DOTATOC: A powerful new tool for receptor-mediated radionuclide therapy

This study presents the first successful use of a peptidic vector, DOTATOC, labelled with the -emitting radioisotope yttrium-90, for the treatment of a patient with somatostatin receptor-positive abdominal metastases of a neuroendocrine carcinoma of unknown localization. Tumour response and symptomatic relief were achieved. In addition, the new substance DOTA-TOC was labelled with the diagnostic chemical analogue indium-111 and studied in three patients with histopathologically verified neuroendocrine abdominal tumours for its diagnostic sensitivity and compared with the commercially available OctreoScan. In all patients the kidney-to-tumour uptake ratio (in counts per pixel) was on average 1.9-fold lower with¹¹¹In-DOTATOC than with OctreoScan. DOTATOC could be a potential new diagnostic and therapeutic agent in the management of neuroendocrine tumours.     

Bone marrow dosimetry in peptide receptor radionuclide therapy with [177Lu-DOTA0,Tyr3]octreotate

Purpose  Adequate dosimetry is mandatory for effective and safe peptide receptor radionuclide therapy (PRRT). Besides the kidneys, the bone marrow is a potentially dose-limiting organ. The radiation dose to the bone marrow is usually calculated according to the MIRD scheme, where the accumulated activity in the bone marrow is calculated from the accumulated radioactivity of the radiopharmaceutical in the blood. This may underestimate the absorbed dose since stem cells express somatostatin receptors. We verified the blood-based method by comparing the activity in the blood with the radioactivity in bone marrow aspirates. Also, we evaluated the absorbed cross-dose from the source organs (liver, spleen, kidneys and blood), tumours and the so-called “remainder of the body” to the bone marrow. Methods  Bone marrow aspirates were drawn in 15 patients after treatment with [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate. Radioactivity in the bone marrow was compared with radioactivity in the blood drawn simultaneously. The nucleated cell fraction was isolated from the bone marrow aspirate and radioactivity was measured. The absorbed dose to the bone marrow was calculated. The results were correlated to the change in platelet counts 6 weeks after treatment. Results  A strong linear correlation and high agreement between the measured radioactivities in the bone marrow aspirates and in the blood was found (r=0.914, p<0.001). No correlation between the calculated absorbed dose in the bone marrow and the change in platelets was found. There was a considerable contribution from other organs and the remainder of the body to the bone marrow absorbed dose. Conclusion  (1) After PRRT with [¹⁷⁷Lu-DOTA⁰,Tyr³]octreotate, the radioactivity concentration in the bone marrow is identical to that in the blood; (2) There is no significant binding of the radiopharmaceutical to bone marrow precursor stem cells; (3) The contribution of the cross dose from source organs and tumours to the bone marrow dose is significant; and (4) There is considerable variation in bone marrow absorbed dose between patients. These findings imply that for individual dose optimization, individual calculation of the bone marrow absorbed dose is necessary.     

Evaluation of 64Cu-labeled DOTA-d-Phe1-Tyr3-octreotide (64Cu-DOTA-TOC) for imaging somatostatin receptor-expressing tumors

Objective  In-111 (¹¹¹In)-labeled octreotide has been clinically used for imaging somatostatin receptor-positive tumors, and radiolabeled octreotide analogs for positron emission tomography (PET) have been developed. Cu-64 (⁶⁴Cu; half-life, 12.7 h) is an attractive radionuclide for PET imaging and is produced with high specific activity using a small biomedical cyclotron. The aim of this study is to produce and fundamentally examine a ⁶⁴Cu-labeled octreotide analog, ⁶⁴Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-d-Phe¹-Tyr³-octreotide (⁶⁴Cu-DOTA-TOC). Methods   ⁶⁴Cu produced using a biomedical cyclotron was reacted with DOTA-TOC for 30 min at 45°C. The stability of ⁶⁴Cu-DOTA-TOC was evaluated in vitro (incubated with serum) and in vivo (blood collected after administration) by HPLC analysis. Biodistribution studies were performed in normal mice by administration of mixed solution of ⁶⁴Cu-DOTA-TOC and ¹¹¹In-DOTA-TOC and somatostatin receptor-positive U87MG tumor-bearing mice by administration of ⁶⁴Cu-DOTA-TOC or ⁶⁴Cu-1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid-octreotide (⁶⁴Cu-TETA-OC). The tumor was imaged using ⁶⁴Cu-DOTA-TOC, ⁶⁴Cu-TETA-OC, and FDG with an animal PET scanner. Results   ⁶⁴Cu-DOTA-TOC can be produced in amounts sufficient for clinical study with high radiochemical yield. ⁶⁴Cu-DOTA-TOC was stable in vitro, but time-dependent transchelation to protein was observed after injection into mice. In biodistribution studies, the radioactivity of ⁶⁴Cu was higher than that of ¹¹¹In in all organs except kidney. In tumor-bearing mice, ⁶⁴Cu-DOTA-TOC showed a high accumulation in the tumor, and the tumor-to-blood ratio reached as high as 8.81 ± 1.17 at 6 h after administration. ⁶⁴Cu-DOTA-TOC showed significantly higher accumulation in the tumor than ⁶⁴Cu-TETA-OC. ⁶⁴Cu-DOTA-TOC PET showed a very clear image of the tumor, which was comparable to that of ¹⁸F-FDG PET and very similar to that of ⁶⁴Cu-TETA-OC. Conclusions   ⁶⁴Cu-DOTA-TOC clearly imaged a somatostatin receptor-positive tumor and seemed to be a potential PET tracer in the clinical phase.     

In vitro and in vivo studies of three radiolabelled somatostatin analogues:123I-Octreotide (OCT),123I-Tyr-3-OCT and111In-TIRA-d-Phe-1-OCT

Scintigraphy with long-acting somatostatin (SST) analogues may be useful for the localization of tumours expressing receptors (R) for SST. In this study we have analysed the in vitro and in vivo binding properties of three SST analogues,¹²³I-octreotide (OCT),¹²³I-Tyr-3-OCT and¹¹¹In-DTPA-d-Phe-l-OCT. In vitro binding studies performed with a variety of primary tumours (n=48) as well as with several tumour cell lines (A431, HT29, PANC1, COLO320, HMC1, KU812) indicated significant in vitro binding of these three radiolabelled SST analogues to two subpopulations of SSTR, high (K _d 0.2–2.0 nM) and low (K _d 5–15 nM) affinity ones. The number of SSTR on tumour cells was at least a 1000-fold higher as compared with normal peripheral blood cells. Comparative scintigraphic studies using¹²³I-OCT and/or¹²³I-Tyr-3-OCT and/or¹¹¹In-DTPA-d-Phe-1-OCT were performed in 21 patients with histologically verified intestinal carcinoid tumours. Corresponding scintigraphic results were obtained in 18 of 21 patients investigated with two different SSTR ligands, either¹²³I-OCT/¹²³I-Tyr-3-OCT (four of five),¹²³I-OCT/¹¹¹In-DTPA-d-Phe-1-OCT (eight of nine), or¹²³I-Tyr-3-OCT/¹¹¹In-DTPA-d-Phe-1-OCT (six of seven). We conclude that various tumours express high amounts of SSTR which are recognized by three radiolabelled SST analogues:¹²³I-OCT,¹²³I-Tyr-3-OCT and¹¹¹In-DTPA-d-Phe-1-OCT. Differences between these SST analogues in their in vitro binding and/or in vivo scanning properties are observed in a minority of patients. Thus, the labelling of OCT with iodine may be an alternative approach for those nuclear medicine departments for which¹¹¹In-DTPA-d-Phe-1-OCT is not easily available, or is too expensive.     

Crossed cerebellar diaschisis: a positron emission tomography study withl-[methyl-11C]methionine and 2-deoxy-2-[18F]fluoro-d-glucose

OBJECTIVE: Crossed cerebellar diaschisis (CCD) is defined as a depression of blood flow and oxidative metabolism of glucose in the cerebellum contralateral to a supratentorial brain lesion, as detected with positron emission tomography (PET) and single photon emission computed tomography. We examined whether L-[methyl-11C]methionine (MET) uptake is affected in CCD. METHODS: In 12 patients with a unilateral supratentorial brain tumor, we evaluated the uptake of 2-deoxy-2-[18F]fluoro-D-glucose (FDG) and MET in the cerebellar hemispheres by means of PET. Asymmetry index (AI) was defined as a difference in the average count between the ipsilateral and contralateral cerebellar hemispheres divided by the average count in both cerebellar hemispheres. Patients with AI of FDG PET more than 0.1 and those with AI equal to 0.1 or less than 0.1 were classified as CCD-positive and CCD-negative, respectively. RESULTS: Six patients were CCD-positive and others were CCD-negative in the FDG PET study. Between CCD-positive and CCD-negative patients, mean AI of MET was not significantly different (0.017 +/- 0.023 and 0.014 +/- 0.039, respectively). CONCLUSIONS: Different from glucose metabolism, cerebellar MET uptake was not affected in CCD. The present study may indicate that cerebellar MET uptake is independent of suppression of cerebellar neuronal activity.     

Comparison of 111In-DOTA-DPhe1-Tyr3-octreotide and 111In-DOTA-lanreotide scintigraphy and dosimetry in patients with neuroendocrine tumours

Purpose Somatostatin receptor scintigraphy with ¹¹¹In-DOTA-DPhe¹-Tyr³-octreotide (¹¹¹In-DOTA-TOC) and ¹¹¹In-DOTA-lanreotide (¹¹¹In-DOTA-LAN) has been used for staging of neuroendocrine tumours (NETs). However, the comparative diagnostic value of these radioligands on a lesion basis has not yet been established. The aim of this study was to compare the diagnostic capacity of ¹¹¹In-DOTA-TOC and ¹¹¹In-DOTA-LAN scintigraphy in patients with NETs, evaluating whether significant differences exist in lesion imaging with these radioligands. Furthermore, dosimetric data were compared. Methods Forty-five patients with NETs were investigated with ¹¹¹In-DOTA-TOC and ¹¹¹In-DOTA-LAN scintigraphy. Scintigraphic results were compared with those of conventional imaging and/or surgery in each patient, and also ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) in 20 patients. Results ¹¹¹In-DOTA-TOC and ¹¹¹In-DOTA-LAN scintigraphy were true positive in 42/45 (93%) and 39/45 (87%) patients, and imaged 74/91 (81%) and 73/91 (80%) tumour lesions, respectively. ¹¹¹In-DOTA-TOC and ¹¹¹In-DOTA-LAN detected liver metastases in 21 and 14 patients, mediastinal metastases in seven and 11 patients, and bone metastases in two and seven patients, respectively. These radioligands revealed lesions not seen by conventional imaging in seven and eight patients, respectively, or by ¹⁸F-FDG-PET in eight and seven patients, respectively. The estimated tumour absorbed doses for ⁹⁰Y-DOTA-TOC were higher than those for ⁹⁰Y-DOTA-LAN in 14 patients, whereas the opposite was true in 12 patients. Conclusion Both ¹¹¹In-DOTA-TOC and ¹¹¹In-DOTA-LAN are suitable for imaging tumour lesions in patients with NETs and can detect lesions that may not be seen by conventional imaging and ¹⁸F-FDG-PET. Compared with ¹¹¹In-DOTA-LAN, ¹¹¹In-DOTA-TOC has a superior diagnostic capacity for liver metastases, but a lower diagnostic capacity for metastatic lesions in mediastinum and bone.     

Value of 111In-DOTA-lanreotide and 111In-DOTA-DPhe1-Tyr3-octreotide in differentiated thyroid cancer: results of in vitro binding studies and in vivo comparison with 18F-FDG PET

Purpose Radioiodine-negative thyroid cancer presents diagnostic and therapeutic difficulties, warranting the implementation of new imaging and treatment strategies. The purpose of this study was twofold. First, we investigated in vitro the binding characteristics of ¹¹¹In-DOTA-lanreotide (¹¹¹In-DOTA-LAN) and ¹¹¹In-DOTA-DPhe¹-Tyr³-octreotide (¹¹¹In-DOTA-TOC) to cells derived from differentiated thyroid cancer (DTC). Second, we evaluated the value of somatostatin receptor (SSTR) scintigraphy with these radioligands, as compared with ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography (PET), for the detection of tumour lesions in DTC patients.Methods Binding of ¹¹¹In-DOTA-LAN and ¹¹¹In-DOTA-TOC to cells isolated from surgically removed thyroid tissue was evaluated in vitro by performing saturation and displacement studies. Eighteen DTC patients with elevated thyroglobulin (12 radioiodine-negative, six radioiodine-positive) were investigated with ¹¹¹In-DOTA-LAN, ¹¹¹In-DOTA-TOC and ¹⁸F-FDG PET scans.Results Large numbers of SSTR binding sites for ¹¹¹In-DOTA-LAN and ¹¹¹In-DOTA-TOC were found on the cells investigated. Both SSTR radioligands exhibited a high binding affinity for these SSTR binding sites. ¹¹¹In-DOTA-LAN and ¹¹¹In-DOTA-TOC scintigraphy detected 37 and 33 lesions, respectively, in 17 (94%) patients each, whereas ¹⁸F-FDG PET revealed 30 lesions in 15 (83%) patients. Uptake of both SSTR radioligands was found in several radioiodine-negative sites. No striking differences in lesion imaging by ¹¹¹In-DOTA-LAN and ¹¹¹In-DOTA-TOC were found. In both radioiodine-negative and radioiodine-positive patients, more lesions were SSTR-positive/¹⁸F-FDG-negative than were ¹⁸F-FDG-positive/SSTR-negative.Conclusion Adding a SSTR scan with these radioligands to the diagnostic work-up increases the diagnostic capacity in DTC, and should be considered particularly in radioiodine-negative patients with elevated thyroglobulin levels.These studies were supported in part by the Austrian National Bank (Anniversary Foundation, Projects No. 7487 and 8185) and by a Foundation of the Mayor of the City of Vienna.     

O-[18F]fluoromethyl-L-tyrosine is a potential tracer for monitoring tumour response to chemotherapy using PET: an initial comparative in vivo study with deoxyglucose and thymidine

Purpose To compare the utility of a new artificial amino acid, O-[¹⁸F]fluoromethyl-L-tyrosine ([¹⁸F]FMT), for monitoring cancer chemotherapy with deoxyglucose and thymidine.Methods [¹⁸F]FMT, [¹⁴C]deoxyglucose ([¹⁴C]DG) and [6-³H]thymidine ([³H]Thd) were applied in this study. A 2.5 mg/kg dose of mitomycin (MMC) was administered to AH272 rat hepatoma-bearing Donryu rats. Tumour uptake of each tracer was measured just before (baseline) and on days 1, 3, 5 and 7 after the MMC administration, 1 h after a mixture of [¹⁸F]FMT, [¹⁴C]DG and [³H]Thd had been injected, and was shown as DURs (% injected dose/gram tissue normalised for the rat body weight). Dual-tracer macroautoradiographs with [¹⁸F]FMT and [¹⁴C]DG were also prepared.Results The tumour uptake for each tracer decreased earlier than did the tumour size. DURs (mean±SD) at baseline and on days 1, 3, 5 and 7 were as follows: [¹⁸F]FMT: 4.68±0.72, 3.34±0.66, 3.13±0.72, 3.42±0.45, 3.01±0.32; [¹⁴C]DG: 3.26±0.40, 3.09±0.55, 3.01±0.97, 2.28±0.35, 1.70±0.72; and [³H]Thd: 2.23±0.46, 1.54±0.45, 1.28±0.37, 1.35±0.20, 0.94±0.12. Decrease in [¹⁸F]FMT uptake compared with baseline was significant from day 1 (p<0.01), and the decrease in [³H]Thd uptake was also significant on day 1 (p<0.05) and days 3–7 (p<0.01). However, decrease in [¹⁴C]DG uptake was only significant from day 5 (p<0.01). Macroautoradiography suggested that the influence of inflammatory cells on the accumulation of [¹⁸F]FMT in tumours is smaller than that on the accumulation of [¹⁴C]DG.Conclusion [¹⁸F]FMT uptake shows a rapid and sensitive response to chemotherapy, comparable to that of [³H]Thd, suggesting that it may be applied as a powerful tracer for monitoring of proliferative activity after cancer chemotherapy using PET.