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.     

In- and Y-DOTA-lanreotide: results and implications of the MAURITIUS trial

The high-level expression of somatostatin receptors (SSTR) on various tumor cells has provided the molecular basis for successful use of radiolabeled peptide analogues as tumor tracers in nuclear medicine. The vast majority of human tumors seem to overexpress one or the other of 5 distinct hSSTR subtype receptors. Whereas neuroendocrine tumors frequently overexpress human(h) SSTR2, intestinal adenocarcinomas frequently express hSSTR3 or hSSTR4, or both of these hSSTRs. In contrast to (111)In-diethylenetriamine pentaacetic acid (DTPA)-(D)he(1)-octreotide (OctreoScan; Mallinckrodt, Petten, NL), which binds to hSSTR2 and 5 with high affinity (K(d)0.1-5 nmol/L), to hSSTR3 with moderate affinity (K(d)10-100 nmol/L), and does not bind to hSSTR1 and hSSTR4, (111)In /(90)Y-DOTA-lanreotide was found to bind to hSSTR2, 3, 4, and 5 with high affinity, and to hSSTR1 with lower affinity (K(d)200 nmol/L). Based on its unique hSSTR binding profile, (111)In-DOTA-lanreotide was suggested to be a potential radioligand for tumor diagnosis, and (90)Y-DOTA-lanreotide suitable for receptor-mediated radionuclide therapy. When directly compared with (111)In-DTPA-(D)he(1)-octreotide and (111)In-DOTA-(D)he(1)-Tyr(3)-octreotide, discrepancies in the scintigraphic imaging pattern are seen in about one third of tumor patients concerning both the tumor uptake as well as the detection of tumor lesions. On a molecular level, these discrepancies seem to be based on a higher high-affinity binding affinity of (111)In-DOTA-(D)he(1)-Tyr(3)-octreotide for hSSTR2 (K(d)0.1-1 nmol/L). Beneficial results of receptor-mediated experimental radionuclide therapy were first reported for high-dose treatment with (111)In-DTPA-(D)he(1)-octreotide, based on the emission of Auger electrons. Phase IIa of the Multicenter Analysis of a Universal Receptor Imaging and Treatment Initiative, a European Study (MAURITIUS), shows in progressive cancer patients (therapy entry criteria) with a calculated tumor dose > 10 Gy/GBq (90)Y-DOTA-lanreotide, the proof-of-principle for treating tumor patients with peptide receptor imaging agents. In the MAURITIUS study, cumulative treatment doses up to 232 mCi (90)Y-DOTA-lanreotide were given as short-term intravenous infusion. Preliminary treatment results in 154 patients indicate stable tumor disease in 41% (63 of 154) of patients and regressive tumor disease in 14% (22 of 154) of tumor patients with different tumor entities expressing hSSTR. No severe acute or chronic hematologic toxicity, change in renal or liver function parameters caused by (90)Y-DOTA-lanreotide treatment were reported for patients in the MAURITIUS trial. In two thirds of patients with neuroendocrine tumor lesions, (90)Y-DOTA-(D)he(1)-Tyr(3)-octreotide showed a higher tumor uptake and should therefore be considered the first choice for experimental receptor-based therapy. Potential indications for (90)Y-DOTA-lanreotide treatment are radioiodine-negative thyroid cancer, hepatocellular cancer, lung cancer, some brain tumors, and possibly melanomas. In conclusion, preclinical data and clinical studies confirm the potential usefulness of radiolabeled lanreotide for tumor diagnosis and therapy. However, careful consideration of the type of radiotracer used for receptor-mediated therapy should be made for the individual patient. Whole-body dosimetry should always be performed to predict doses for tumors and the critical organs, which are kidney and bone marrow.     

Therapy using labelled somatostatin analogues: comparison of the absorbed doses with 111In-DTPA-D-Phe1-octreotide and yttrium-labelled DOTA-D-Phe1-Tyr3-octreotide

OBJECTIVE: We estimated the absorbed doses for (111)In-DTPA-D-Phe(1)-octreotide and (90)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide in the same patients in order to compare the potential effectiveness (tumour dose) and safety (kidney and red marrow dose) of these drugs for peptide-targeted radiotherapy of somatostatin receptor positive tumours. METHODS: Six patients with neuroendocrine tumours underwent quantitative (111)In-DTPA-D-Phe(1)-octreotide SPECT and (86)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide PET scan at intervals of 1 week. All studies were performed with a co-infusion of amino acids for renal protection. PET and SPECT were reconstructed using iterative algorithms, incorporating attenuation and scatter corrections. Tissue uptakes (IA%) were measured and used to calculate residence times. Absorbed doses to tissues were estimated and the maximal allowed activity, defined as either the activity delivering 23 Gy to the kidneys (MAA(K)) or 2 Gy to the red marrow (MAA(RM)), was calculated and the resulting tumour absorbed doses were computed. RESULTS: For the MAA(K) the mean absorbed dose to the red marrow was lower for (90)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide than for (111)In-DTPA-D-Phe(1)-octreotide (1.8+/-0.9 Gy vs. 6.4+/-1.6 Gy; P<0.001). The median absorbed dose to tumours for the MAA(K) was two-fold higher for (90)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide as compared to (111)In-DTPA-D-Phe(1)-octreotide (30.1 vs. 12.6 Gy; P<0.05). The median absorbed dose to tumours estimated for the MAA(RM) was 10-fold higher for (90)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide than for (111)In-DTPA-D-Phe(1)-octreotide (35.1 Gy vs. 3.9 Gy; P<0.05). CONCLUSIONS: This direct intra-patient comparison confirms that the use of (90)Y-DOTA-D-Phe(1)-Tyr(3)-octreotide is more appropriate for therapy of somatostatin receptor bearing tumours. When using (111)In-DTPA-D-Phe(1)-octreotide, the red marrow represents the major critical organ; this can result in significant toxicity if high activities have to be administered to obtain efficient tumour irradiation.     

Evaluating the clinical effectiveness of 90Y-SMT 487 in patients with neuroendocrine tumors.

Because of the presence of cell membrane somatostatin receptors (SSTRs), many neuroendocrine tumors will bind analogs of somatostatin. (90)Y-Dodecanetetraacetic acid-Phe1-Tyr3-octreotide (SMT 487) is an SSTR radiopharmaceutical currently under investigation as a therapeutic option for neuroendocrine tumors. Although there are a variety of methods for evaluating response to a given cancer therapy, an important indicator of success is the impact on the clinical status of the patient. The purpose of this work was to develop a semiquantitative method and assess the clinical effectiveness of (90)Y-SMT 487 therapy in patients with neuroendocrine tumors. METHODS: A scoring system was developed to evaluate clinical response that included the following parameters: weight, health status score (determined by the patient), Karnofsky score, and tumor-related symptoms. RESULTS: We applied this scoring system to 21 patients who had completed 3 cycles of therapy with (90)Y-SMT 487. Fourteen of the 21 showed a favorable clinical response, whereas 5 were clinically stable after treatment and 2 showed evidence of clinical progression. There was also a significant reduction in the amount of octreotide being used after completion of (90)Y-SMT 487 therapy in the 20 patients who were on this medication. CONCLUSION: Using this scoring method, (90)Y-SMT 487 appears effective in improving the clinical status of patients with (111)In-pentetreotide-positive neuroendocrine tumors.     

Gelatin-based plasma expander effectively reduces renal uptake of 111In-octreotide in mice and rats.

111In-Diethylenetriaminepentaacetic acid-octreotide generally is used for the scintigraphic imaging of neuroendocrine and other somatostatin receptor-positive tumors. On the basis of the successful targeting of octreotide, radiolabeled somatostatin analogs, such as 90Y-(1,4,7,10-tetraazacyclododecane-N,N',N',N'-tetraacetic acid [DOTA])0-Tyr3-octreotide and 177Lu-DOTA0-Tyr3-octreotate, were developed for peptide receptor radionuclide therapy. However, the maximum tolerated doses of these analogs are limited because of the high and persistent renal uptake that leads to relatively high radiation doses in the kidneys. Renal uptake can be reduced by coinfusion of basic amino acids or polypeptides. However, high doses of basic amino acids can induce severe side effects. It was reported that the infusion of gelatin-based plasma expanders resulted in increased low-molecular-weight proteinuria, suggesting that these plasma expanders interfere with the tubular reabsorption of peptides and proteins. In the present study, we analyzed the effects of several plasma expanders on the renal uptake of 111In-octreotide in rats and mice. METHODS: Wistar rats and BALB/c mice were injected with 0.5 or 0.1 mL of plasma expander, respectively. Thereafter, the animals received 111In-octreotide intravenously. Animals were killed at 20 h after the injection of the radiopharmaceutical. Organs were dissected, and the amount of radioactivity in the organs and tissues was measured. RESULTS: The administration of 20 mg of Gelofusine in rats or 4 mg in mice was as effective in reducing the renal uptake of 111In-octreotide as the administration of 80 or 20 mg of lysine in rats or mice, respectively, without reducing 111In-octreotide uptake in receptor-positive organs. Plasma expanders based on starch or dextran had no effect on the renal uptake of 111In-octreotide. CONCLUSION: The gelatin-based plasma expander Gelofusine significantly reduced the kidney uptake of 111In-octreotide as effectively as did lysine. Because Gelofusine is a well-known and generally used blood volume substitute that can be applied safely without the induction of toxicity, evaluation of this compound for its potential to reduce the kidney uptake of radiolabeled peptides in patients is warranted.     

In situ radiotherapy with 111In-pentetreotide. State of the art and perspectives.

111In-pentetreotide (Octreoscan) and other radiolabeled somatostatin analogs are useful in the management of well differentiated neuroendocrine malignancies such as carcinoid or islet cell neoplasms. These radiopeptides bind to membrane bound somatostatin receptors (sst 1-5) which are over-expressed in a wide variety of neoplasms, especially those arising from the neuroectoderm. Imaging advances allow for the noninvasive determination of the presence of sst receptors by combining radioactivity [111Indium with a somatostatin analog, DTPA-D-phe1-octreotide (pentetreotide)]. Radiolabeled somatostatin analogs bind to membrane receptors and internalization of the complex occurs. Auger emitting somatostatin analogs offer a novel and significantly less toxic approach to controlling neoplastic diseases by delivering targeted radiation specifically to receptor bearing cells while sparing receptor negative cells. Responses of 62-69% in 85 patients with metastatic neuroendocrine tumors treated with high dose (6-19.6 GBq) 111In-pentetreotide, specifically targeting tumor somatostatin receptors, have been reported. Objective responses observed included biochemical and radiographic responses with prolonged survival. This article will discuss and review the multi-center data available to date, the mechanisms of action of radiolabeled somatostatin analogs, dosimetry, clinical response parameters, and toxicity.     

Large-volume liver metastases from neuroendocrine tumors: hepatic intraarterial 90Y-DOTA-lanreotide as effective palliative therapy

PURPOSE: To prospectively evaluate the safety and effectiveness of hepatic intraarterial injection of yttrium 90 ((90)Y) tetraazacyclododecane tetraacetic acid (DOTA) lanreotide as a treatment for patients with progressive large-volume somatostatin receptor-positive liver metastases from neuroendocrine tumors. MATERIALS AND METHODS: The study was local ethics committee approved, and all patients gave informed consent. Twenty-three patients (13 men, 10 women; age range, 21-69 years; median age, 57 years) with histologically proved large-volume liver metastases from neuroendocrine cancers were treated. All patients had radiologic evidence of liver disease progression and high uptake of indium 111 ((111)In) pentetreotide at scintigraphy. Selective hepatic intraarterial injection of (90)Y-DOTA-lanreotide (total of 36 treatments; median activity per dose, 1 GBq) was administered with or without embolization. Treatment cycles were performed in 8-week intervals. Clinical, biologic, and radiologic tumor responses were assessed 8-12 weeks after each treatment cycle. Objective tumor response was classified according to World Health Organization response criteria as complete regression, partial response, stable disease, or disease progression. Kaplan-Meier survival curves were used to calculate 1-year survivals. RESULTS: Partial response to treatment was achieved in three (16%) of 19 patients, and stable disease was achieved in 12 (63%). Four (21%) of 19 patients had continued disease progression. Clinical improvement was reported by 14 (61%) of the 23 patients, and a reduction in biologic marker levels was observed in nine (60%) of 15 patients. Reversible hematologic toxicity (National Cancer Institute common toxicity criteria grade > 2) occurred in three patients. The 1-year survival rate was 63% (median survival time, 15 months). CONCLUSION: Hepatic intraarterial injection of (90)Y-DOTA-lanreotide is a safe and effective palliative treatment for patients with progressive large-volume somatostatin receptor-positive liver metastases from neuroendocrine tumors.     

Uptake kinetics of the somatostatin receptor ligand [86Y]DOTA-DPhe1- Tyr3-octreotide ([86Y]SMT487) using positron emission tomography in non-human primates and calculation of radiation doses of the 90Y-labelled analogue

[90Y]DOTA-DPhe1-Tyr3-octreotide ([90Y]-SMT487) has been suggested as a promising radiotherapeutic agent for somatostatin receptor-expressing tumours. In order to quantify the in vivo parameters of this compound and the radiation doses delivered to healthy organs, the analogue [86Y]DOTA-DPhe1-Tyr3-octreotide was synthesised and its uptake measured in baboons using positron emission tomography (PET). [86Y]DOTA-DPhe1-Tyr3-octreotide was administered at two different peptide concentrations, namely 2 and 100 microg peptide per m2 body surface. The latter concentration corresponded to a radiotherapeutic dose. In a third protocol [86Y]DOTA-DPhe1-Tyr3-octreotide was injected in conjunction with a simultaneous infusion of an amino acid solution that was high in l-lysine in order to lower the renal uptake of radioyttrium. Quantitative whole-body PET scans were recorded to measure the uptake kinetics for kidneys, liver, lung and bone. The individual absolute uptake kinetics were used to calculate the radiation doses for [90Y]DOTA-DPhe1-Tyr3-octreotide according to the MIRD recommendations extrapolated to a 70-kg human. The highest radiation dose was received by the kidneys, with 2.1-3.3 mGy per MBq [90Y]DOTA-DPhe1-Tyr3-octreotide injected. For the 100 microg/m2 SMT487 protocol with amino acid co-infusion this dose was about 20%-40% lower than for the other two treatment protocols. The liver and the red bone marrow received doses ranging from 0.32 to 0.53 mGy and 0.03 to 0.07 mGy per MBq [90Y]DOTA-DPhe1-Tyr3-octreotide, respectively. The average effective dose equivalent amounted to 0. 23-0.32 mSv/MBq. The comparatively low estimated radiation doses to normal organs support the initiation of clinical phase I trials with [90Y]DOTA-DPhe1-Tyr3-octreotide in patients with somatostatin receptor-expressing tumours.     

Radiolabeled somatostatin analog scintigraphy in oncology and immune diseases: an overview

[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. Received 19 June 1996; Revision received 28 October 1996; Accepted 6 November 1996     

131I]-TYR3-octreotide: clinical dosimetry and use for internal radiotherapy of metastatic paraganglioma and carcinoid tumors

Dosimetry and therapeutic application of [(131)I]-Tyr3-octreotide were evaluated in three patients with metastatic paraganglioma and carcinoid tumor. The in vitro stability of [(131)I]-Tyr3-octreotide was verified. Tumor uptake and residence time were between 0.02 and 0.1% and 0.5 to 9.8 h, respectively. The calculated tumor radiation doses were between 0.105 and 0.696 mGy.MBq(-1). No intolerance or adverse effects were observed after the therapeutic doses (3.3-6.6 GBq). A partial tumor response was obtained in one patient and no response occurred in two patients.     

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.     

Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use

In vivo somatostatin receptor scintigraphy using Octreoscan is a valuable method for the visualisation of human endocrine tumours and their metastases. Recently, several new, alternative somatostatin radioligands have been synthesised for diagnostic and radiotherapeutic use in vivo. Since human tumours are known to express various somatostatin receptor subtypes, it is mandatory to assess the receptor subtype affinity profile of such somatostatin radiotracers. Using cell lines transfected with somatostatin receptor subtypes sst1, sst2, sst3, sst4 and sst5, we have evaluated the in vitro binding characteristics of labelled (indium, yttrium, gallium) and unlabelled DOTA-[Tyr3]-octreotide, DOTA-octreotide, DOTA-lanreotide, DOTA-vapreotide, DTPA-[Tyr3]-octreotate and DOTA-[Tyr3]-octreotate. Small structural modifications, chelator substitution or metal replacement were shown to considerably affect the binding affinity. A marked improvement of sst2 affinity was found for Ga-DOTA-[Tyr3]-octreotide (IC50 2.5 nM) compared with the Y-labelled compound and Octreoscan. An excellent binding affinity for sst2 in the same range was also found for In-DTPA-[Tyr3]-octreotate (IC50 1.3 nM) and for Y-DOTA-[Tyr3]-octreotate (IC50 1.6 nM). Remarkably, Ga-DOTA-[Tyr3]-octreotate bound at sst2 with a considerably higher affinity (IC50 0.2 nM). An up to 30-fold improvement in sst3 affinity was observed for unlabelled or Y-labelled DOTA-octreotide compared with their Tyr3-containing analogue, suggesting that replacement of Tyr3 by Phe is crucial for high sst3 affinity. Substitution in the octreotide molecule of the DTPA by DOTA improved the sst3 binding affinity 14-fold. Whereas Y-DOTA-lanreotide had only low affinity for sst3 and sst4, it had the highest affinity for sst5 among the tested compounds (IC50 16 nM). Increased binding affinity for sst3 and sst5 was observed for DOTA-[Tyr3]-octreotide, DOTA-lanreotide and DOTA-vapreotide when they were labelled with yttrium. These marked changes in subtype affinity profiles are due not only to the different chemical structures but also to the different charges and hydrophilicity of these compounds. Interestingly, even the coordination geometry of the radiometal complex remote from the pharmacophoric amino acids has a significant influence on affinity profiles as shown with Y-DOTA versus Ga-DOTA in either [Tyr3]-octreotide or [Tyr3]-octreotate. Such changes in sst affinity profiles must be identified in newly designed radiotracers used for somatostatin receptor scintigraphy in order to correctly interpret in vivo scintigraphic data. These observations may represent basic principles relevant to the development of other peptide radioligands.     

Comparison of 111In-DOTA-Tyr3-octreotide and 111In-DTPA-octreotide in the same patients: biodistribution, kinetics, organ and tumor uptake.

Scintigraphy with [111In-diethylenetriamine pentaacetic acid0-D-Phe1]-octreotide (DTPAOC) is used to demonstrate neuroendocrine and other somatostatin-receptor-positive tumors. Despite encouraging results, this 111In-labeled compound is not well suited for peptide-receptor-mediated radiotherapy of somatostatin-receptor-positive tumors. Another somatostatin analog, [1,4,7,10-tetraazacyclododecane-N,N',N",N'-tetraacetic acid0, D-Phe1, Tyr3]-octreotide (DOTATOC), can be labeled with the beta-emitter 90Y in a stable manner. METHODS: We compared the distribution, kinetics and dosimetry of 111In-DTPAOC and 111In-DOTATOC in eight patients to predict the outcomes of these parameters in patients who will be treated with 90Y-DOTATOC. RESULTS: Serum radioactivity levels for the radiopharmaceuticals did not differ significantly 2-24 h after injection (P>0.05). Up to 2 h postinjection they were slightly, but significantly, lower after administration of 111In-DOTATOC (P < 0.01 at most time points). The percentage of peptide-bound radioactivity in serum did not differ after administration of either compound. Urinary excretion was significantly lower after administration of 111In-DOTATOC (P < 0.01). The visualization of known somatostatin-receptor-positive organs and tumors was clearer after administration of 111In-DOTATOC than after administration of 111In-DTPAOC. This was confirmed by significantly higher calculated uptakes in the pituitary gland and spleen. The uptake in the tumor sites did not differ significantly (P > 0.05), although in three of the four patients in whom tumor uptake could be calculated, it was higher after administration of 111In-DOTATOC. CONCLUSION: The distribution and excretion pattern of 111In-DOTATOC resembles that of 111In-DTPAOC, and the uptake in somatostatin-receptor-positive organs and most tumors is higher for 111In-DOTATOC. If 90Y-DOTATOC shows an uptake pattern similar to 111In-DOTATOC, it is a promising radiopharmaceutical for peptide-receptor-mediated radiotherapy in patients with somatostatin-receptor-positive tumors.     

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.     

The inhibitory effect of (111)In-DTPA(0)-octreotide on intrahepatic tumor growth after partial hepatectomy.

The aim of this animal study was to evaluate whether peptide receptor radionuclide therapy with (111)In-diethylenetriaminepentaacetic acid (DTPA)(0)-octreotide was able to reduce tumor growth even under tumor growth-stimulating conditions induced by partial hepatectomy (PHx). METHODS: Rats underwent 70% PHx or sham operation. The development of hepatic metastases was determined 21 d after direct injection of somatostatin receptor (SS-R)-positive or SS-R-negative tumor cells into the portal vein. Groups of 8 or 9 animals that underwent PHx or sham operation were treated with octreotide 50 micro g/kg subcutaneously twice daily or with 370 MBq (111)In-DTPA(0)-octreotide intravenously on days 1 and 8. Both treatments were compared with control treatment. Forty non-tumor-bearing rats were used to determine the influence of (111)In-DTPA(0)-octreotide therapy on liver regeneration after PHx. RESULTS: PHx induced an increase in tumor growth in all experiments (P < 0.01). Octreotide treatment did not influence tumor growth after PHx or sham operation. (111)In-DTPA(0)-octreotide could effectively reduce tumor growth in the liver of SS-R-positive tumors also under conditions of increased tumor growth as generated by PHx (P < 0.01). (111)In-DTPA(0)-octreotide was also effective on SS-R-negative tumors after PHx (P = 0.01) but not after sham operation. Furthermore, (111)In-DTPA(0)-octreotide therapy did not influence liver regeneration or liver function after PHx. CONCLUSION: Peptide receptor radionuclide therapy with (111)In-DTPA(0)-octreotide is effective in SS-R-positive tumors. During liver regeneration, the growth of SS-R-negative tumors is also reduced. This effect is not induced by impairment of liver regeneration or liver function. Radionuclide therapy could therefore be a promising treatment modality for patients with symptomatic liver metastases of neuroendocrine tumors in combination with liver resection.     

Preclinical comparison of (111)In-labeled DTPA- or DOTA-bombesin analogs for receptor-targeted scintigraphy and radionuclide therapy.

The 14-amino-acid peptide bombesin (BN) has a high affinity for the gastrin-releasing peptide (GRP) receptor that is expressed by a variety of tumors. Recently, high densities of GRP receptors were identified by in vitro receptor autoradiography in human prostate and breast carcinomas using [(125)I-Tyr(4)]BN as radioligand. Radiometal-labeled diethylenetriaminepentaacetic acid (DTPA)-BN derivatives are potentially useful radioligands for receptor-targeted scintigraphy and radiotherapy of GRP receptor-expressing tumors. METHODS: [DTPA-Pro(1),Tyr(4)]BN (A), [DOTA-Pro(1),Tyr(4)]BN (B), [DTPA-epsilon-Lys(3),Tyr(4)]BN (C), and [DOTA-epsilon-Lys(3),Tyr(4)]BN (D) (where DOTA is dodecanetetraacetic acid) were synthesized and studied for competition with binding of [(125)I-Tyr(4)]BN to the GRP receptor. The (111)In-labeled BN analogs were studied in vitro for binding and internalization by GRP receptor-expressing CA20948 and AR42J pancreatic tumor cells as well as in vivo for tissue distribution in rats. Specific tissue binding was tested by coinjection of 0.1 mg [Tyr(4)]BN. RESULTS: All BN analogs competitively inhibited the binding of [(125)I-Tyr(4)]BN to the GRP receptor with 50% inhibitory concentration values in the range of 2-9 nmol/L. All (111)In-labeled analogs showed high and specific time- and temperature-dependent binding and internalization by CA20948 and AR42J cells. In in vivo studies, high and specific binding was found in GRP receptor-positive tissues such as pancreas (0.90, 1.2, 0.54, and 0.79 percentage injected dose per gram for A-D, respectively). In a rat model, the AR42J tumor could clearly be visualized by scintigraphy using [(111)In-DTPA-Pro(1),Tyr(4)]BN as the radioligand. Although [(111)In-DOTA-Pro(1),Tyr(4)]BN showed the highest uptake of radioactivity in GRP receptor-positive tissues as well as higher target-to-blood ratios, [(111)In-DTPA-Pro(1),Tyr(4)]BN was easier to handle and is more practical to use. Therefore, we decided to start phase I studies with this DTPA-conjugated radioligand. CONCLUSION: [(111)In-DTPA-Pro(1),Tyr(4)]BN is a promising radioligand for scintigraphy of GRP receptor-expressing tumors. We are currently performing a phase I study on patients with invasive prostate carcinoma.     

[I]-TYR3-octreotide: clinical dosimetry and use for internal radiotherapy of metastatic paraganglioma and carcinoid tumors

Dosimetry and therapeutic application of [¹³¹I]-Tyr3-octreotide were evaluated in three patients with metastatic paraganglioma and carcinoid tumor. The in vitro stability of [¹³¹I]-Tyr3-octreotide was verified. Tumor uptake and residence time were between 0.02 and 0.1% and 0.5 to 9.8 h, respectively. The calculated tumor radiation doses were between 0.105 and 0.696 mGy·MBq⁻¹. No intolerance or adverse effects were observed after the therapeutic doses (3.3–6.6 GBq). A partial tumor response was obtained in one patient and no response occurred in two patients.     

Preliminary data on biodistribution and dosimetry for therapy planning of somatostatin receptor positive tumours: comparison of (86)Y-DOTATOC and (111)In-DTPA-octreotide.

The somatostatin analogue (90)Y-DOTATOC (yttrium-90 DOTA- D-Phe(1)-Tyr(3)-octreotide) is used for treatment of patients with neuroendocrine tumours. Accurate pretherapeutic dosimetry would allow for individual planning of the optimal therapeutic strategy. In this study, the biodistribution and resulting dosimetric calculation for therapeutic exposure of critical organs and tumour masses based on the positron emission tomography (PET) tracer (86)Y-DOTATOC, which is chemically identical to the therapeutic agent, were compared with results based on the tracer commonly used for somatostatin receptor scintigraphy, (111)In-DTPA-octreotide (indium-111 DTPA- D-Phe(1)-octreotide, OctreoScan). Three patients with metastatic carcinoid tumours were investigated. Dynamic and static PET studies with 77-186 MBq (86)Y-DOTATOC were performed up to 48 h after injection. Serum and urinary activity were measured simultaneously. Within 1 week, but not sooner than 5 days, patients were re-investigated by conventional scintigraphy with (111)In-DTPA-octreotide (110-187 MBq) using an equivalent protocol. Based on the regional tissue uptake kinetics, residence times were calculated and doses for potential therapy with (90)Y-DOTATOC were estimated. Serum kinetics and urinary excretion of both tracers showed no relevant differences. Estimated liver doses were similar for both tracers. Dose estimation for organs with the highest level of radiation exposure, the kidneys and spleen, showed differences of 10.5%-20.1% depending on the tracer. The largest discrepancies in dose estimation, ranging from 23.1% to 85.9%, were found in tumour masses. Furthermore, there was a wide inter-subject variability in the organ kinetics. Residence times (tau(organs)) for (90)Y-DOTATOC therapy were: tau(liver) 1.59-2.79 h; tau(spleen) 0.07-1.68 h; and tau(kidneys) 0.55-2.46 h (based on (86)Y-DOTATOC). These data suggest that dosimetry based on (86)Y-DOTATOC and (111)In-DTPA-octreotide yields similar organ doses, whereas there are relevant differences in estimated tumour doses. Individual pretherapeutic dosimetry for (90)Y-DOTATOC therapy appears necessary considering the large differences in organ doses between individual patients. If possible, the dosimetry should be performed with the chemically identical tracer (86)Y-DOTATOC.     

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.     

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

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