Indium-111-pentetreotide prolongs survival in gastroenteropancreatic malignancies

Somatostatin and its analogues bind to somatostatin receptors (sst) 1 through 5 that are overexpressed in neuroendocrine neoplasms such as gastroenteropancreatic (GEP) malignancies. After ligand-receptor binding, a fraction of the ligand-receptor complexes internalize. This internalization process is an effective means of delivering cytotoxic radiolabeled somatostatin analogues, especially those emitting short-range decay particles such as Auger electrons, to the neoplastic cell nucleus. Indium-111-pentetreotide, an sst 2 preferring somatostatin analogue with gamma and Auger electron decay characteristics, is commonly used for the scintigraphic evaluation and management of neuroendocrine cancer patients. This clinical trial was performed to determine the effectiveness and tolerability of therapeutic doses of (111)In-pentetreotide in patients with GEP tumors. GEP tumor patients who had failed all forms of conventional therapy, with worsening of tumor-related signs and symptoms and/or radiographically documented progressive disease, an expected survival less than 6 months, and sst positivity as determined by the uptake on a 6.0 mCi (111)In-pentetreotide scan (OctreoScan; Mallinckrodt Medical, Inc, St. Louis, MO), were treated with at least 2 monthly 180-mCi intravenous injections of (111)In-pentetreotide. Baseline clinical assessments, serum chemistries, and plasma pancreastatin levels were measured and repeated before each (111)In-pentetreotide treatment. From February 1997 to February 1998, 27 GEP (24 carcinoid neoplasms with carcinoid syndrome and 3 pancreatic islet cells) patients were accrued, with 26 patients evaluable for clinical and radiographic responses, 21 patients evaluable for biochemical assessments, and 27 patients evaluable for survival analysis and safety. Toxicity was evaluated by using standard National Cancer Institute (NCI) Common Toxicity Criteria guidelines. Clinical benefit occurred in 16 (62%) patients. Pancreastatin levels decreased by 50% or more in 81% of the patients. Objective partial radiographic responses occurred in 2 (8%) patients, and significant tumor necrosis (defined by 20 Hounsfield units or greater decrease from baseline) developed in 7 (27%) patients. The following transient Grades 3/4 NCI Common Toxicity Criteria side effects were observed, respectively: leukocyte: 1/1; platelets: 0/2; hemoglobin: 3/0; bilirubin: 1/3; creatinine: 1/0; neurologic: 1/0. Myeloproliferative disease and/or myelodysplastic syndrome have not been observed in the 6 patients followed-up for 48+ months. The median survival was 18 months (range, 3-54+ mo). Two doses (180 mCi) of (111)In-pentetreotide are safe, well-tolerated, and improve symptoms in 62% of patients, decrease hormonal markers in 81% of patients, decrease Hounsfield units on computed tomography (CT) scans in 27% of patients, with 8% partial radiographic responses and increased expected survival in GEP cancer patients with somatostatin receptor-expressing tumors. The maximal tolerated dose of (111)In-pentetreotide and the optimal dosing schedules remain under investigation.     

The role of octreotide scintigraphy in rheumatoid arthritis and sarcoidosis.

Somatostatin receptors are widely expressed on cells and tissues throughout the human body. Apart from their expression in the physiological target organs of the peptide, somatostatin receptors are also expressed in various tumours. The expression of somatostatin receptors on neuroendocrine tumours led to the development of somatostatin receptor scintigraphy using [(111)In-DTPA-D-Phe(1)]-octreotide ((111)In-pentetreotide) in order to visualize somatostatin receptor positive tumours and their metastases in vivo. Previous studies reported the expression of somatostatin receptors in both normal and pathological cells and tissues of the human immune system as well. Somatostatin receptors have been demonstrated in Hodgkin's and non-Hodgkin's lymphomas and sst scintigraphy has shown to be a useful tool in diagnosis and staging of these diseases. Moreover, sst expression has also been detected in granulomateus diseases, like sarcoidosis and auto-immune diseases, like rheumatoid arthritis. In this paper we discuss the (possible) role of somatostatin receptor scintigraphy in diagnosis, staging or follow-up of patients suffering from sarcoidosis and rheumatoid arthritis.     

In vitro modeling of the clinical interactions between octreotide and 111In-pentetreotide: is there evidence of somatostatin receptor downregulation?

Some authors have suggested that chronic octreotide use enhances the efficiency of radiolabeled somatostatin receptor (sst) imaging. Conversely, desensitization of sst on tumor tissue (tachyphylaxis) may occur occasionally in patients on chronic octreotide therapy. Assuming that chronic exposure to octreotide induces tachyphylaxis, we hypothesized that chronic exposure of sst subtype 2 (sst2)-expressing cells to octreotide would downregulate binding of 111In-pentetreotide to sst and that this downregulation would be due to a reduction in the gene copy number for sst2. METHODS: The clinical scenarios of acute (24 h) and chronic (2 wk) octreotide use, followed by either nuclear imaging exposure (8.6 pmol/L) or therapeutic exposure (510 pmol/L) to (111)In-pentetreotide, were modeled in vitro. Receptor binding in IMR-32 human neuroblastoma cells (high sst2 expression) and PANC-1 human pancreatic cancer cells (no detectable sst2 expression) was evaluated. Gene copy numbers for sst subtypes 1-5 in IMR-32 cells were determined by quantitative polymerase chain reaction. RESULTS: Acute or chronic octreotide exposure at low or high doses did not significantly alter sst2 gene copy numbers or binding of either the diagnostic dose or the therapeutic dose of 111In-pentetreotide. CONCLUSION: In vitro exposure of cells to low or high doses of octreotide for 1-14 d does not result in the development of either tachyphylaxis or upregulation of sst as assessed by changes in gene expression or in high-affinity binding.     

Progressive nuclear translocation of somatostatin analogs.

Optimal cancer radiotherapy using Auger electron emitters requires selective localization of radionuclides in close proximity to tumor DNA. METHODS: Intracellular trafficking of (125)I-Tyr1-somatostatin-14 somatotropin-release inhibiting factor (SRIF) and 2 of its analogs, (125)I-WOC 4a and (111)In-pentetreotide, was studied in human neuroblastoma cells. RESULTS: After 24-h incubation, SRIF was degraded or recycled, whereas its protease-resistant analogs progressively accumulated in nuclear fractions. (111)In-pentetreotide binding to DNA increased over time in somatostatin receptor-positive cells but not in somatostatin receptor-negative cells. CONCLUSION: These in vitro studies show that prolonged exposure to radiolabeled SRIF analogs significantly increases their cellular internalization, nuclear translocation, and DNA binding. Clinically, infusion of radiolabeled somatostatin analogs may enhance tumor uptake and retention and provide more effective in situ radiotherapy.     

Imaging tumors with peptide-based radioligands.

Regulatory peptides are small, readily diffusable and potent natural substances with a wide spectrum of receptor-mediated actions in humans. High affinity receptors for these peptides are (over-) expressed in many neoplasms, and these receptors may represent, therefore, new molecular targets for cancer diagnosis and therapy. This review aims to give an overview of the peptide-based radiopharmaceuticals which are presently already commercially available or which are in advanced stages of their clinical testing so that their broader availability is anticipated soon. Physiologically, these peptides bind to and act through G protein-coupled receptors in the cell membrane. Historically, somatostatin analogs are the first class of receptor binding peptides having gained clinical application. 111In-DTPA-[D-Phe1]-octreotide is the first and only radiopeptide which has obtained regulatory approval in Europe and the United States to date. Extensive clinical studies involving several thousands of patients have shown that the major clinical application of somatostatin receptor scintigraphy is the detection and the staging of gastroenteropancreatic neuroendocrine tumors (carcinoids). In these tumors, octreotide scintigraphy is superior to any other staging method. However, its sensitivity and accuracy in other, more frequent neoplasms is limited. Radiolabeled vasoactive intestinal peptide (VIP) has been shown to visualize the majority of gastrointestinal adenocarcinomas, as well as some neuroendocrine tumors, including insulinomas (the latter being often missed by somatostatin receptor scintigraphy). Due to the outstanding diagnostic accuracy of the pentagastrin test in detecting the presence, persistence, or recurrence of medullary thyroid cancer (MTC), we postulated the expression of the corresponding (ie. cholecystokinin [CCK-] -B) receptor type in human MTC. This receptor is also widely expressed on human small-cell lung cancer. Indeed, 111In-labeled DTPA derivatives of gastrin showed excellent targeting of CCK-B receptor expressing tissues in animals and patients. A variety of further peptide-based radioligands, e.g. among many others, gastrin-releasing peptide/bombesin, neurotensin, substance-P, pan-somatostatin (somatostatin derivatives which bind to all five receptor subtypes) or glucagon-like peptide-1 (glp-1) analogs (the latter for the specific detection of insulinomas), is currently under development. Summarizing, radiolabeled regulatory peptides have opened new horizons in nuclear oncology for diagnosis (and potential internal radionuclide therapy). Future work will probably reveal a multitude of novel potentially clinically useful peptide-based radioligands.     

Diagnostic applications of radiolabeled peptides in nuclear endocrinology.

Regulatory peptides are small, readily diffusable and potent natural substances with a wide spectrum of receptor-mediated actions in humans. High affinity receptors for these peptides are (over-) expressed in many neoplasms, and these receptors may represent, therefore, new molecular targets for cancer diagnosis and therapy. This review intends to give an overview of the peptide-based radiopharmaceuticals which are presently already commercially available or which are in advanced stages of their clinical testing so that their broader availability is anticipated soon. Physiologically, these peptides bind to and act through G protein-coupled receptors in the cell membrane. Historically, somatostatin analogs are the first class of receptor binding peptides having gained clinical application. 111In-DTPA-[D-Phe1]-octreotide is the first and only radiopeptide which has obtained regulatory approval in Europe and the United States to date. Extensive clinical studies involving several thousands of patients have shown that the major clinical application of somatostatin receptor scintigraphy is the detection and the staging of gastroenteropancreatic neuroendocrine tumors (carcinoids). In these tumors, octreotide scintigraphy is superior to any other staging method. However, its sensitivity and accuracy in other, more frequent neoplasms is limited. Radiolabeled vasoactive intestinal peptide (VIP) has been shown to visualize the majority of gastrointestinal adenocarcinomas, as well as some neuroendocrine tumors, including insulinomas (the latter being often missed by somatostatin receptor scintigraphy). Due to the outstanding diagnostic accuracy of the pentagastrin test in detecting the presence, persistence, or recurrence of medullary thyroid cancer (MTC), we postulated the expression of the corresponding [i.e., cholecystokinin (CCK-)-B] receptor type in human MTC. This receptor is also widely expressed on human small-cell lung cancer. Indeed, 111In-labeled DTPA derivatives of gastrin showed excellent targeting of CCK-B receptor expressing tissues in animals and patients. A variety of further peptide-based radioligands is currently under development. Summarizing, radiolabeled regulatory peptides have opened new horizons in nuclear oncology for diagnosis (and potential internal radionuclide therapy). Further work will probably reveal a multitude of novel potentially clinically useful peptide-based radioligands.     

Internalization of sst2, sst3, and sst5 receptors: effects of somatostatin agonists and antagonists.

The uptake of radiolabeled somatostatin analogs by tumor cells through receptor-mediated internalization is a critical process for the in vivo targeting of tumoral somatostatin receptors. In the present study, the somatostatin receptor internalization induced by a variety of somatostatin analogs was measured with new immunocytochemical methods that allow characterization of trafficking of the somatostatin receptor subtype 2 (sst2), somatostatin receptor subtype 3 (sst3), and somatostatin receptor subtype 5 (sst5) in vitro at the protein level. METHODS: Human embryonic kidney 293 (HEK293) cells expressing the sst2, sst3, or the sst5 were used in a morphologic immunocytochemical internalization assay using specific sst2, sst3 and sst5 antibodies to qualitatively and quantitatively determine the capability of somatostatin agonists or antagonists to induce somatostatin receptor internalization. In addition, the internalization properties of a selection of these agonists have been compared and quantified in sst2-expressing CHO-K1 cells using an ELISA. RESULTS: Agonists with a high sst2-binding affinity were able to induce sst2 internalization in the HEK293 and CHO-K1 cell lines. New sst2 agonists, such as Y-DOTA-TATE, Y-DOTA-NOC, Lu-DOTA-BOC-ATE (where DOTA is 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid; TATE is [Tyr3, Thr8]-octreotide; NOC is [1-NaI3]-octreotide; and BOC-ATE is [BzThi3, Thr8]-octreotide), iodinated sugar-containing octreotide analogs, or BIM-23244 were considerably more potent in internalizing sst2 than was DTPA-octreotide (where DTPA is diethylenetriaminepentaacetic acid). Similarly, compounds with high sst3 affinity such as KE108 were able to induce sst3 internalization. In sst2- or sst3-expressing cell lines, agonist-induced receptor internalization was efficiently abolished by sst2- or sst3-selective antagonists, respectively. Antagonists alone had no effect on sst2 or sst3 internalization. We also showed that somatostatin-28 and somatostatin-14 can induce sst5 internalization. Unexpectedly, however, potent sst5 agonists such as KE108, BIM-23244, and L-817,818 were not able to induce sst5 internalization under the same conditions. CONCLUSION: Using sensitive and reproducible immunocytochemical methods, the ability of various somatostatin analogs to induce sst2, sst3, and sst5 internalization has been qualitatively and quantitatively determined. Whereas all agonists triggered sst2 and sst3 internalization, sst5 internalization was induced by natural somatostatin peptides but not by synthetic high-affinity sst5 agonists. Such assays will be of considerable help for the future characterization of ligands foreseen for nuclear medicine applications.     

Large cell neuroendocrine carcinoma of the lung with atypical evolution and a remarkable response to lutetium Lu 177 dotatate

Large cell neuroendocrine carcinoma of the lung (LCNEC) is a high-grade, poorly differentiated tumor that typically does not express somatostatin receptors. Thus, it does not benefit from treatment with somatostatin analogs and peptide receptor radionuclide therapy (PRRT). The current study objective was to demonstrate that treatment with PRRT may be a valid option in neuroendocrine carcinomas with high expression of somatostatin receptors. This is a case report of a 58-year-old man who was diagnosed with LCNEC and received chemotherapy treatment with little benefit. Extensive hepatic and bone metastasis was detected on ¹¹¹In-pentetreotide scintigraphy following high uptake of the radionuclide by the tumors. The patient benefitted from neuroendocrine treatment initially and from lutetium Lu 177 dotatate subsequently. A significant clinical and radiological response was observed, along with an improvement in quality of life. The use of PRRT is a valid alternative to chemotherapy in patients with LCNEC involving the expression of somatostin receptors.     

Peptide receptor imaging and therapy.

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.     

New trends in peptide receptor radioligands.

The high level expression of somatostatin receptors (SSTR) on various tumor cells has provided the molecular basis for successful use of radiolabeled octreotide/lanreotide analogs as tumor tracers in nuclear medicine. The vast majority of human tumors seem to overexpress the one or the other of five distinct hSSTR sub-type receptors. Whereas neuroendocrine tumors frequently overexpress hSSTR2, intestinal adenocarcinomas seem to over-express more often hSSTR3 or hSSTR4, or both of these hSSTR. In contrast to 111In-DTPA-DPhe1-octreotide (OCTREOSCAN) which binds to hSSTR2 and 5 with high affinity (Kd 0.1-5 nM), to hSSTR3 with moderate affinity (Kd 10-100 nM) and does not bind to hSSTR1 and hSSTR4, 111In/90Y-DOTA-lanreotide was found to bind to hSSTR2, 3, 4, and 5 with high affinity, and to hSSTR1 with lower affinity (Kd 200 nM). Based on its unique hSSTR binding profile, 111In-DOTA-lanreotide was suggested to be a potential radioligand for tumor diagnosis, and 90Y-DOTA-lanreotide suitable for receptor-mediated radionuclide therapy. As opposed to 111In-DTPA-DPhe1-octreotide and 111In-DOTA-DPhe1-Tyr3-octreotide, discrepancies in the scintigraphic results were seen in about one third of (neuroendocrine) tumor patients concerning both the tumor uptake as well as detection of tumor lesions. On a molecular level, these discrepancies seem to be based on a "higher" high-affinity binding of 111In-DOTA-DPhe1-Tyr3-octreotide to hSSTR2. Other somatostatin analogs with divergent affinity to the five known hSSTR subtype receptors have also found their way into the clinics, including 99mTc-HYNIC-octreotide or 99mTc-depreotide (NEOSPECT; NEOTECT). Most of the imaging results are reported for neuroendocrine tumors (octreotide analogs) or non-small cell lung cancer (99mTc-depreotide), indicating high diagnostic capability of this type of receptor tracers. Consequently to their use as receptor imaging agents, hSSTR recognizing radioligands have also been implemented for experimental receptor-targeted radionuclide therapy. The study "MAURITIUS" (MulticenterAnalysis of a Universal Receptor Imaging and Treatment Initiative, a eUropean Study), a Phase IIa study, showed in patients with a calculated tumor dose >10 Gy/GBq 90Y-DOTA-lanreotide, the proof-of-principle for treating tumor patients with receptor imaging agents. Overall treatment results in >60 patients indicated stable tumor disease in roughly 35% of patients and regressive disease in 15% of tumor patients with different tumor entities. No acute or chronic severe hematological toxicity, change in renal or liver function parameters due to 90Y-DOTA-lanreotide, was reported. 90In-DOTA-DPhe1-Tyr3-octreotide may show a higher tumor uptake in neuroendocrine tumor lesions and may therefore provide even better treatment results in tumor patients, but there is only limited excess to long-term and survival data at present. Besides newer approaches and recent developments of 188Re-labeled radioligands no clinical results on the treatment response is available yet. In conclusion, several radioligands have been implemented on the basis of peptide receptor recognition throughout the last decade. A plentitude of preclinical data and clinical studies confirm "proof-of-principle" for their use in diagnosis as well as therapy of cancer patients. However, an optimal radiopeptide formulation does not yet exist for receptor-targeted radionuclide therapy.     

Peptide-based probes for cancer imaging

Receptors for regulatory peptides are overexpressed in a variety of human cancers. They represent the molecular basis for in vivo imaging with radiolabeled peptide probes. Somatostatin-derived tracers, designed to image the sst2-overexpressing neuroendocrine tumors, have enjoyed almost 2 decades of successful development and extensive clinical applications. More recent developments include second- and third-generation somatostatin analogs, with a broader receptor subtype profile or with antagonistic properties. Emerging tracers for other peptide receptors, including cholecystokinin/gastrin and GLP-1 analogs for neuroendocrine tumors, bombesin and neuropeptide-Y analogs for prostate or breast cancers, or Arg-Gly-Asp peptides for neoangiogenesis labeling, are also in current development. Application fields include both SPECT/CT and PET/CT.     

Results and potential of somatostatin receptor imaging in gastroenteropancreatic tract tumours.

BACKGROUND: Somatostatin receptor imaging with 111In-pentetreotide is widely accepted as an essential step in the management of patients affected by neuroendocrine tumours of the gastro-entero-pancreatic tract. Many data are already available on the high sensitivity of this technique. METHODS: We present a review of the published data together with the results of a study involving 253 patients submitted to somatostatin receptor imaging in three Italian hospitals. The patients were divided into two groups treated with different acquisition and processing protocols. RESULTS: The overall sensitivity was as high as (169/176) 96% in both groups, while the specificity was higher in the group in which semi-quantitative evaluation of somatostatin receptor density was performed: (23/26) 88% vs (39/51) 76%. The use of this method is recommended to increase the specificity of 111In-pentetreotide imaging. CONCLUSIONS: Our results with somatostatin receptor imaging in neuroendocrine tumours of the gastro-entero-pancreatic tract demonstrate that all figures of merit are excellent when imaging is accurately performed and analysed by experienced operators.     

Radiopeptide imaging and therapy in the United States

Radiolabeled peptides targeted against receptors on the cell surface have been shown to be remarkably specific and effective in the diagnosis and therapy of malignant disease. Much of the early work in this field took place outside the United States, but in recent years the research effort within the United States has accelerated. Most of the initial studies in the United States focused on somatostatin receptor ligands. (111)In-pentetreotide was approved in 1994 and has been used extensively in the diagnosis and management of a wide variety of neuroendocrine tumors, particularly carcinoid. This work was extended to (99m)Tc-labeled analogs, and the most successful, (99m)Tc-depreotide, was approved in 1999. This agent was found to be accurate in the diagnosis of lung cancer, but it was not particularly successful because it was supplanted by (18)F-FDG imaging with positron tomography. More recently, studies with (68)Ga-labeled somatostatin analogs were initiated in the United States. This effort was delayed relative to that in other parts of the world because of difficulty in obtaining the necessary generators and regulatory uncertainty, both of which are less of a problem currently. Several ligands are being developed to image melanoma through targeting of the melanocyte-stimulating hormone receptor. Other ligands are being developed to use the arginine-glycine-aspartate oligopeptide to target angiogenesis and to use bombesin analogs to target the gastrin-releasing peptide receptor for the diagnosis and potential therapy of prostate cancer. Peptide dimers that target 2 receptors simultaneously are also being constructed, potentially increasing the selectivity of the approach significantly. Radiopeptide therapy has been explored with these ligands, initially with high-dose (111)In-pentetreotide. This step has been followed by U.S. participation in several trials with (90)Y-, (177)Lu-, and (188)Re-labeled analogs. Some of these agents are now available clinically outside the United States, and it is important to design and conduct the appropriate trials so that this therapy can be offered within the United States.     

Somatostatin receptor-targeted radionuclide therapy of tumors: preclinical and clinical findings

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 center in 63 patients (238 administrations), Interim analysis of 18 patients with neuroendocrine tumors was performed very recently. According to the WHO, toxicity criteria no dose limiting toxicity was observed. Minor CT-assessed tumor shrinkage (25% - 50% reduction) was noticed in 6% of 18 patients and partial remission (50% - 100% reduction, SWOG criteria) in 39%. Eleven percent of patients had tumor progression and in 44% no changes were seen. These data show that radionuclide therapy with radiolabelled somatostatin analogs, like [DOTA, Tyr(3)]octreotide and [DOTA, Tyr(3)octreotate is a most promising new treatment modality for patients who have sst(2)-positive tumors.     

Reconstruction parameters for 111In-pentetreotide SPECT: variability with respect to body weight and body region

This study, which was based on a large series of consecutive patients imaged by (111)In-pentetreotide SPECT for a neuroendocrine tumor, evaluated variability in reconstruction parameters in relation to patient body weight and the body region imaged, looking for the possibility of standardizing such parameters. METHODS: One hundred twenty-four patients underwent (111)In-pentetreotide scintigraphy: 4- and 24-h whole-body and planar scans and a 24-h SPECT examination. All patients were injected with 140-150 MBq of (111)In-pentetreotide at least 1 wk after somatostatin analogs had been discontinued. SPECT images were systematically acquired at the levels of the head, chest, and abdomen. SPECT was performed using a dual-head gamma-camera with medium-energy collimators, step-and-shoot method, no circular orbit, a 64 x 64 matrix, and 30 s per view for a total of 64 views. Two reconstruction procedures were compared: the iterative method using 10 iterations and the filtered backprojection method using a Butterworth filter with different cutoffs and orders. RESULTS: Optimal SPECT images were obtained by applying the Butterworth filter. The reconstruction parameters could be standardized for the head and chest but were more variable for the abdomen, mainly because (111)In-pentetreotide is physiologically trapped in different intestinal areas and varies over time, especially in the liver, spleen, bowel, and urinary tract. CONCLUSION: Filtered backprojection using a Butterworth filter appears adequate for standardizing the reconstruction parameters for (111)In-pentetreotide SPECT of the head and chest. Processing of abdominal images is more operator-dependent. A 150-MBq dose of (111)In-pentetreotide is recommended when planning multiple SPECT acquisitions in the same patient.     

Receptor-mediated radiotherapy with Y-DOTA-DPhe-Tyr-octreotide: the experience of the European Institute of Oncology Group

High concentrations of subtype 2 somatostatin tumor receptors (sst(2)) are expressed in numerous tumors, enabling primary and metastatic masses to be localized by scintigraphy after injecting (111)In-labeled somatostatin analogue octreotide. In addition to neuroendocrine tumors, somatostatin receptors have been identified on cancers of the central nervous system, breast, lung, and lymphatic tissue, and the use of radionuclide-labeled somatostatin analogues appeared promising for therapy as well as for diagnosis of such malignancies. The somatostatin analogue [DOTA-(D)Phe(1)-Tyr(3)] octreotide (DOTATOC) possesses favorable characteristics for its potential therapeutic use in that it shows high affinity for sst(2), moderately high affinity for sst(5), and intermediate affinity for sst(3), high hydrophilicity, stable and facile labeling with (111)In and (90)Y. We began to investigate the potential therapeutic applications of (90)Y DOTATOC in 1997 by performing a thorough dosimetric study in 18 patients who were administered (111)In DOTATOC to estimate the absorbed doses during(90)Y-DOTATOC therapy. Then, we moved on and treated an overall number of 256 patients, mostly recruited in 2 distinct protocols with and without the administration of kidney protecting agents, with (90)Y DOTATOC. No major acute reactions were observed up to the activity of 5.55 GBq per cycle. The MTD per cycle was defined as 5.18 GBq. Objective therapeutic responses were documented in more than 20% of patients in terms of partial and complete responses. The present article reports in details our clinical experience (still ongoing) and outcomes with the use of (90)Y DOTATOC.     

Imaging of neuroendocrine tumors

Neuroendocrine tumors (NETs) are rare neoplasms, which are characterized by the presence of neuroamine uptake mechanisms and/or peptide receptors at the cell membrane and these features constitute the basis of the clinical use of specific radiolabeled ligands, both for imaging and therapy. Radiolabeled metaiodobenzylguanidine (MIBG) was the first radiopharmaceutical used to specifically depict and localize catecholamine-secreting tumors (pheochromocytomas, paragangliomas, and neuroblastomas) and is still regarded as a first-choice imaging technique for diagnosis and follow-up; in patients with malignant disease, MIBG scintigraphy is an essential step to select patients for (131)I-MIBG therapy. Scintigraphy with (111)In- or (99m)Tc-labeled somatostatin analogs has become the main imaging technique for NETs, particularly those expressing a high density of somatostatin receptors, such as gastroenteropancreatic tumors; this procedure is used routinely for localizing the primary tumor, evaluating disease extension, monitoring the effect of treatment and for selecting patients for radioreceptor therapy. Since the recent development of hybrid machines, it has been possible to obtain images that simultaneously hold both anatomic (computed tomography [CT]) and functional (single-photon emission computed tomography [SPECT] or positron emission tomography [PET]) information, with great impact on diagnostic accuracy. Significant improvements have been made during the past few years with the development of highly specific radiopharmaceuticals for PET studies that reflect the different metabolic pathways of NETs, such as glucose metabolism ((18)F-fluorodeoxyglucose), the uptake of hormone precursors ((11)C-5-hydroxytryptophan, (11)C- or (18)F-dihydroxyphenylalanine, (18)F-fluorodopamine), the expression of receptors ((68)Ga-labeled somatostatin analogs), as well as the synthesis, storage, and release of hormones ((11)C-hydroxyephedrine and others). Among these radiopharmaceuticals, (68)Ga-labeled somatostatin analogs are increasingly used in specialized centers in Europe for PET and PET/CT imaging and show very promising results with high diagnostic sensitivity. New somatostatin analogs with different receptor affinity as well as other peptides are currently under investigation and will further improve our diagnostic and therapeutic capabilities in the future.     

New radiopharmaceuticals for receptor scintigraphy and radionuclide therapy.

In vitro data have demonstrated a high amount of receptors for various hormones and peptides on malignant cells of neuroendocrine origin. Among these, binding sites for members of the SST-family (hSSTR1-5) are frequently found, and their expression has led to therapeutic and diagnostic attempts to specifically target these receptors. Receptor scintigraphy using radiolabeled peptide ligands has proven its effectiveness in clinical practice. In addition, initial results have indicated a clinical potential for receptor-targeted radiotherapy. Based on somatostatin (SST) receptor (R) recognition, the novel radiopharmaceuticals 111In/90Y-DOTA-lanreotide developed at the University of Vienna as well as 111In/90Y-DOTA-DPhe1-Tyr3-octreotide (NOVARTIS) both have provided promising data for diagnosis and treatment of hSSTR-positive tumors. SSTR scintigraphy using 111In-DTPA-DPhe1-octreotide has a high positive predictive value for the vast majority of neuroendocrine tumors and has gained its place in the diagnostic work-up as well as follow-up of patients. We have used 111In-DOTA-lanreotide scintigraphy in 166 patients since 1997 and have seen positive results in 93% of patients. In 42 patients with neuroendocrine tumors comparative data were obtained. As opposed to 111In-DTPA-DPhe1-octreotide and 111In-DOTA-DPhe1-Tyr3-octreotide, discrepancies in the scintigraphic results were seen in about one third of patients concerning both the tumor uptake as well as tumor lesion detection. Initial results both with 90Y-DOTA-lanreotide as well as 90Y-DOTA-DPhe1-Tyr3-octreotide has pointed out the clinical potential of radionuclide receptor-targeted radiotherapy. This new therapy could offer palliation and disease control at a reduced cost. The final peptide therapy strategy is most probably cheaper than conventional radiotherapies or prolonged chemotherapies. Overall, receptor-mediated radiotherapy with 90Y-DOTA-lanreotide/90Y-DOTA-DPhe1-Tyr3-octre otide might also be effective in patients refractory to conventional strategies.     

Initial staging of lymphoma with octreotide and other receptor imaging agents

Somatostatin receptor scintigraphy is useful in diagnosing tumors with increased expression of somatostatin receptors. The correct use of this technique reveals the localization of neuroendocrine primary tumors and unknown metastases in approximately 90% of patients. However, somatostatin receptor scintigraphy also can image many other human tumors expressing somatostatin receptors, including malignant lymphomas and thymomas. The sensitivity of somatostatin receptor scintigraphy to image somatostatin receptor-positive tumors is very high, but due to the variable expression of specific receptor subtypes, the specificity can be relatively low. This drawback is crucial in evaluating lymphoproliferative diseases, or, in general, when immune cells are involved. The sensitivity of somatostatin receptor scintigraphy for Hodgkin's lymphoma is 95%-100%, whereas for non-Hodgkin's lymphoma it is around 80%. It has been shown that the uptake of [(111)In-DTPA(0)]octreotide in lymphomas is lower compared to the uptake in neuroendocrine tumors. This is mainly attributed to the low number of receptors on immune cells compared to neuroendocrine cells; however, ligand-induced internalization and differential receptor regulation may also participate in determining this phenomenon. Therefore, caution should be taken when interpreting data from some studies. Several new ligands are currently under study to improve these limits and the expression of other neuropeptide receptors is being investigated to provide a molecular basis for in vivo multireceptor targeting of tumors. With the use of currently available somatostatin analogs, somatostatin receptor scintigraphy does not seem to have a significant impact in patients with lymphomas for diagnostic purposes. There are a few exceptions, however. Among these, the staging and restaging of extragastric lymphoma MALT-type may present some advantages. Conversely, somatostatin receptor scintigraphy in the imaging of thymic malignancies could enhance both our diagnostic and therapeutic capabilities. Somatostatin receptor scintigraphy is diagnostically relevant in differentiating malignant from benign lesions, especially in those patients with associated paraneoplastic syndromes, and is the main criterion to select patients suitable for therapy with somatostatin analogs. Recent findings emerging from in vitro studies on somatostatin receptor physiology in immune cells will certainly reopen and expand the potential applications of somatostatin analogs for in vivo diagnostic and therapeutic options.     

Fundamental study of radiogallium-labeled aspartic acid peptides introducing octreotate derivatives

Annals of Nuclear Medicine - Somatostatin receptors are highly expressed in neuroendocrine tumors, and many radiolabeled somatostatin analogs for diagnosis and treatment have been developed. To...