(dtpa-phe(1))-octreotide and Neuroendocrine-Tumors

This paper is a critical review of the literature on NET radionuclide therapy with (111)In-DTPA(0)-octreotide (Octreoscan) and (131)I-MIBG, focusing on efficacy and toxicity. Some potential future applications and new candidate therapeutic agents are also mentioned. Octreoscan has been a pioneering agent for somatostatin receptor radionuclide therapy. It has achieved symptomatic responses and disease stabilization, but it is now outperformed by the corresponding β-emitter agents (177)Lu-DOTATATE and (90)Y-DOTATOC. (131)I-MIBG is the radionuclide therapy of choice for inoperable or metastatic phaeochromocytomas/paragangliomas, which avidly concentrate this tracer via the noradrenaline transporter. Symptomatic, biochemical and tumour morphological response rates of 50-89%, 45-74% and 27-47%, respectively, have been reported. (131)I-MIBG is a second-line radiopharmaceutical for treatment of enterochromaffin carcinoids, mainly offering the benefit of amelioration of hormone-induced symptoms. High specific activity, non-carrier-added (131)I-MIBG and meta-astato((211)At)-benzylguanidine (MABG) are tracers with potential for enhanced therapeutic efficacy, yet their integration into clinical practice awaits further exploration. Amongst other promising agents, radiolabelled exendin analogues show potential for imaging and possibly therapy of insulinomas, while preclinical studies are currently evaluating DOTA peptides targeting the CCK-2/gastrin receptors that are overexpressed by medullary thyroid carcinoma cells.

Topics: 3-Iodobenzylguanidine; Carcinoid Tumor; Carcinoma, Neuroendocrine; Humans; Iodine Radioisotopes; Neuroendocrine Tumors; Octreotide; Paraganglioma; Pentetic Acid; Pheochromocytoma; Radiopharmaceuticals; Receptors, Somatostatin; Thyroid Neoplasms

Peptide receptor radionuclide therapy with radiolabelled somatostatin analogues is an emerging and convincing treatment modality for patients with unresectable, somatostatin-receptor-positive neuroendocrine tumours. Using radiolabelled somatostatin analogues for imaging became the gold standard for staging of neuroendocrine tumours. The somatostatin receptor is strongly over-expressed in most tumours, resulting in high tumour-to-background ratios. Consequently, the next step was to try to treat these patients by increasing the radioactivity of the administered radiolabelled somatostatin analogue in an attempt to bring about tumour cure. Many patients have been treated successfully with this approach, roughly 25% of them achieving objective tumour shrinkage >50%. Serious side-effects have been rare. This article reviews the effectiveness and safety of the different radiolabelled somatostatin analogues used. Furthermore, clinical issues--including indication and timing of therapy--are discussed. Finally, important directions for future research are mentioned to illustrate new strategies for increasing therapy efficacy.

Topics: Blood; Heterocyclic Compounds; Humans; Kidney; Liver; Neuroendocrine Tumors; Octreotide; Organometallic Compounds; Pentetic Acid; Radioisotopes; Receptors, Peptide; Somatostatin; Time Factors

The majority of Neuroendocrine tumors (NET) express somatostatin (SS) receptors, and thus can be successfully targeted with radiolabeled SS analogs in vivo. Somatostatin receptor scintigraphy (SRS) with (111)In-DTPA Octreotide is the main imaging technique for evaluation of NETs. Radio-guided surgery for NETs, therefore, primarily utilizes (111)In-DTPA Octreotide tumor localization mechanism and kinetics. Somatostatin analog radiopharmacy continues to evolve to include the development of more selective and higher affinity analogs and PET tracers. These changes are expected to open new venues for radio-guided surgery technology.

Topics: Gamma Cameras; Humans; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Radioimmunodetection; Radioligand Assay; Radiopharmaceuticals; Receptors, Somatostatin; Somatostatin; Surgery, Computer-Assisted; Tomography, Emission-Computed, Single-Photon

[(111)In-DTPA(0)]octreotide is a radiopharmaceutical with a great potential for the visualization of somatostatin receptor-positive tumors. The overall sensitivity of Somatostatin Receptor Imaging (SRI) to localize neuroendocrine tumors is high. In a number of neuroendocrine tumor types, as well as in Hodgkin's disease, inclusion of SRI in the localization or staging procedure may be very rewarding, either in terms of cost-effectiveness, patient management, or quality of life. The value of SRI in patients with other tumors, like breast cancer, or in patients with granulomatous diseases, has to be established. The development of Peptide Receptor Radionuclide Therapy (PRRT) is expected to stimulate peptide receptor imaging.

Topics: Brain Neoplasms; Breast Neoplasms; Carcinoma, Small Cell; Humans; Indium Radioisotopes; Lung Neoplasms; Lymphoma; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Radionuclide Imaging; Receptors, Somatostatin; Sarcoidosis

In preclinical studies in rats we evaluated biodistribution and therapeutic effects of different somatostatin analogs, [(111)In-DTPA]octreotide, [(90)Y-DOTA,Tyr(3)]octreotide and [(177)Lu-DOTA,Tyr(3)]octreotate, currently also being applied in clinical radionuclide therapy studies. [Tyr(3)]octreotide and [Tyr(3)]octreotate, chelated with DTPA or DOTA, both showed high affinity binding to somatostatin receptor subtype 2 (sst(2)) in vitro. The radiolabelled compounds all showed high tumor uptake in sst(2)-positive tumors in vivo in rats, the highest uptake being reached with [(177)Lu-DOTA,Tyr(3)]octreotate. In preclinical therapy studies in vivo in rats, excellent, dose dependent, tumor size responses were found, responses appeared to be dependent on tumor size at therapy start. These preclinical data showed the great promise of radionuclide therapy with radiolabelled somatostatin analogues. They emphasised the concept that especially the combination of somatostatin analogs radiolabeled with different radionuclides, like (90)Y and (177)Lu, is most promising to reach a wider tumor size region of high curability. Furthermore, different phase I clinical studies, using [(111)In-DTPA]octreotide, [(90)Y-DOTA,Tyr(3)]octreotide or [(177)Lu-DOTA, Tyr(3)]octreotate are described. Fifty patients with somatostatin receptor-positive tumors were treated with multiple doses of [(111)In-DTPA(0)]octreotide. Forty patients were evaluable after cumulative doses of at least 20 GBq up to 160 GBq. Therapeutic effects were seen in 21 patients: partial remission in 1 patient, minor remissions in 6 patients, and stabilization of previously progressive tumors in 14 patients. The toxicity was generally mild bone marrow toxicity, but 3 of the 6 patients who received more than 100 GBq developed a myelodysplastic syndrome or leukemia. Radionuclide therapy with [(90)Y-DOTA,Tyr(3)]octreotide started in 3 different phase I trials. Overall, antimitotic effects have been observed: about 20% partial response and 60% stable disease (N = 92) along with complete symptomatic cure of several malignant insulinoma and gastrinoma patients. Maximum cumulative [(90)Y-DOTA,Tyr(3)]octreotide dose was about 26 GBq, without reaching the maximum tolerable dose. New is the use of [(177)Lu-DOTA,Tyr(3)]octreotate, which shows the highest tumor uptake of all tested octreotide analogs so far, with excellent tumor-to-kidney ratios. Radionuclide therapy with this analog in a phase 1 trial started recently in our c

Topics: Animals; Humans; Indium Radioisotopes; Liver Neoplasms; Neuroendocrine Tumors; Octreotide; Organometallic Compounds; Pancreatic Neoplasms; Pentetic Acid; Radiopharmaceuticals; Rats; Receptors, Somatostatin; Tumor Cells, Cultured; Yttrium Radioisotopes

Surgery is the only therapy able to cure patients with digestive neuroendocrine tumor. However, due to the presence of diffuse metastases, radical surgery is often not feasible. In these cases, medical treatment plays a critical role, because of its ability to control symptoms in functioning tumors and to inhibit tumor growth. Different therapeutic approaches, such as chemotherapy, hepatic artery chemoembolization and targeted radio-nuclide therapy can be used alone or combined to the biologic treatment with somatostatin analogues and interferon. However, an accurate staging by imaging procedures plus a histological, immunohistochemical and biomolecular examination must be performed before planning an optimal medical treatment.

Topics: Algorithms; Antineoplastic Agents, Hormonal; Carcinoid Tumor; Cell Differentiation; Combined Modality Therapy; Digestive System Neoplasms; Embolization, Therapeutic; Humans; Indium Radioisotopes; Neoplasm Proteins; Neoplasm Staging; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Peptides, Cyclic; Receptors, Somatostatin; Retrospective Studies; Somatostatin; Treatment Outcome

Current therapeutic approaches in neuroendocrine tumours include surgery, radiotherapy and polychemotherapy. Different metabolic patterns of neuroendocrine tumours allow the use of a wide range of diagnostic options in nuclear medicine, due to the presence of a wide spectrum of radiotracers electively concentrating in these neoplasms. Nuclear medicine, and in particular 111In Octreotide (OCT) scintigraphy, 123I Methaiodobenzylguanidine (MIBG) and pentavalent 99mTc-DMSA (V-DMSA), together with biohumoral markers, are currently able to locate tumours also not detectable using traditional diagnostic techniques. Somatostatin analogs, such as octreotide have become increasingly important over the years in the treatment of patients with neuroendocrine tumours. At present the therapeutic use of somatostatin analogs can be schematised as 1) pharmacological treatment (with cold octreotide); 2) surgical treatment (radioguided surgery); 3) radiometabolic treatment (with marked octreotide). The development of new synthetic molecules and new radiocompounds will probably open up interesting scenarios in the near future.

Topics: Adrenal Gland Neoplasms; Adrenalectomy; Antineoplastic Agents, Hormonal; Carcinoma, Medullary; Carcinoma, Non-Small-Cell Lung; Combined Modality Therapy; Humans; Indium Radioisotopes; Lung Neoplasms; Neoplasm Proteins; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Pheochromocytoma; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Somatostatin; Somatostatin; Surgery, Computer-Assisted; Thyroid Neoplasms; Thyroidectomy; Tomography, X-Ray Computed

This article reviews the results of somatostatin receptor imaging (SRI) in patients with somatostatin receptor-positive neuroendocrine tumors, such as pituitary tumors, endocrine pancreatic tumors, carcinoids, gastrinomas, and paragangliomas, or other diseases in which somatostatin receptors may also be expressed, like sarcoidosis and autoimmune diseases. [(111)In-DTPA0]octreotide is a radiopharmaceutical that has great potential for helping visualize whether somatostatin receptor-positive tumors have recurred. The overall sensitivity of SRI to localize neuroendocrine tumors is high. In several neuroendocrine tumor types, inclusion of SRI in the localization or staging procedure may be very rewarding in terms of cost effectiveness, patient management, or quality of life. The value of SRI in patients with other tumors, such as breast cancer or malignant lymphomas, or in patients with granulomatous diseases has to be established. The application of radiolabeled peptides may be clinically useful in another way: after the injection of [(111)In-DTPA0]octreotide, surgeons can detect tumor localizations by a probe that is used during the operation. This may be of particular value if small tumors with a high receptor density are present (e.g., gastrinomas). As the success of peptide receptor scintigraphy for tumor visualization became clear, the next logical step was to try to label these peptides with radionuclides emitting alpha or beta particles, or Auger or conversion electrons, and to perform radiotherapy with these radiolabeled peptides. The results of the described studies with 90Y- and (111)In-labeled octreotide show that peptide receptor radionuclide therapy using radionuclides with appropriate particle ranges may become a new treatment modality. One might consider the use of radiolabeled somatostatin analogs first in an adjuvant setting after surgery of somatostatin receptor-positive tumors to eradicate occult metastases and second for cancer treatment at a later stage.

Topics: Humans; Indium Radioisotopes; Neoplasms; Neuroendocrine Tumors; Octreotide; Oligopeptides; Pentetic Acid; Radiopharmaceuticals; Receptors, Somatostatin; Tomography, Emission-Computed, Single-Photon; Yttrium Radioisotopes

Topics: Algorithms; Animals; Binding, Competitive; Biomarkers, Tumor; Clinical Trials, Phase I as Topic; Gastrointestinal Neoplasms; Humans; Indium Radioisotopes; Neoplasm Metastasis; Neoplasm Proteins; Neoplasm Staging; Neuroendocrine Tumors; Neuropeptides; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radiology, Interventional; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Somatostatin; Sensitivity and Specificity; Somatostatin

In patients with gastro-enteropancreatic neuroendocrine tumours the localization of all the neoplastic lesions and an accurate staging of the diseases have important therapeutic implications. Somatostatin receptor scintigraphy with In-111 pentatreotide has proved to be useful in detecting gastro-enteropancreatic tumours; however, the role of abdominal single photon emission computed tomography has not yet been definitively established. In a series of 52 patients with gastro-enteropancreatic tumours (9 non-functioning islet cell carcinomas, 4 insulinomas, 3 somatostatinomas, 2 VIPomas, 1 glucagonoma and 33 carcinoids) we compared somatostatin receptor scintigraphy with the results of computed tomography and magnetic resonance imaging performed within one month. Four and 24-hour total body planar images and 4-hour abdominal single photon emission computed tomography were acquired after the i.v. injection of approximately 250 MBq of In-111 pentatreotide. Only abdominal localizations were considered: planar scans detected 16 extrahepatic lesions in 13 patients and 54 liver sites in 21 patients; single photon emission computed tomography visualized 31 extrahepatic lesions and 89 liver metastases in 27 and 28 patients, respectively; computed tomography and magnetic resonance imaging detected 11 extrahepatic lesions in 10 patients and 73 liver sites in 21 patients. In-111 pentatreotide single photon emission computed tomography was the only imaging method able to localize tumoural lesions in 13 patients; all these localizations were then histologically verified. The scintigraphic positivity did not depend on the site or on the presence of hormonal hypersecretions. In conclusion, our results indicate that single photon emission computed tomography is more sensitive than planar images and computed tomography/magnetic resonance imaging in detecting abdominal gastro-enteropancreatic tumours and their metastases; it is able to increase both the number of visualized lesions and that of patients with positive findings. Single photon emission computed tomography is particularly useful in patients in whom tumoural lesions have not been already localized; it should be the first imaging modality in patients with gastro-enteropancreatic tumours: its initial use will result in more information and proper management.

Topics: Female; Gastrointestinal Neoplasms; Humans; Male; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Receptors, Somatostatin; Sensitivity and Specificity; Tomography, Emission-Computed, Single-Photon

The study of breast carcinogenesis is complicated by the heterogeneity of the disease. One way of simplifying is to subdivide these tumors into clinically relevant subgroups. There are indications that breast carcinomas, of which some express the somatostatin receptor (SS-R), can be divided this way. Expression of somatostatin receptors (SS-R's) in human primary breast cancer has a very high incidence. This can be demonstrated by in vitro autoradiography and in vivo by somatostatin receptor scintigraphy. However the clinical significance of somatostatin receptor expression in human breast cancer needs to be investigated. In this review article we summarize the current understanding of the functional role of somatostatin receptors in human breast cancer. Their relationship with neuroendocrine differentiation of the cancers and genetic and patient characteristics, the role of in vivo SS-R's visualization, and the possible medical and radiotherapeutic implications of these findings are discussed.

Topics: Autoradiography; Breast Neoplasms; Carcinoma; Cell Differentiation; Female; Gene Expression Regulation, Neoplastic; Humans; Indium Radioisotopes; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Prognosis; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Somatostatin; Terbium

[111In-DTPA-D-Phe1]-octreotide is a new radiopharmaceutical with a great potential for the visualization of somatostatin receptor-positive tumors, granulomas, and diseases in which activated leukocytes play a role. The overall sensitivity of [111In-DTPA-D-Phe1]-octreotide scintigraphy to localize neuroendocrine tumors is high. In several neuroendocrine tumor types, inclusion of somatostatin receptor imaging in the localization or staging procedure may be very rewarding, either in terms of cost-effectiveness, patient management, or quality of life. In our opinion, this holds true for patients with carcinoids, gastrinomas, paragangliomas, small-cell lung carcinoma, and selected cases of patients with insulinomas. The value of [111In-DTPA-D-Phe1]-octreotide scintigraphy in patients with other tumors, such as breast cancer, malignant lymphomas, or in patients with granulomatous diseases, has to be established.

Topics: Humans; Indium Radioisotopes; Neoplasms; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Radiopharmaceuticals; Tomography, Emission-Computed, Single-Photon

Somatostatin, a naturally occurring 14-amino acid peptide, can be thought of as an anti-growth hormone and functional down-regulator of sensitive tissue. Most neuroendocrine tumors seem to possess somatostatin receptors in sufficient abundance to allow successful scintigraphic imaging with radiolabeled somatostatin congeners. Several of these, including Indium-III-DTPA Pentetreotide (Octreoscan [Mallinckrodt Medical, St. Louis, MO]), which was approved for clinical use by the Food and Drug Administration in June 1994, have been of considerable value in scintigraphically identifying various neuroendocrine tumors. The Octreoscan compares favorably with other imaging modalities. The success of somatostatin receptor imaging in evaluating patients with suspected neuroendocrine tumors, including identifying otherwise radiographically occult lesions, has resulted in ranking somatostatin receptor imaging as the prime imaging procedure in patients with suspected neuroendocrine tumors at The Ohio State University.

Topics: Humans; Indium Radioisotopes; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Radiation Dosage; Radionuclide Imaging; Receptors, Somatostatin

This review has focused on the unique role of radionuclide scintigraphy in characterization of hepatic mass lesions. Radionuclide scintigraphy, unlike most other imaging modalities, is based on specific physiological and biochemical properties of each pathological entity that affects the liver. Hepatic scintigraphy, with its widespread availability, noninvasive nature, and relatively low cost is a powerful adjunct to other imaging techniques in the investigation of hepatic mass lesions. We have reviewed clinical presentation and characteristic findings of most hepatic lesions and have described reported findings with all available imaging modalities with particular emphasis on hepatic scintigraphy (Table 1) as well as a suggested algorithm for workup of solid hepatic masses (Fig 6). Additionally, the role of newer, more specialized techniques including PET scanning, 123I-labeled VIP, and 111In-labeled DTPA-D-Phe-octreotide scanning are reviewed. Hepatic nuclear scintigraphy continues to play an important role in the management of patients with solid hepatic masses.

Topics: Algorithms; Carcinoma, Hepatocellular; Costs and Cost Analysis; Hemangioma, Cavernous; Humans; Indium Radioisotopes; Iodine Radioisotopes; Liver Diseases; Liver Neoplasms; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Terbium; Tomography, Emission-Computed; Vasoactive Intestinal Peptide

Topics: Europe; Humans; Indium Radioisotopes; Neoplasm Metastasis; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Receptors, Somatostatin; Stomach Neoplasms; Tomography, Emission-Computed, Single-Photon

Various tumours, classically specified as either neuroendocrine or non-neuroendocrine, contain high numbers of somatostatin receptors, which enable in vivo localization of the primary tumour and its metastases by scintigraphy with the radiolabelled somatostatin analogue octreotide. In addition granulomas and autoimmune processes can be visualized because of local accumulation of somatostatin receptor-positive activated mononuclear leucocytes. In many instances a positive scintigram predicts a favourable response to treatment with octreotide. It is tempting to speculate that octreotide labelled with an appropriate radionuclide might be used in cancer therapy. The successful application of radiolabelled octreotide in scintigraphy indicates the possible usefulness of other radiolabelled peptides, either native peptides or derivatives of these, in, for example, nuclear oncology. The small size of these peptides, e.g. bombesin and substance P, is of the utmost importance for a relatively fast blood clearance, thus leading to low background radioactivity. In this way peptides are powerful alternatives to (fragments of) monoclonal antibodies, the application of which to scintigraphic localization of specific cell surface antigen-bearing tumours is plagued by slow blood clearance and, hence, high background levels.

Topics: Humans; Indium Radioisotopes; Iodine Radioisotopes; Netherlands; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Radionuclide Imaging; Receptors, Somatostatin

The aim of the present study was to prospectively evaluate the add value provided by [(111)In]DTPA-octreotide single-photon emission computed tomography/computed tomography (Octreo-SPECT/CT) with respect to [(111)In]DTPA-octreotide SPECT (Octreo-SPECT) in terms of diagnostic accuracy and localization of neuroendocrine tumors (NETs).. Eighty-one consecutive patients with known or suspected NET underwent [(111)In]DTPA-octreotide scintigraphy using an integrated SPECT/low-energy-CT system (Infinia & Hawkeye; GE Medical Systems, Milwaukee, WI, USA). SPECT and fused SPECT/CT images were interpreted separately and a lesion-by-lesion analysis was performed with regard to classification (probability of NET graded on a 5-point scale) and localization of each abnormal focal tracer uptake. A subgroup analysis, distinguishing between abdominal and thoracic lesions, and a patient-by-patient analysis for likelihood of NET in each patient was also performed. Standard of reference for confirming presence or absence of NET was either histopathology or clinical/imaging follow-up data. The value of SPECT/CT imaging was assessed by ROC analysis and McNemar test.. A final diagnosis of NET was achieved in 43 out of 81 patients and a total of 169 areas (138 NET and 31 benign/physiological) with focal tracer uptake were included in the final lesion-by-lesion analysis. SPECT/CT imaging led to a significantly higher proportion of patients (75/81=92.6% vs 64/81=79%) and lesions (163/169=96.4% vs 138/169=81.1%) correctly classified vs SPECT alone. ROC analysis confirmed that Octreo-SPECT/CT performed significantly better than Octreo-SPECT for the detection of NET on both patient- and lesion-based analysis, improving especially evaluation of abnormal tracer uptake in the abdomen. Moreover, Octreo-SPECT/CT accurately localized 160/169 (94.7%) lesions, significantly higher than SPECT alone (77/169= 45.6%).. Octreo-SPECT/CT allows more accurate detection and localization of NETs than simple Octreo-SPECT, with major benefits for lesions located in the abdomen.

Topics: Abdomen; Adult; Aged; Aged, 80 and over; False Positive Reactions; Female; Humans; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Paraganglioma; Pentetic Acid; Radiography, Abdominal; Radiography, Thoracic; Recurrence; ROC Curve; Sensitivity and Specificity; Thorax; Time Factors; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed

As scintigraphy with [(111)In-DTPA(0)]octreotide has become a standard technique in analysing somatostatin receptor-receptor positive lesions such as neuroendocrine tumours, a logical next step is peptide receptor radionuclide therapy (PRRT). Initial studies on PRRT were performed with high doses of [(111)In-DTPA(0)]octreotide, and recently other radionuclides coupled to other somatostatin analogues have been used for this purpose. However, the dose delivered to the kidney is a major dose-limiting factor. Amino acid solutions have previously been used to reduce renal uptake of radioactivity, but these solutions have some disadvantages, i.e. their hyperosmolarity and their propensity to cause vomiting and metabolic changes. In this study we tested various amino acid solutions in patients receiving [(111)In-DTPA(0)]octreotide PRRT in order to assess their safety and their capacity to inhibit the renal uptake of radioactivity. Patients served as their own non-infused control. Renal radioactivity at 24 h following the injection of [(111)In-DTPA(0)]octreotide was inhibited by (1) a commercially available amino acid solution (AA) (21%+/-14%, P<0.02), (2) by 25 g (17%+/-9%, P<0.04), 50 g (15%+/-13%, P<0.04) or 75 g of lysine (44%+/-11%, P<0.001) and (3) by a combination of 25 g of lysine plus 25 g of arginine (LysArg) (33%+/-23%, P<0.01). Fluid infusion alone (500, 1,000 or 2,000 ml of saline/glucose) did not change renal uptake of radioactivity. In patients studied with 75 g of lysine (Lys75) and LysArg, serum potassium levels rose significantly. Maximal potassium levels were within the toxic range (6.3, 6.7 and 6.8 mmol/l) in three out of six patients infused with Lys75, whereas with LysArg the highest concentration measured was 6.0 mmol/l. Electrocardiographic analysis did not reveal significant changes in any of the patients. Vomiting occurred in 50% of patients infused with AA, but in only 6% of patients receiving no amino acid infusion (controls) and 9% of patients receiving LysArg. We conclude that co-infusion of Lys75 or LysArg results in a significant inhibition of renal radioactivity in PRRT, allowing higher treatment doses and thus resulting in higher tumour radiation doses. Because Lys75 produced serious hyperkalaemia, it is not suitable for clinical use. LysArg, however, is effective in offering renal protection in PRRT and is safe.

Topics: Arginine; Carcinoma, Neuroendocrine; Female; Humans; Hyperkalemia; Infusions, Intravenous; Kidney; Lysine; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Radionuclide Imaging; Radiopharmaceuticals; Vomiting

Fifty patients with somatostatin receptor-positive tumors were treated with multiple doses of [(111)In-diethylenetriamine pentaacetic acid(0)]octreotide. Forty patients were evaluable after cumulative doses of at least 20 GBq up to 160 GBq. Therapeutic effects were seen in 21 patients: partial remission in 1 patient, minor remissions in 6 patients, and stabilization of previously progressive tumors in 14 patients. Our results thus underscore the therapeutic potential of Auger-emitting radiolabelled peptides. The toxicity was generally mild bone marrow toxicity, but 3 of the 6 patients who received more than 100 GBq developed a myelodysplastic syndrome or leukemia. Therefore, we consider 100 GBq as the maximal tolerable dose. With a renal radiation dose of 0.45 mGy/MBq (based on previous studies) a cumulative dose of 100 GBq [(111)In-DTPA(0)]octreotide will lead to 45Gy on the kidneys, twice the accepted limit for external beam radiation. However, no development of hypertension, proteinuria, or significant changes in serum creatinine or creatinine clearance were observed in our patients including 2 patients who received 106 and 113 GBq [(111)In-DTPA(0)]octreotide without protection with amino acids, over a follow-up period of respectively 3 and 2 years. These findings show that the radiation of the short-range (maximal 10 microns) Auger electrons originating from the cells of the proximal tubules is not harmful for the renal function. The decrease in serum inhibin B and concomitant increase of serum FSH levels in men indicate that the spermatogenesis was impaired.

Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Neoplasms; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Radionuclide Imaging; Radiopharmaceuticals; Radiotherapy Dosage; Receptors, Somatostatin

Peptide receptor scintigraphy with the radioactive somatostatin analogue [111In-DTPA-D-Phe1]octreotide is a sensitive and specific technique to show in vivo the presence and abundance of somatostatin receptors on various tumors. With this technique primary tumors and metastases of neuroendocrine cancers as well as of many other cancer types can be localized. This technique is currently used to assess the possibility of peptide receptor radionuclide therapy with repeated administration of high doses of [111In-DTPA-D-Phe1]octreotide. 111In emits Auger and conversion electrons, having a tissue penetration of 0.02-10 microns and 200-500 microns, respectively. Thirty end-stage patients with mostly neuroendocrine progressing tumors were treated with [111In-DTPA-D-Phe1]octreotide, up to a maximal cumulative patient dose of about 74 GBq, in a phase-I trial. There were no major clinical side effects after up to 2 years of treatment, except that in a few patients a transient decline in platelet counts and lymphocyte subsets occurred. Promising beneficial effects on clinical symptoms, hormone production, and tumor proliferation were found. Of the 21 patients who received a cumulative dose of more than 20 GBq, eight showed stabilization of disease and six others a reduction in tumor size. There is a tendency towards better results in patients whose tumors have a higher accumulation of the radioligand. Peptide receptor radionuclide therapy is also feasible with 111In as the radionuclide. Theoretically, depending on the homogeneity of distribution of tumor cells expressing peptide receptors and the size of the tumor, beta-emitting radionuclides, e.g., 90Y, labeled to DOTA-chelated peptides may be more effective than 111In for peptide receptor radionuclide therapy. The first peptide receptor radionuclide therapy trials with [90Y-DOTA-Tyr3]octreotide started recently.

Topics: Cell Division; Dose-Response Relationship, Radiation; Female; Humans; Indium Radioisotopes; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Radiopharmaceuticals; Radiotherapy Dosage

Disseminated neuroendocrine tumours are difficult to treat and are generally not responsive to radiotherapy or chemotherapy. Nuclear medicine techniques using a radiolabelled somatostatin analogue, 111In-Octreotide, have been used for the diagnosis of neuroendocrine tumours. It has been suggested that high activities of such an agent may have a therapeutic effect. The aims of this study were to assess toxicity and to determine if there had been evidence of efficacy. Eight patients with known disseminated neuroendocrine tumours were enrolled in the study; six had carcinoid tumours, one had a medullary cell carcinoma of the thyroid and one patient had a malignant gastrinoma. Between 1.3 and 4.6 GBq of 111In-Octreotide were administered to each patient for up to five administrations over 12 months. A total of 23 administrations were given. Tests of vital signs, renal, liver and endocrine function as well as haematological markers were taken before and after treatment. The treatment was well tolerated with only one patient suffering from a sensation of flushing during the infusion but no changes in vital sings. There was a transient (up to 48 h) drop in circulating lymphocytes in four patients and platelets in two patients; no supportive therapy was needed. One patient with severe renal impairment had a slight reduction in glomerular filtration rate. We conclude that high-activity 111In-Octreotide is well tolerated with low toxicity and can be considered for use in patients with disseminated neuroendocrine tumours. Further work is now being performed to assess efficacy.

Topics: Adult; Aged; Bone and Bones; Carcinoid Tumor; Female; Gastrinoma; Glomerular Filtration Rate; Humans; Lymphocyte Count; Male; Middle Aged; Multiple Endocrine Neoplasia; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Radionuclide Imaging; Radiopharmaceuticals

Peptide receptor scintigraphy with the radioactive somatostatin analogue, [111In-DTPA0]octreotide, is a sensitive and specific technique to show in vivo the presence and abundance of somatostatin receptors on various tumours.. With this technique primary tumours and metastases of neuroendocrine cancers as well as of many other cancer-types can be localised. This technique is currently used to assess the possibility of peptide receptor radionuclide therapy (PRRT) with repeated administrations of high doses of [111In-DTPA0)octreotide. 111In emits Auger and conversion electrons having a tissue penetration of 0.02-10 microns and 200 to 500 microns, respectively.. Thirty end-stage patients with mostly neuroendocrine progressing tumours were treated with [111In-DTPA0]octreotide, up to a maximal cumulative patient dose of about 74 GBq, in a phase I trial.. There were no major clinical side effects after up to two years treatment, except that in a few patients a transient decline in platelets counts and lymphocyte subsets occurred. Promising beneficial effects on clinical symptoms, hormone production and tumour proliferation were found. Of the 21 patients who received a cumulative dose of more than 20 GBq, eight patients showed stabilisation of disease and six other patients a reduction in size of tumours. There is a tendency towards better results in patients whose tumours have a higher accumulation of the radioligand.. PRRT is feasible, also with 111In as radionuclide. Depending on the homogeneity of distribution of tumour cells expressing peptide receptors and the size of the tumour, beta-emitting radionuclides, e.g., 90Y, labelled to DOTA-chelated peptides, are also attractive candidates for PRRT. The first PRRT trials with [90Y-DOTA0,Tyr3]octreotide started recently.

Topics: Animals; Humans; Indium Radioisotopes; Liver Neoplasms; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Radiopharmaceuticals; Rats; Receptors, Peptide; Receptors, Somatostatin

To investigate possible changes in somatostatin receptor expression during treatment with high dose lanreotide, eight patients with neuroendocrine tumors were investigated by [(111)In-DTPA-D-Phe1]-octreotide scintigraphy before and during treatment. The spleen-to-background ratio decreased in all patients, whereas tumor-to-background ratio revealed a heterogeneous pattern with an average increase of 50% (-79% to +1,087%). This finding indicates that lanreotide treatment may influence the binding of radioactively labeled somatostatin to the spleen, while changes in the binding to functioning somatostatin receptors in tumor cells are more complex and not clearly related to treatment.

Topics: Aged; Antineoplastic Agents; Female; Humans; Image Processing, Computer-Assisted; Indium Radioisotopes; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Peptides, Cyclic; Radiopharmaceuticals; Receptors, Somatostatin; Somatostatin; Tomography, Emission-Computed, Single-Photon

The presence of lymph node metastases significantly influences the modality of treatment in patients with liver metastases of neuroendocrine tumors (NET). Somatostatin receptor scintigraphy (Octreo-Scan, Mallinckrodt-Diagnostica, Petten, the Netherlands) is a method for localization and staging NET. The aim of our prospective study was to evaluate the effectiveness of somatostatin receptor scintigraphy in the identification of extrahepatic tumor spread.. Thirty-five patients with liver metastases of NET were studied over a 5-year period. The presence of NET was confirmed histologically in all cases. To detect extrahepatic metastases or local tumor recurrence, conventional imaging techniques and somatostatin receptor scintigraphy were carried out.. In correlation with the findings of conventional imaging methods, somatostatin receptor scintigraphy confirmed liver metastases in all patients. Additionally, 19 of 35 patients (54.2%) had extrahepatic tumor lesions not detected by other imaging techniques. Of those, 15 had extensive abdominal or thoracic lymph node metastases, 3 patients had bone metastases, and in 1 patient with bronchial carcinoid local tumor recurrence was detected. All 19 patients were excluded from further evaluation for liver resection or transplantation and subjected to conservative treatment. The somatostatin receptor scintigraphy sensitivity, confirmed at the time of operation, was 91.6%. In 1 patient, in whom cluster transplantation was performed, somatostatin receptor scintigraphy failed to disclose disseminated carcinosis of the pleural cavity, detected at autopsy (false-negative rate 8.3%).. In our experience, somatostatin receptor scintigraphy provides a highly sensitive diagnostic method to localize metastases of NET. We recommend somatostatin receptor scintigraphy before liver surgery in every patient with hepatic metastases of NET to identify candidates suitable for resection.

Topics: Bone Neoplasms; Humans; Liver Neoplasms; Lymphatic Metastasis; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Prospective Studies; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Somatostatin

After injection of 111In-labelled DTPA-D-Phe1-octreotide, intraoperative tumour localisation was performed using a scintillation detector in 23 patients with neuroendocrine tumours. Count rates from suspect tumour lesions and adjacent normal tissue were expressed as a ratio before (Rin situ) and after (Rex vivo) excision. 111In activity concentration ratios of tumour tissue to blood (T/B) were determined in a gamma counter. In patients with midgut carcinoids, (all scintigraphy positive), false Rin situ recordings were found in 4/29 macroscopically identified tumours. T/B ratios were all high (27-650). In patients with medullary thyroid carcinomas (eight out of ten scintigraphy positive), misleading Rin situ results were found in 4/37 macroscopically identified tumours. T/B ratios were lower (3-39) than those seen in midgut carcinoids. Two out of four patients with endocrine pancreatic tumours had positive scintigraphy, reliable intraoperative measurements and very high T/B ratios (910-1500). One patient with a gastric carcinoid had correct measurements in situ and ex vivo with high T/B ratios (71-210). In situ measurements added little information to preoperative scintigraphy and surgical findings using the present detection system. Rex vivo measurements were more reliable. The very high T/B ratios seen in midgut carcinoids and some endocrine pancreatic tumours would be favourable for future radiation therapy via somatostatin receptors.

Topics: Carcinoid Tumor; Female; Humans; Indium Radioisotopes; Intraoperative Care; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radionuclide Imaging; Receptors, Somatostatin; Stomach Neoplasms; Thyroid Neoplasms; Uterine Cervical Neoplasms

Peptide receptor scintigraphy is more sensitive at the biological than anatomical level, in contrast to conventional imaging, which it complements. Neuroendocrine tumours have the most somatostatin receptors in vitro and their metastases are somatostatin receptor positive in vitro, so that [111In-DTPA-D-Phe1]octreotide (OCT) can be used to image them. OCT was compared with conventional imaging techniques (CON) in a European Multicentre Trial. In 350 evaluable patients, CON detected 88%, and OCT 80% (glucagonomas 100%, VIPomas 88%, carcinoids 87%, non-functioning islet cell tumours 82%, insulinomas 46%) of tumour sites but there was no systematic use of abdominal single-photon-emission computerised tomography. OCT demonstrated multiple tumour sites in 62 of 178 patients in whom CON had found only 1 lesion, with 60% confirmed. 12/16 lesions detected by OCT in 11 patients with no lesions according to CON were also confirmed. The impact of OCT on management was evaluated in 235 patients and affected 40%: it determined 29 surgical decisions, led to octreotide therapy in 47, and modified octreotide dose in 18. Six end-stage patients with neuroendocrine tumours were treated with OCT radionuclide therapy (up to a cumulative dose of 53 GBq per patient) in a phase I trial. There were no major side-effects after up to 2 years treatment, with impressive effects on hormone production and a likely anti-proliferative effect.

Topics: Humans; Indium Radioisotopes; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radionuclide Imaging; Receptors, Somatostatin; Stomach Neoplasms

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.. 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.. 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.. 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.

Topics: Humans; Models, Biological; Neuroendocrine Tumors; Octreotide; Organometallic Compounds; Pentetic Acid; Radiation Dosage; Radiotherapy Dosage; Receptors, Somatostatin

In the absence of preoperative somatostatin receptor ( SST) scans, knowledge of immunohistochemical SST2 tumor expression may help predicting the success of somatostatin analogue-based follow-up studies and treatment of neuroendocrine tumors (NET). We studied the association between SST immunostaining and tracer uptake in [(111)In]-DTPA octreotide (DTPAOC) scintigraphy and [(68)Ga]-DOTA-D-Phe(1)-Tyr(3)-octreotide (DOTATOC) positron emission tomography (PET)/computed tomography (CT). Retrospective analy-sis of 36 NET patients was carried out. In 40 tumors, immunohistochemical SST2, SST3, and SST5 expressions were analyzed using a pathological scoring, applying monoclonal ( SST2) or polyclonal antibodies (SST3, SST5). In 14 lesions, [(111)In]-DTPAOC uptake was assessed by a semiquantitative score. In 26 tumors, [(68)Ga]-DOTATOC PET/CT was quantified using an uptake score and maximal standard uptake value (SUV(max)). Combined and separate qualitative analysis of SST scans revealed significant associations between increased tracer uptake and immunohistochemical SST2 detection (combined: rho=0.56, p=0.0002, [(111)In]-DTPAOC: rho=0.63, p=0.0152, and [(68)Ga]-DOTATOC: rho=0.52, p=0.0065, respectively). In contrast, SST3 and SST5 immunostaining was not associated with tracer uptake (all p>0.14). The semiquantitative immunohistochemical score for SST2 was associated with the [(68)Ga]-DOTATOC uptake score and SUV (max) values (rho=0.67, p=0.0002 and rho=0.63, p=0.0010, respectively), but not with the [(111)In]-DTPAOC uptake score (rho=0.24, p=0.4). In patients without preoperative SST scans, knowledge of immunohistochemical SST2 expression may help estimating the value of SST imaging in the clinical follow-up, in particular in those lesions with positive SST2 immunostaining. Negativity for SST2, however, does not rule out tracer uptake in some patients, with heterogeneous SST2 expression within the tumor as a potential explanation.

Topics: Female; Humans; Immunohistochemistry; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Positron-Emission Tomography; Receptors, Somatostatin; Tomography, X-Ray Computed

(111)In-diethylenetriaminepentaacetic acid (DTPA)-octreotide scintigraphy is currently the nuclear medicine imaging modality of choice for identifying neuroendocrine tumors. However, there are cohorts of patients in whom scintigraphy findings are negative or equivocal. We evaluated the role of (68)Ga-DOTATATE PET in a selected group of patients with negative or weakly positive findings on (111)In-DTPA-octreotide scintigraphy to determine whether (68)Ga-DOTATATE PET is able to detect additional disease and, if so, whether patient management is altered.. Fifty-one patients with a histologically confirmed diagnosis of neuroendocrine tumors were included. Of the 51 patients, 35 who were negative and 16 equivocal for uptake on (111)In-DTPA-octreotide scintigraphy underwent (68)Ga-DOTATATE PET. Findings were compared using a region-by-region analysis. All findings were verified with CT or MRI. After (68)Ga-DOTATATE PET, all cases were reviewed to determine whether the (68)Ga-DOTATATE PET findings resulted in any alteration in management, in terms of suitability for peptide receptor therapy, somatostatin analogs, and surgery.. Of the 51 patients, 47 had evidence of disease on cross-sectional imaging or biochemically. (68)Ga-DOTATATE PET was positive in 41 of these 47 patients (87.2%). No false-positive lesions were identified. (68)Ga-DOTATATE PET detected 168 of the 226 lesions (74.3%) that were identified with cross-sectional imaging. (68)Ga-DOTATATE PET identified significantly more lesions than (111)In-DTPA-octreotide scintigraphy (P < 0.001). There was no correlation between (68)Ga-DOTATATE uptake and histologic grade of neuroendocrine tumors. (68)Ga-DOTATATE imaging changed management in 36 patients (70.6%), who were subsequently deemed suitable for peptide receptor-targeted therapy.. In patients with negative or equivocal (111)In-DTPA-octreotide findings, (68)Ga-DOTATATE PET identifies additional lesions and may alter management in most cases.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biological Transport; Humans; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Organometallic Compounds; Pentetic Acid; Positron-Emission Tomography; Receptors, Somatostatin; Retrospective Studies; Tomography, X-Ray Computed; Young Adult

Topics: Aged; Colonic Neoplasms; Diagnosis, Differential; Graves Ophthalmopathy; Humans; Indium Radioisotopes; Ki-67 Antigen; Magnetic Resonance Imaging; Male; Neuroendocrine Tumors; Octreotide; Orbital Neoplasms; Pentetic Acid; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Somatostatin

111In-DTPA octreotide (DTPAOC) has been used for detecting somatostatin receptor positive tumor for years. In-111 DOTA-Tyr3-octreotide (DOTATOC) is newly developed for diagnostic and therapeutic purposes. In this study, we compared the biodistribution and tumor uptake ratio after injection of In-111 DTPAOC and In-111 DOTATOC in rats. Twelve rats bearing pancreatic tumors were divided into two groups: six rats were sacrificed at 4 hr after injection of 3.7 MBq of In-111 DTPAOC and another 6 rats were sacrificed at the same time after injection of 3.7 MBq of In-111 DOTATOC. Samples of various organs were obtained and counted to calculate the tissue concentration. In addition, 12 rats bearing pancreatic tumors were scanned at 4, 24, and 48 hr after injection of 37 MBq of In-111 DTPAOC or In-111 DOTATOC. The tumor uptake ratios (T/N ratio) were calculated. The biodistribution data showed that the activity in the tumor as well as in the kidney was significantly higher in the In-111 DOTATOC group than in the In-111 DTPAOC group, although both radiopharmaceuticals had the expected high affinity to the tumor. The T/N ratios in the In-111 DOTATOC group were also significantly higher than those in the In-111 DTPAOC group at 24 hr after injection. We conclude that In-111 DOTATOC showed lower clearance than In-111 DTPAOC in the rats bearing pancreatic tumors, although both of these radiopharmaceuticals showed expected high tumor uptake.

Topics: Animals; Indium Radioisotopes; Male; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radiopharmaceuticals; Rats; Rats, Inbred Lew; Tissue Distribution

Gastrin receptor scintigraphy (GRS) is a new imaging method primarily developed for the detection of metastases of medullary thyroid carcinoma (MTC). As gastrin-binding CCK(2) receptors are also expressed on a variety of other neuroendocrine tumours (NET), we compared GRS to somatostatin receptor scintigraphy (SRS) in patients with NET. SRS and GRS were performed within 21 days in a series of 60 consecutive patients with NET. GRS was directly compared with SRS. If lesions were visible on GRS but not detectable by SRS, other imaging modalities (MRI, CT) and follow-up were used for verification. Of the 60 evaluable patients, 51 had carcinoid tumours, 3 gastrinomas, 2 glucagonomas, 1 insulinoma and 3 paragangliomas. The overall tumour-detection rate was 73.7% for GRS and 82.1% for SRS. In the 11 patients with negative SRS, GRS was positive in 6 (54.5%). Based on the number of tumour sites detected and the degree of uptake, GRS performed better than SRS in 13 patients (21.7%), equivalent images were obtained in 18 cases (30.0%) and SRS performed better in 24 (40.0%) cases. In six of the SRS positive patients, 18 additional sites of tumour involvement could be detected. Overall, GRS detected additional tumour sites in 20% of the patients. Localisation of the primary tumours or their functional status had no influence on the outcome of imaging. GRS should be performed in selected patients as it may provide additional information in patients with NET with equivocal or absent somatostatin uptake.

Topics: Adult; Aged; Carcinoid Tumor; Diagnosis, Differential; Female; Glucagonoma; Humans; Indium Radioisotopes; Insulinoma; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Paraganglioma; Pentetic Acid; Prognosis; Radionuclide Imaging; Radiopharmaceuticals; Receptor, Cholecystokinin B; Receptors, Somatostatin

The objective was the evaluation of single photon emission computed tomography (SPECT) with integrated low dose computed tomography (CT) in comparison with a retrospective fusion of SPECT and high-resolution CT and a side-by-side analysis for lesion localisation in patients with neuroendocrine tumours. Twenty-seven patients were examined by multidetector CT. Additionally, as part of somatostatin receptor scintigraphy (SRS), an integrated SPECT-CT was performed. SPECT and CT data were fused using software with a registration algorithm based on normalised mutual information. The reliability of the topographic assignment of lesions in SPECT-CT, retrospective fusion and side-by-side analysis was evaluated by two blinded readers. Two patients were not enrolled in the final analysis because of misregistrations in the retrospective fusion. Eighty-seven foci were included in the analysis. For the anatomical assignment of foci, SPECT-CT and retrospective fusion revealed overall accuracies of 91 and 94% (side-by-side analysis 86%). The correct identification of foci as lymph node manifestations (n=25) was more accurate by retrospective fusion (88%) than from SPECT-CT images (76%) or by side-by-side analysis (60%). Both modalities of image fusion appear to be well suited for the localisation of SRS foci and are superior to side-by-side analysis of non-fused images especially concerning lymph node manifestations.

Topics: Adult; Aged; Bone Neoplasms; Female; Humans; Image Processing, Computer-Assisted; Indium Radioisotopes; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Radiation Dosage; Radiographic Image Enhancement; Radiopharmaceuticals; Retrospective Studies; Tomography, Emission-Computed, Single-Photon; Tomography, X-Ray Computed

64Cu (half-life, 12.7 h; beta+, 0.653 MeV [17.4%]; beta-, 0.579 MeV [39%]) has shown potential as a radioisotope for PET imaging and radiotherapy. (111)In-diethylenetriaminepentaacetic acid (DTPA)-D-Phe1-octreotide (OC) was developed for imaging somatostatin-receptor-positive tumors using conventional scintigraphy. With the advantages of PET over conventional scintigraphy, an agent for PET imaging of these tumors is desirable. Here, we show that 64Cu-TETA-OC (where TETA is 1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid) and PET can be used to detect somatostatin-receptor-positive tumors in humans.. Eight patients with a history of neuroendocrine tumors (five patients with carcinoid tumors and three patients with islet cell tumors) were imaged by conventional scintigraphy with (111)In-DTPA-OC (204-233 MBq [5.5-6.3 mCi]) and by PET imaging with 64Cu-TETA-OC (111 MBq [3 mCi]). Blood and urine samples were collected for pharmacokinetic analysis. PET images were collected at times ranging from 0 to 36 h after injection, and the absorbed doses to normal organs were determined.. In six of the eight patients, cancerous lesions were visible by both (111)In-DTPA-OC SPECT and 64Cu-TETA-OC PET. In one patient, (111)In-DTPA-OC showed mild uptake in a lung lesion that was not detected by 64Cu-TETA-OC PET. In one patient, no tumors were detected by either agent; however, pathologic follow-up indicated that the patient had no tumors. In two patients whose tumors were visualized with (111)In-DTPA-OC and 64Cu-TETA-OC, 64Cu-TETA-OC and PET showed more lesions than (111)In-DTPA-OC. Pharmacokinetic studies showed that 64Cu-TETA-OC was rapidly cleared from the blood and that 59.2% +/- 17.6% of the injected dose was excreted in the urine. Absorbed dose measurements indicated that the bladder wall was the dose-limiting organ.. The high rate of lesion detection, sensitivity, and favorable dosimetry and pharmacokinetics of 64Cu-TETA-OC indicate that it is a promising radiopharmaceutical for PET imaging of patients with neuroendocrine tumors.

Topics: Adenoma, Islet Cell; Aged; Animals; Carcinoid Tumor; Female; Gastrointestinal Neoplasms; Humans; Indium Radioisotopes; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Organometallic Compounds; Pancreatic Neoplasms; Papio; Pentetic Acid; Radiation Dosage; Radiopharmaceuticals; Receptors, Somatostatin; Sensitivity and Specificity; Tomography, Emission-Computed

A method for production of carrier-free (114m)In (half-life 49.5 days), which is a potential radionuclide for radionuclide therapy of slowly growing tumors, is presented. A target consisting of five enriched cadmium ((114)Cd) foils, each 50 microm thick, was irradiated by protons (from 12.6-6.5 MeV) giving a target yield of 0. 8 MBq/microAh. A simple and cost-efficient thermal diffusion method was used for the separation. The irradiated target foils were heated for 2 h at 306 degrees C and then etched in 0.05 M HCl. The obtained cadmium/indium solution was purified using a cation ion-exchange resin (AG 1 x 8, Bio-Rad Laboratories, Hercules, CA USA). An overall yield of approximately 60% was obtained, whereas the loss of the target material was <1% per separation cycle. The (114m)In production gave (114m)In with high specific radioactivity and was successfully used to label diethylenetriamine pentaacetic acid (DTPA)-D-Phe-octreotide. Furthermore, no difference in biodistribution between [(114m)In]- and [(111)In]-DTPA-D-Phe(1)-octreotide in tumor-bearing nude mice was seen. The high radionuclide uptake in the tumors indicates a good receptor binding of the labeled octreotide.

Topics: Animals; Cadmium Radioisotopes; Cyclotrons; Indium Radioisotopes; Isotope Labeling; Mice; Mice, Nude; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Protons; Radiopharmaceuticals; Tissue Distribution

Treatment with tumor-targeting substances is currently being evaluated in clinical trials. For patients with neuroendocrine tumors expressing somatostatin receptors, the 111In-labeled somatostatin analog [diethylenetriaminepentaacetic acid (DTPA)-DPhe1]-octreotide has been used with promising results. To further investigate the clinical effect of the injected conjugate, we analyzed the cellular distribution of 111In by ultrastructural autoradiography.. Seven patients with somatostatin receptor-expressing midgut carcinoid tumors scheduled for abdominal surgery were investigated by somatostatin receptor scintigraphy. During operation, tumor tissue samples and samples of normal intestine were collected, fixed, and processed for electron microscopy. A thin layer of film emulsion was applied on sections and after the exposure film was developed. The cellular distribution of silver precipitations indicating the presence of isotope was evaluated.. Cell surface receptor binding and internalization of [111In-DTPA-D-Phe1]-octreotide in the tumor cells was easily revealed by silver precipitations in the film. Multiple silver grains were seen at the plasma membrane, in the cytoplasmic area among secretory granules and vesicular compartments, and in the perinuclear area. Silver grains were also regularly located in the nucleus. For all patients, the silver precipitation patterns from 111In decay were identical in all examined cells from removed tumors, and in most cells 111In could be seen in the nucleus. The specificity of the silver reaction products is supported by the observation that enterocytes in intestinal tissue specimens from near the tumor did not show any silver grains and no background labeling was seen in the plastic.. After internalization through the somatostatin receptor system, 111In is translocated to the perinuclear area and into the nucleus. Whether the nuclide is still conjugated to the intact somatostatin analog or to part of it cannot be evaluated in this study. Despite the short irradiation range of 111In, the nuclear localization can explain its clinical effectiveness. The results from this study suggest that [111In-DTPA-D-Phe1]-octreotide may act as a powerful tumor cell-targeting substance.

Topics: Adult; Aged; Autoradiography; Carcinoid Tumor; Cell Membrane; Cell Nucleus; Cytoplasm; Female; Humans; Indium Radioisotopes; Intestinal Neoplasms; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Radiopharmaceuticals; Receptors, Somatostatin; Tomography, Emission-Computed, Single-Photon

Carcinoid tumors and endocrine pancreatic tumors often express somatostatin receptors (sst). Tumor spread may be visualized by sst scintigraphy using [(111)In-DTPA-D-Phe1]-octreotide. In this study, tumor targeting therapy with [(111)In-DTPA-D-Phe1]-octreotide at high doses (6 GBq every third week) was used to treat patients with sst-expressing tumors. Five patients entered the protocol and three were evaluable for response, while all could be evaluated for toxicity. Two patient responded with a significant reduction in tumor markers (> 50%). The third patient showed increasing levels of tumor markers. Side effects were expressed as depression of bone-marrow function. In one patient a grade 4 reduction in platelet count was observed requiring several thrombocyte transfusions. In another two patients platelet counts decreased significantly. We conclude that treatment with [(111)In-DTPA-D-Phe1]-octreotide can be used in patients with neuroendocrine tumors but blood parameters have to be carefully monitored to avoid severe side effects.

Topics: Aged; Dose-Response Relationship, Radiation; Female; Humans; Indium Radioisotopes; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Treatment Outcome

A wide variety of neuroendocrine tumours express somatostatin receptors, and can be visualized by radiolabelled somatostatin analogue scintigraphy. To investigate the value of [111In]-octreotide scintigraphy (Octreoscan), 48 patients (37 with proven carcinoid, pancreatic endocrine and medullary carcinoma of thyroid tumours, 11 with neuroendocrine syndromes multiple endocrine neoplasia (MEN-I) and Zollinger-Ellison syndrome (ZES) were examined with 111In-DTPA-D-Phe1-octreotide. Scintigrams were obtained at 24 and 48 h, and the results were compared with CT and magnetic resonance imaging (MRI). Thirty-five of 48 patients had positive [111In]-octreotide scintigraphy (23/25 (92%) carcinoids, 8/9 (89%) PETs, 4/11 (36%) MEN-I & ZES). Of the 42 lesions located by conventional imaging techniques, 37 (88%) were also identified by Octreoscan. Unexpected lesions (40 sites), not detected by CT or MR imaging were found in 24/48 (50%) patients. [111In]-octreotide scintigraphy has a higher sensitivity for tumour detection, and is superior to MR imaging and CT scanning in the identification of previously unsuspected extraliver and lymph node metastases. It may also be helpful for the localization of clinically suspected tumours in patients with MEN-I and ZES.

Topics: Adolescent; Adult; Aged; Carcinoid Tumor; Carcinoma, Medullary; Child; Female; Humans; Indium Radioisotopes; Magnetic Resonance Imaging; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radionuclide Imaging; Radiopharmaceuticals; Sensitivity and Specificity; Thyroid Neoplasms; Tomography, X-Ray Computed

This study presents the first successful use of a peptidic vector, DOTATOC, labelled with the beta-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 DOTATOC 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 with 111In-DOTATOC than with OctreoScan. DOTATOC could be a potential new diagnostic and therapeutic agent in the management of neuroendocrine tumours.

Topics: Abdominal Neoplasms; Adult; Humans; Indium Radioisotopes; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Radionuclide Imaging; Radiopharmaceuticals; Receptors, Somatostatin; Sensitivity and Specificity; Yttrium Radioisotopes

The authors report their preliminary experience and results of the use of 111In-DTPA-octreotide scintigraphy (octreoscan) in the staging of neuroendocrine and non-neuroendocrine tumors of the lung.. From July 1995 to May 1996 twenty-six scintigraphic studies were performed in patients affected by lung cancer at the Department of Thoracic Surgery and at the Service of Nuclear Medicine of the University of Turin.. Scintigraphy made it possible to detect the lesion in all the patients affected by neuroendocrine tumors and in 63.2% of the patients affected by non-neuroendocrine neoplasm of the lung. Scintigraphy also revealed mediastinal lymphnodal metastases in patients in which thoracic CT scan was negative: this result was confirmed by postoperative TNM.. The authors stress the importance of 111In-DTPA-octreotide scintigraphy in a correct procedure of staging of neuroendocrine and non-neuroendocrine tumors of the lung and in the follow-up of neoplastic patients.

Topics: Adenocarcinoma; Carcinoma, Large Cell; Carcinoma, Squamous Cell; Humans; Lung Neoplasms; Neoplasm Staging; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Preoperative Care; Radionuclide Imaging; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity

The purpose of this study was to estimate the radiation doses to nursing staff, other patients, accompanying persons and family members deriving from patients undergoing 111In-DTPA-d-Phe-1-octreotide (111In-OCT) scintigraphy. Dose rates were measured from 16 patients who had received an intravenous injection of 140+/-40 MBq 111In-OCT. The measurements were performed at three different distances (0.5, 1 and 2 m) at 10-20 min, 5-7 h and 24 h (and in some cases, up to 48 h) after administration of 111In-OCT. The effective half-lives of the biexponential decrease of the dose rates were estimated to be 2.94+/-0.27 h (T1) and 65.17+/-0. 58 h (T2). The calculated maximum dose to other persons in the waiting area was 27.2 microSv, to family members 61.5 microSv, to nursing staff in a ward 24.1 microSv and to neighbouring patients in the ward 69.5 microSv. Our results clearly demonstrate that the calculated maximum radiation exposure to accompanying persons, personnel, family members and other patients is well below the maximum annual dose limit for non-professionally exposed persons.

Topics: Air Pollutants, Radioactive; Ambulatory Care; Environmental Exposure; Family; Humans; Indium Radioisotopes; Neuroendocrine Tumors; Nursing Staff; Octreotide; Pentetic Acid; Radiation Dosage; Radiation Protection; Radionuclide Imaging; Radiopharmaceuticals; Time Factors

Personal experience on the use of 111In-DTPA-octreotide scintigraphy (Octreoscan) in the staging of neuroendocrine and non-neuroendocrine tumors of the lung is reported. From July 1995 to May 1996 26 scintigraphic studies were performed in patients affected by lung cancer at the Department of Thoracic Surgery and at the Service of Nuclear Medicine of the University of Turin. The scintigraphy allowed to detect the lesion in all the neuroendocrine tumors and in 63.2% of the non neuroendocrine ones. Their preliminary results are discussed and stress is laid on the importance of this scintigraphic procedure in the staging and the follow-up of neoplastic patients.

Topics: Carcinoma; Humans; Indium Radioisotopes; Lung Neoplasms; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Radionuclide Imaging

We analyzed the results of conventional imaging and somatostatin receptor scintigraphy in 150 patients with neuroendocrine tumors.. The outcomes of combinations of imaging modalities were compared in terms of tumor localization, effect on patient management and financial costs.. In patients with carcinoids, a combination of somatostatin receptor scintigraphy, chest radiograph and ultrasound of the upper abdomen had a high sensitivity for tumor localization, and detected lesions in patients in whom no tumor was found with conventional imaging, justifying the greater cost. In patients with medullary thyroid carcinoma, somatostatin receptor scintigraphy adds little to the information obtained with conventional imaging and therefore should not be used as a screening method. In patients with paraganglioma, CT scanning of the region where a paraganglioma is suspected, followed by somatostatin receptor scintigraphy to detect multicentricity has the best cost effectiveness ratio. In patients with gastrinomas, the combination of somatostatin receptor scintigraphy and CT scanning of the upper abdomen had the highest sensitivity. The relatively high cost of this process is outweighed by its demonstrating a resectable tumor. In patients with insulinomas, the highest yield against the lowest cost is obtained if somatostatin receptor scintigraphy is only performed if CT scanning fails to demonstrate the tumor.. Somatostatin receptor scintigraphy should be performed in patients with small-cell lung carcinoma because it can lead to a change of stage and may demonstrate otherwise undetected brain metastases. The cost increase is outweighed by the omission of unnecessary treatment for some of the patients and by the possibility of irradiating brain metastases at an early stage, which may lead to a better quality of life.

Topics: Carcinoid Tumor; Carcinoma, Medullary; Carcinoma, Small Cell; Cost-Benefit Analysis; Costs and Cost Analysis; Humans; Indium Radioisotopes; Lung Neoplasms; Netherlands; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Paraganglioma; Pentetic Acid; Radionuclide Imaging; Receptors, Somatostatin; Sensitivity and Specificity; Thyroid Neoplasms; Tomography, X-Ray Computed

Compared with other imaging modalities and clinical investigation, the 111In-pentetreotide scan identified additional metastatic disease sites in 12 carcinoid patients and 2 occult primaries, and influenced the therapeutic outcome in 36 patients [29 carcinoids, 2 atypical carcinoids, 3 cancers of unknown primaries (CUPs) and 2 medullary thyroid carcinomas (MCTs)]. No adverse reactions were noted. Somatostatin receptors were detected in 59/60 carcinoid patients, 3/4 atypical carcinoid patients, 0/2 MCT patients, and 0/3 cases of CUP. Somatostatin receptor presence is underestimated in some patients using standard hormonal response criteria rather than scintigraphy. 18 patients with metastatic carcinoids who underwent 111In-pentetreotide scanning were all somatostatin receptor positive. Their mean (+/- SE) 5-hydroxyindoleacetic acid (5-HIAA) suppression with octreotide therapy was -53% (+/- 6%). 8 patients had < 50% and 10 had > 50% 5-HIAA suppression (ranges: -4 to -47% and -58 to -94%, respectively). To investigate the effect of somatostatin analogues on survival, 90 consecutive cases of carcinoid syndrome patients treated during the somatostatin analogue era were reviewed. Survival according to primary site was 12.01, 18.29 and 6.05 years (overall median 12.01 years) for patients with foregut, midgut and unknown primaries, respectively. The difference from historical controls is substantial (67 vs. 18% 5-year survival), although our series is neither prospective nor randomised. The heterogeneity in patient and tumour response to somatostatin analogue therapy is discussed.

Topics: Carcinoid Tumor; Female; Hormone Antagonists; Humans; Hydroxyindoleacetic Acid; Indium Radioisotopes; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Radionuclide Imaging; Receptors, Somatostatin; Somatostatin; Survival Analysis

We evaluated a hand-held scintillation detector for intra-operative localisation of somatostatin-receptor-positive tumours in situ, and after excision, as an addition to preoperative scintigraphy with [111In-DTPA-Phe1]octreotide. Using the hand-held detector, the suspect tumour/normal tissue ratio R(in situ) between measurements was calculated for 23 patients with neuroendocrine tumours. The count rates of excised tumour and normal tissue were also measured ex vivo and their ratio R(ex vivo) was calculated. In midgut carcinoid (MC) patients (all scintigraphy positive), 4/29 macroscopically identified tumours gave false R(in situ). Tumour/blood 111In activity (T/B) ratios measured in a gamma counter were all high (27-650). In patients with medullary thyroid carcinoma (8/10 scintigraphy positive), misleading R(in situ) were found in 4/37 macroscopically identified tumours. T/B ratios were lower (3-39) than those seen in MC patients. 2/4 patients with endocrine pancreatic tumours (EPTs) had positive scintigraphy, reliable intra-operative measurements, and very high T/B ratios (910-1,500). 1 patient with a gastric carcinoid had correct R(in situ) and R(ex vivo), with high T/B ratios (71-210). 1 patient with sporadic insulinoma had negative scintigraphy and 1 patient with neuroendocrine carcinoma of the uterus also had low T/B ratios. In most cases, in situ measurements added little information to preoperative scintigraphy and surgical findings. The very high T/B ratios seen in MC tumours and some EPTs seem promising for future radiotherapy via somatostatin receptors.

Topics: Carcinoid Tumor; Carcinoma, Medullary; Humans; Indium Radioisotopes; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radionuclide Imaging

Indium-111 activity concentrations in human tumor and normal tissue samples were determined at 24, 48 and 120 hr after i.v. injection of 111In-DTPA-D-Phe-1-octreotide. Fourteen patients were included in the study. Seven patients had medullary thyroid carcinoma, four had midgut carcinoid tumors, two had endocrine pancreatic tumors and one had chronic pancreatitis.. For midgut carcinoids, the tumor-to-blood ratio was 51:220, for medullary thyroid carcinoma 4:39, and for two endocrine pancreatic tumors 6 and 1500. Tumor-to-muscle ratios varied between 1 and 1200 and tumor-to-fat between 2 and 1500 depending on tumor type.. The sometimes extremely high tumor-to-normal tissue ratios present the possibility for use of radiolabeled octreotide for radiation therapy of somatostatin receptor positive tumors.

Topics: Abdominal Neoplasms; Adult; Aged; Carcinoid Tumor; Chronic Disease; Female; Humans; Indium Radioisotopes; Injections, Intravenous; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Pancreatitis; Pentetic Acid; Radionuclide Imaging; Receptors, Somatostatin; Reference Values; Thyroid Neoplasms

Topics: Diagnostic Imaging; Follow-Up Studies; Gastrointestinal Neoplasms; Humans; Image Enhancement; Indium Radioisotopes; Neoplasm Recurrence, Local; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Prospective Studies; Receptors, Somatostatin; Tomography, Emission-Computed, Single-Photon

Topics: Adult; Aged; Carcinoid Tumor; Female; Follow-Up Studies; Gamma Cameras; Gastrointestinal Neoplasms; Humans; Indium Radioisotopes; Intraoperative Care; Male; Middle Aged; Neuroendocrine Tumors; Octreotide; Pentetic Acid; Postoperative Care; Preoperative Care; Radiology, Interventional; Receptors, Somatostatin; Tomography, Emission-Computed, Single-Photon

Topics: Carcinoid Tumor; Gastrointestinal Neoplasms; Humans; Indium Radioisotopes; Neuroendocrine Tumors; Octreotide; Pancreatic Neoplasms; Pentetic Acid; Radionuclide Imaging; Receptors, Somatostatin; Sensitivity and Specificity