therapy management., (Copyright 2010 Elsevier Inc. All rights reserved.)

Purpose: In recent years, targeted radionuclide therapy with [(177)Lu-DOTA(0), Tyr(3)]octreotate for neuroendocrine tumours has yielded promising results. This therapy may be further improved by using individualized dosimetry allowing optimization of the absorbed dose to the tumours and the normal organs. The aim of this study was to investigate the feasibility and reliability of individualized dosimetry based on SPECT in comparison to conventional planar imaging., Methods: Attenuation-corrected SPECT data were analysed both by using organ-based volumes of interest (VOIs) to obtain the total radioactivity in the organ, and by using small VOIs to measure the tissue radioactivity concentration. During the first treatment session in 24 patients, imaging was performed 1, 24, 96 and 168 h after [(177)Lu-DOTA(0), Tyr(3)]octreotate infusion. Absorbed doses in non tumour-affected kidney, liver and spleen were calculated and compared for all three methods (planar imaging, SPECT organ VOIs, SPECT small VOIs)., Results: Planar and SPECT dosimetry were comparable in areas free of tumours, but due to overlap the planar dosimetry highly overestimated the absorbed dose in organs with tumours. Furthermore, SPECT dosimetry based on small VOIs proved to be more reliable than whole-organ dosimetry., Conclusion: We conclude that SPECT dosimetry based on small VOIs is feasible and more accurate than conventional planar dosimetry, and thus may contribute towards optimising targeted radionuclide therapy.

Abstract: Objectives: The aim of this pilot study was to explore the impact of peptide mass on binding of [68Ga]-DOTATOC to neuroendocrine tumour somatostatin receptors in vivo using a tracer of variable specific radioactivity (SRA) and to show the logistic feasibility of sequential PET scans in the same patient. Material and Methods: Nine patients with gastroenteropancreatic neuroendocrine tumours were included. Six of them underwent three sequential PET-CT examinations with intravenous injections of [68Ga]-DOTATOC proceeded by 0, 50 and 250 or 500 μg of octreotide, administered 10 min before the tracer. Three patients were examined by dynamic and static PET/CT for pharmacokinetic and dosimetric calculations. The [68Ga]-DOTATOC synthesis included preconcentration and purification of the generator eluate and microwave heating in a semi-automated in-house procedure. Results: [68Ga]-DOTATOC synthesis and quality control were accomplished within 30 min and radiochemical purity was >95%. The tracer accumulation in the tumours varied and depended on the total amount of the administered peptide. In five of six patients, the highest tumour-to-normal tissue ratio was found when 50 μg of octreotide was preadministered. One patient showed a continuously increasing tumour uptake. Dosimetrically, a large variation in organ doses was found (kidney: 0.086–0.168 mSv/MBq; liver: 0.026–0.096 mSv/MBq; spleen: 0.046–0.226 mSv/MBq). The effective dose (0.015, 0.0067 and 0.0042 mSv/MBq) was correlated to the total amount of decays. Discussion: Three sequential PET-CT examinations using 68Ga-based tracer was carried out in 1 day. The use of high SRA [68Ga]-DOTATOC and unlabelled octreotide indicates an optimal mass leading to better image contrast. [68Ga]-DOTATOC-PET-CT employing variable SRA may be utilised for accurate quantification of tumour uptake with subsequent dosimetry for personalized therapy management. [Copyright &y& Elsevier]