Gastrointestinal neuroendocrine tumors (NETs): new diagnostic and therapeutic challenges.

This paper summarizes the current understanding of the biology of somatostatin receptor (sst), role of immunotherapy in neuroendocrine tumor (NET), new agents for PPRT, and methods to assess response and clinical benefit in NET. One of the most interesting aspects of sst biology is the recent discovery of truncated variants of the sst5 receptor subtype with unique tissue distribution and response to somatostatin (SST). These truncated receptors are associated with bad patient prognosis, decreased response to SST analogs, and may be new targets for diagnoses and treatment. IFN remains a cost-effective agent, particularly in classic mid gut carcinoids, and there is interest to continue examining immunotherapy's in this disease. PRRT remains a key strategy for treatment and imaging. In addition to the classic agents, there are a series of new agents targeting other receptors such as the incretin receptors (GLP-1R; GIPR) and other G-protein coupled receptors with great potential. With regards to therapy monitoring, the most commonly used criteria are Response Criteria Evaluation in Solid Tumors (RECIST). However, for different reasons, these criteria are not very useful in NET. Incorporation of other criteria such as Choi as well as functional imaging assessment with PET would be of great interest in this area.

Somatostatin-based radiopeptide therapy with [177Lu-DOTA]-TOC versus [90Y-DOTA]-TOC in neuroendocrine tumours.

PURPOSE: Somatostatin-based radiopeptide treatment is generally performed using the ß-emitting radionuclides (90)Y or (177)Lu. The present study aimed at comparing benefits and harms of both therapeutic approaches. METHODS: In a comparative cohort study, patients with advanced neuroendocrine tumours underwent repeated cycles of [(90)Y-DOTA]-TOC or [(177)Lu-DOTA]-TOC until progression of disease or permanent adverse events. Multivariable Cox regression and competing risks regression were employed to examine predictors of survival and adverse events for both treatment groups. RESULTS: Overall, 910 patients underwent 1,804 cycles of [(90)Y-DOTA]-TOC and 141 patients underwent 259 cycles of [(177)Lu-DOTA]-TOC. The median survival after [(177)Lu-DOTA]-TOC and after [(90)Y-DOTA]-TOC was comparable (45.5 months versus 35.9 months, hazard ratio 0.91, 95% confidence interval 0.63-1.30, p = 0.49). Subgroup analyses revealed a significantly longer survival for [(177)Lu-DOTA]-TOC over [(90)Y-DOTA]-TOC in patients with low tumour uptake, solitary lesions and extra-hepatic lesions. The rate of severe transient haematotoxicities was lower after [(177)Lu-DOTA]-TOC treatment (1.4 vs 10.1%, p = 0.001), while the rate of severe permanent renal toxicities was similar in both treatment groups (9.2 vs 7.8%, p = 0.32). CONCLUSION: The present results revealed no difference in median overall survival after [(177)Lu-DOTA]-TOC and [(90)Y-DOTA]-TOC. Furthermore, [(177)Lu-DOTA]-TOC was less haematotoxic than [(90)Y-DOTA]-TOC.

[Somatostatin receptor PET/CT (SSTR-PET/CT)]. / Somatostatinrezeptor-PET/CT.

The present guideline is focused on quality assurance of somatostatin receptor PET/CT (SSTR-PET/CT) in oncology patients. The document has been developed by a multidisciplinary board of specialists providing consensus of definitions, prerequisites, methodology, operating procedures, assessment, and standardized reporting. In particular, imaging procedures for the two most commonly used radioligands of human SSTR, i. e. 68Ga-DOTATOC and 68Ga-DOTATATE are presented. Overall, SSTR-PET/CT requires close interdisciplinary communication and cooperation of referring and executing medical disciplines, taking into account existing guidelines and recommendations of the European and German medical societies, including the European Association of Nuclear Medicine (EANM), German Society for Endocrinology (DGE), German Society for Nuclear Medicine (DGN) and German Society for Radiology (DRG).

Targeted therapy in nuclear medicine--current status and future prospects.

In recent years, a number of new developments in targeted therapies using radiolabeled compounds have emerged. New developments and insights in radioiodine treatment of thyroid cancer, treatment of lymphoma and solid tumors with radiolabeled monoclonal antibodies (mAbs), the developments in the application of radiolabeled small receptor-specific molecules such as meta-iodobenzylguanidine and peptides and the position of locoregional treatment in malignant involvement of the liver are reviewed. The introduction of recombinant human thyroid-stimulating hormone and the possibility to enhance iodine uptake with retinoids has changed the radioiodine treatment protocol of patients with thyroid cancer. Introduction of radiolabeled mAbs has provided additional treatment options in patients with malignant lymphoma, while a similar approach proves to be cumbersome in patients with solid tumors. With radiolabeled small molecules that target specific receptors on tumor cells, high radiation doses can be directed to tumors in patients with disseminated disease. Radiolabeled somatostatin derivatives for the treatment of neuroendocrine tumors are the role model for this approach. Locoregional treatment with radiopharmaceuticals of patients with hepatocellular carcinoma or metastases to the liver may be used in inoperable cases, but may also be of benefit in a neo-adjuvant or adjuvant setting. Significant developments in the application of targeted radionuclide therapy have taken place. New treatment modalities have been introduced in the clinic. The concept of combining therapeutic radiopharmaceuticals with other treatment modalities is more extensively explored.

68Ga-PET radiopharmacy: A generator-based alternative to 18F-radiopharmacy.

Positron emission tomography (PET) is becoming a dominating method in the field of molecular imaging. Most commonly used radionuclides are accelerator produced 11C and 18F. An alternative method to label biomolecules is the use of metallic positron emitters; among them 68Ga is the most promising as it can be produced from a generator system consisting of an inorganic or organic matrix immobilizing the parent radionuclide 68Ge. Germanium-68 has a long half-life of 271 days which allows the production of long-lived, potentially very cost-effective generator systems. A commercial generator from Obninsk, Russia, is available which uses TiO2 as an inorganic matrix to immobilize 68Ge in the oxidation state IV+. 68Ge(IV) is chemically sufficiently different to allow efficient separation from 68Ga(III). Ga3+ is redox-inert; its coordination chemistry is dominated by its hard acid character. A variety of mono- and bifunctional chelators were developed which allow immobilization of 68Ga3+ and convenient coupling to biomolecules. Especially peptides targeting G-protein coupled receptors overexpressed on human tumour cells have been studied preclinically and in patient studies showing high and specific tumour uptake and specific localization. 68Ga-radiopharmacy may indeed be an alternative to 18F-based radiopharmacy. Freeze-dried, kit-formulated precursors along with the generator may be provided, similar to the 99Mo/99mTc-based radiopharmacy, still the mainstay of nuclear medicine.

Preclinical evaluation of 67Cu-labeled intact and fragmented anti-colon carcinoma monoclonal antibody MAb35.

The anti-carcinoembryonic antigen murine monoclonal antibody MAb35 and its F(ab')2 fragment were labeled with 131I or the potential therapeutic nuclide 67Cu. In vivo distribution patterns were compared in nude mice bearing human tumor xenografts by coinjection of the 131I- and 67Cu-labeled materials, thereby minimizing variations due to xenograft and host animal. The results showed that the 67Cu-labeled intact MAb35 achieved twice the percentage of injected dose/g tumor when compared to its 131I-labeled counterpart, without significant impairment of the wholebody distribution pattern. However, this effect was not evident in the case of F(ab')2, where high uptake of 67Cu was found in the kidney without any enhancement of accumulation in the target xenografts. To investigate the underlying causes of the different distribution patterns observed, iodine labeling was also performed using a more stable linkage, and the results indicated that the observed differences cannot be explained by simple deiodination of conventionally labeled preparations. We conclude that the intact form of the 67Cu-labeled antibody may be superior to the F(ab')2 fragment for use in our intended clinical studies. Our continuing work on the processing of radiometal-labeled F(ab')2 fragments, at the systemic and cellular level, will hopefully lead to a strategy to circumvent the problem of high kidney accumulation.

Radiolabeled peptides in nuclear oncology: influence of peptide structure and labeling strategy on pharmacology.

Radiometallo-labeled analogs of SS have shown great benefit in the in vivo localization and targeted radiotherapy of human tumors. The progress and innovation in this clinical application came from the change in strategy, leaving the most widely used radiohalogens for a coordination chemistry approach. The use of chelators appended to the biologically active peptide which convey high thermodynamic and kinetic stability to the radiopeptides did not only improve the pharmacokinetics and pharmacodynamics of the molecules, but surprisingly the biological potency as well. The most urgent problem to be solved in the field is to improve the kidney clearance of the radiopeptides. The kidney turned out to be the dose-limiting organ in this type of targeted radiotherapy. Coordination chemical strategies have already paved the way to a successful clinical application; it is most likely that chelator modification will further help to improve the renal handling of radiometallopeptides.

Receptor targeting for tumor localisation and therapy with radiopeptides.

Receptor targeting with radiolabeled peptides has become very important in nuclear oncology in the past few years. The most frequently used peptides in the clinic are analogs of somatostatin (SRIF), e.g. OctreoScan, which contain chelators for the radioisotopes 111In, 86Y, 90Y, 67Ga, 68Ga and 64Cu or for 99mTc and 188Re. and were labelled with the halogens 123I and 18F. Radiolabeled analogs of &alpha-melanocyte-stimulating hormone (&alpha-MSH), neurotensin, vasoactive intestinal peptide (VIP), bombesin (BN), substance P (SP) and gastrin/cholecystokinin (CCK) are also being developed, evaluated in vitro and in vivo and tested for clinical application. This review focuses on the expression in tumors and the regulation of receptors for these neuropeptides as well as the development of novel chelator-peptide conjugates suitable for in vivo scintigraphy or internal radiotherapy. The state of the art of radiopeptide pharmaceuticals is illustrated with four SRIF analogs, modified with the macrocyclic chelator 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid (DOTA): [D-Phe1]-octreotide (DOTAOC), [D-Phe1, Tyr3]-octreotide (DOTATOC), vapreotide (DOTAVAP) and lanreotide (DOTALAN). DOTA is almost a universal chelator capable of strongly encapsulating hard metals such as 111In and 67Ga for Single Photon Emission Tomography (SPET), 68Ga, 86Y and 64Cu for Positron Emission Tomography (PET) as well as 90Y for receptor-mediated radionuclide therapy and radiolanthanides which exhibit different interesting decay schemes. From biodistribution studies in experimental animals and from clinical data it is concluded that DOTATOC is currently the most suitable SRIF radiopeptide with the best potential in the clinic.

The molecular structure of indium-DTPA.

The x-ray structural characterization of Na2In(DTPA).7 H2O is described. The structure is notable for two reasons. It is the first In3+-complex with relevance to antibody attachment to be structurally characterized. Surprisingly, the complex has coordination number eight and is the first monomeric In3+-complex with such a high coordination number. The potentially octadentate ligand binds through three amino groups and five deprotonated carboxylate groups to the metal ion. The ligand atoms surround the central indium atom in a slightly distorted Archimedian antiprismatic configuration. High resolution nuclear magnetic resonance studies in solution show that this high coordination number also pertains in aqueous medium. Consequently, one may conclude that octadentate ligands are optimal for the thermodynamic and kinetic stabilization of In3+ in living systems. It is also indicated that bifunctional diethylenetriaminepentaacetic acid (DTPA) is superior to amide bound (= sevendentate) DTPA in antibody labeling.

Tumor uptake and metabolism of copper-67-labeled monoclonal antibody chCE7 in nude mice bearing neuroblastoma xenografts.

METHODS: ChCE7, an internalizing, neuroblastoma-specific monoclonal antibody (MAb), and its F(ab')2 fragments were derived with the bifunctional ligand 4-(1,4,8,11-tetraazacyclotetradec-1-yl)-methyl benzoic acid tetrahydrochloride (CPTA) and labeled with the potential therapeutic nuclide 67Cu. After internalization and degradation of these immunoconjugates in SKN-AS human neuroblastoma cells, the terminal degradation product was found to be the lysine adduct of the copper complex. In vivo distributions in nude mice bearing neuroblastoma xenografts were studied and extracts from tumor and tissue samples were analyzed. RESULTS: The intact MAb showed high tumor uptake, stable over 4 days postinjection (33.7% +/- 2.8% ID/g), with tumor/blood ratios increasing from 4.4 on Day 1 to 23.0 on Day 7 postinjection and low levels of radioactivity in other tissues. Analysis of tumor extracts by gel filtration chromatography and high-pressure liquid chromatography (HPLC) showed that over the period of 4 days radioactivity was present both in a high M(r) form, consisting of the MAb/antigen complex, as well as in a low M(r) form, consisting of the copper complex attached to short peptides, including the lys-CPTA complex. There was no evidence of aggregates or MAb/antigen complexes in the blood, radioactivity being exclusively in the form of intact MAb, and radioactivity in the liver was found to consist of intact MAb, MAb fragments and the lys-CPTA metabolite. In the case of the F(ab')2 fragments, high accumulation of radioactivity in the kidneys was observed and analysis of kidney extracts showed it to be due to rapid accumulation of the lys-CPTA complex. When kidney uptake and retention of the CPTA complex as well as of its lysine and glycine adducts was investigated, the lysine complex was taken up more strongly and retained longer in the kidneys than the other compounds. CONCLUSION: Copper-67-labeled MAb chCE7 F(ab')2 fragments were prepared using a novel bifunctional copper ligand 1-(p-aminobenzyl)-1,4,7,10-tetraazacyclodecane-4,7,10-triacetate (DO3A). Compared with MAb-chCE7 F(ab')2 fragments labeled by the CPTA ligand, labels using the DO3A ligand showed improved biodistributions resulting, 48 hr postinjection, in a 4-fold increase in tumor uptake and a 4-fold reduction of radioactivity in the kidneys.

Quantitative comparison of direct antibody labeling and tumor pretargeting in uveal melanoma.

UNLABELLED: SPECT radioimmunoscintigraphy with 99mTc-labeled anti-melanoma monoclonal antibodies (MAbs) 225.28S is being used to detect uveal melanoma. Recently, pretargeting methods have been described to reduce background activity and perform imaging in a shorter time interval. METHODS: We compared the three-step pretargeting method with conventional radioimmunoscintigraphy in 15 patients with a clinical and laboratory diagnosis of uveal lesion. High-resolution SPECT radioimmunoscintigraphy was performed in all patients with directly labeled MAbs and, 1 wk later, with the three-step pretargeting technique. Eleven patients underwent eye enucleation and specimens of uveal melanoma were available for histology, whereas four patients underwent conservative therapy. The percent injected dose (%ID) delivered to the tumor and the tumor-to-background ratio were calculated. RESULTS: In all three-step radioimmunoscintigraphy studies, there was a reduction of nonspecific nasopharyngeal background. The three-step radioimmunoscintigraphy tumor-to-nontumor ratio was 3.1 +/- 1.3 versus 1.5 +/- 0.5 of conventional radioimmunoscintigraphy, while the percent injected dose on the tumor was similar for the two methods (4.4 +/- 3.0 versus 3.8 +/- 2.8) x 10(-3). CONCLUSION: Improved SPECT imaging with the three-step radioimmunoscintigraphy results from reduced background and from higher counting statistics due to reduction of time interval between radiotracer administration and imaging, whereas the absolute amount of tracer delivered to the tumor by the two methods is comparable.

A new cause of renal thrombotic microangiopathy: yttrium 90-DOTATOC internal radiotherapy.

The chelator somatostatin analogue dota-D-phe(1)-tyr(3)-octreotide (DOTATOC), which is stably labeled with the beta-emitting radioisotope yttrium 90 ((90)Y), is used as internal radiotherapy for the treatment of patients with advanced neuroendocrine tumors. We report 5 patients who developed chronic renal failure, caused in 3 patients by biopsy-proven thrombotic microangiopathy (TMA). Twenty-nine patients (14 men, 15 women) with normal renal function before therapy were treated with divided intravenous doses of (90)Y-DOTATOC approximately 6 weeks apart (mean normalized cumulative dose, 165.4 +/- 36.4 mCi/m(2)). Twenty-two of 29 patients were administered a normalized cumulative dose of 200 mCi/m(2) without side effects. Among the 7 patients (6 women, 1 man) administered a normalized cumulative dose greater than 200 mCi/m(2), 5 patients (4 women, 1 man) developed renal failure. Increasing serum creatinine levels were observed within 3 months after the last (90)Y-DOTATOC injection. The evolution was rapidly progressive in 3 patients, resulting in end-stage renal failure within 6 months. The remaining 2 patients developed chronic renal insufficiency (mean serum creatinine level, 300 micromol/L an average 16 months after the end of treatment). Renal biopsies performed in 3 patients showed typical signs of TMA involving glomeruli, arterioles, and small arteries. Patients treated with high-dose (90)Y-DOTATOC internal radiotherapy (cumulative dose > 200 mCi/m(2)) are at high risk to develop severe renal failure caused by TMA lesions. The histopathologic lesions are identical to those found after external radiotherapy, which suggests a causal relationship between (90)Y-DOTATOC and renal TMA.

Exceptional results in neuroendocrine-metastases-caused paraplegia treated with [90Y-DOTA]-D-Phe1-Tyr3-octreotide (90Y-DOTATOC), a radiolabelled somatostatin analogue.

The case history is presented of a patient with paraplegia caused by progressive spinal cord compression due to bone metastases of a neuroendocrine pulmonary tumour. After failed external radiotherapy, the patient received targeted internal radiotherapy administered as a fractionated treatment with intravenous injections of a total of 7400 MBq/m2 of [90YDOTA]-D-Phe1-Tyr3-octreotide (90Y-DOTATOC), a radiolabelled somatostatin analogue. This case history highlights the value of 90Y-DOTATOC in the treatment of neuroendocrine tumours and the importance and possibility of good palliation of neuroendocrine bone metastases.

Radiopeptide transmitted internal irradiation of non-iodophil thyroid cancer and conventionally untreatable medullary thyroid cancer using.

AIM: Differentiated thyroid carcinomas (DTC) and medullary thyroid carcinomas (MTC) overexpress somatostatin receptor subtypes (sstr). The aim of this pilot study was to evaluate the tumour response of thyroid carcinomas to targeted irradiation with the radiolabelled somatostatin analogue [90Y]-1,4,7,10-tetra-azacyclododecan-4,7,10-tricarboxy-methyl-1-yl-acetyl-D-Phe1-Tyr3-octreotide ([90Y]-DOTA-D-Phe1-Tyr3-octreotide, or 90Y-DOTATOC) which has a high affinity to subtype 2 and a low affinity to subtype 5. It shows no affinity to sstr1, sstr3 and sstr4. PATIENTS AND METHODS: Twenty patients (mean age 58 years; 50% female, 50% male) with thyroid cancer were included (medullary thyroid cancer (MTC), 12 patients; differentiated thyroid cancer (DTC), seven patients; papillar carcinoma (PC), four patients; follicular carcinoma (FC), three patients; anaplastic carcinoma (AC), one patient). All patients had been therapy resistant and had progressive disease before 90Y-DOTATOC therapy. The dose applied was between totals of 1700 MBq x m(-2) to 7400 MBq x m(-2) 90Y-DOTATOC, administered in one to four injections at intervals of 6 weeks. In the case of tumour progression under therapy, treatment was terminated. RESULTS: The overall antitumour effect (objective response and stable disease) was 35%; in MTC 42%, in DTC 29%, and in AC 0%. The objective overall response rate was 0%. A stable disease was achieved in 35% (7/20), and progressive disease was found in 65% (13/20). The median time to progression was 8 months, with a median follow-up of 15 months. The treatment was very well tolerated. There were no grade III/IV haematological or renal toxicities. CONCLUSION: Targeted radiotherapy using 90Y-DOTATOC is able to stop tumour progression in a small number of patients and therefore may be an alternative treatment option for resistant disease. More significant tumour responses in thyroid and medullary thyroid cancer may be obtained by using radiopeptides with pan-somatostatin characteristics.

Comparing monoclonal antibodies and small peptidic hormones for local targeting of malignant gliomas.

Monoclonal antibodies, F(ab')2 fragments and peptidic vectors have been clinically tested for systemic and locoregional treatment of malignant gliomas. Since these brain-intrinsic neoplasms are characterized by relentless tumor cell infiltration of normal brain parenchyma, targeting agents require diffusive properties in order to reach invading tumor cell clusters that migrate along vascular clefts and axonal pathways. Tumor uptake was significantly improved by using small peptidic hormone receptors, e.g. modified octreotide, following systemic injections as compared to macromolecules which only led to limited stabilization of the disease. More importantly, biodistribution was found to be superior following direct intratumoral injection by using these small drug-like radioconjugates. Rapid and extensive distribution within 30 minutes was observed in large tumors, even crossing the corpus callosum in bihemispheric lesions following injection of 2-3 ml of the radiopharmakon injected into the center of non-resected tumors. Distribution was far more extensive after direct intratumoral injection as compared to intracavitary injection after surgical debulking. Increased interstitial pressure gradients and the much larger and chaotic structure of the interstitial space of a tumor compared to the extremely tight architecture of normal brain tissue might explain this unexpected biodistribution pattern. Peptidic hormone vectors might become useful agents to deliver radiopharmaceuticals into human invasive gliomas.

Radiolabeled peptides: valuable tools for the detection and treatment of cancer.

Human cancer cells overexpress many peptide receptors as molecular targets. Radiolabeled peptides that bind with high affinity and specificity to the receptors on tumor cells hold great potential for both diagnostic imaging and targeted radionuclide therapy. The advantage of solid-phase peptide synthesis, the availability of different chelating agents and prosthetic groups and bioconjugation techniques permit the facile preparation of a wide variety of peptide-based targeting molecules with diverse biological and tumor targeting properties. Some of these peptides, including somatostatin, bombesin, vasoactive intestinal peptide, gastrin, neurotensin, exendin and RGD are currently under investigation. It is anticipated that in the near future many of these peptides may find applications in nuclear oncology. This article presents recent developments in the field of small peptides, and their applications in the diagnosis and treatment of cancer.

Biodistribution of two octreotate analogs radiolabeled with indium and yttrium in rats.

BACKGROUND: In this study, two octreotate derivatives N-[4-carboxy-4-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]butanoyl]-Tyr(3)-octreotate (DOTAGA-tate) and N-[[4,10-bis(carboxymethyl)-7-(1(1,3-dicarboxypropyl))-1,4,7,10-tetraaza-cyclododec-1-yl]acetyl]-Tyr(3)-octreotate (DOTA-t-GA-tate) were radio-labeled with (111)In or (88)Y and their biodistribution profiles together with their elimination characteristics in rats were compared. MATERIALS AND METHODS: Radiolabeling of the peptides with high radiochemical purity was carried out in an acetate buffer with gentisic acid as radioprotective compound. Biodistribution profiles of the radiolabeled peptides were determined in intact male Wistar rats after an intravenous dose of 1 microg/kg. For elimination pathways analysis, studies in intact rats in metabolic cages and perfused rat kidney and liver were carried out. RESULTS: Fast radioactivity clearance from rat tissues (excepting somatostatin receptor-rich organs and the kidney) was determined for all agents under study. Profound radioactivity uptake in organs with a high density of somatostatin receptors (namely the adrenals and pancreas as biomarkers of somatostatin receptor-positive tissue) was slightly higher for radiolabeled DOTAGA-tate when compared with DOTA-t-GA-tate. Significantly higher accumulation in kidney and somewhat lower urinary elimination of (111)In-labeled peptides in comparison with that of (88)Y-agents were determined. Perfused rat kidney experiments confirmed that glomerular filtration was the main elimination mechanism for the compounds under study; their bile clearances in the perfused rat liver were negligible. CONCLUSION: (111)In((88)Y)-DOTAGA-tates exhibited higher distribution into somatostatin receptor-rich organs when compared with the corresponding radiolabeled DOTA-t-GA-tates. Higher uptake of (111)In-labeled peptides in the kidney is attributed to its different coordination properties.

Radiolabeled DOTATOC in patients with advanced paraganglioma and pheochromocytoma.

AIM: Paragangliomas and pheochromocytomas are rare tumors arising from chromaffin cells. Approximately 10% are malignant. Treatment options are limited in metastatic, surgically incurable situations. These tumors often express somatostatin receptors in high density. Therefore, treatment with the radiolabeled somatostatin analogue [DOTA-Tyr(3)]-octreotide (DOTATOC) is an option. We evaluated the effectiveness and toxicity of radiolabeled DOTATOC in patients with metastatic paraganglioma and pheochromocytoma. METHODS: Twenty-eight patients (16 female and 12 male) with surgically incurable paragangliomas and pheochromocytomas were included. Twenty-five patients were scheduled for treatment with a total of 200 mCi/m(2) body surface [(90)Y]DOTATOC and 3 for one cycle with 100 mCi/m(2) [(90)Y]DOTATOC followed by 2 cycles of 200 mCi [(177)Lu]DOTATOC. Restaging was performed 8-12 weeks after the last treatment cycle, followed by regular controls every 3 to 6 months. RESULTS: The treatment was well tolerated. At restaging we found 2 partial remissions, 5 minor responses; 13 stable disease, 2 mixed responses and 6 patients remained progressive. We found 1 thrombocytopenia grade I and 1 anemia grade I. No non-hematological toxicity, especially no kidney toxicity occurred. The follow-up ranged from 6 to 50 months (mean: 19+/-14.6 months). Time to progression ranged from 3 to >42 months. Ten responses, 9 stable diseases and one partial remission, are still ongoing. CONCLUSIONS: In these 28 patients, it was shown that radiolabeled DOTATOC can be effective in patients with somatostatin receptor positive paraganglioma. However, the therapy seems to be less effective than in gastroentero-pancreatic neuroendocrine tumors. Nevertheless, DOTATOC appears to be a treatment option for surgically incurable paragangliomas, because toxicity is very low and especially the fact that long lasting remissions could be achieved justifies the treatment. The final time to progression is not yet reached after a mean follow-up time of 19 months.