Gastroenterology
Volume 139, Issue 3 , Pages 742-753.e1, September 2010

Role of Somatostatins in Gastroenteropancreatic Neuroendocrine Tumor Development and Therapy

  • Kjell E. Öberg

      Affiliations

    • Department of Endocrine Oncology, University Hospital, Uppsala, Sweden
    • Corresponding Author InformationReprint requests Address requests for reprints to: Kjell E. Öberg, MD, PhD, Department of Endocrine Oncology, University Hospital, Entrance 78, SE-751 85 Uppsala, Sweden. fax: (46) 18 72 68
    • ,
  • Jean–Claude Reubi

      Affiliations

    • Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Berne, Switzerland
    • ,
  • Dik J. Kwekkeboom

      Affiliations

    • Department of Nuclear Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands
    • ,
  • Eric P. Krenning

      Affiliations

    • Department of Nuclear Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands

Received 19 April 2010; accepted 8 July 2010. published online 15 July 2010.

John P. Lynch and David C. Metz, Section Editors

Article Outline

The incidence and prevalence of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) have increased in the past 20 years. GEP-NETs are heterogeneous tumors, in terms of clinical and biological features, that originate from the pancreas or the intestinal tract. Some GEP-NETs grow very slowly, some grow rapidly and do not cause symptoms, and others cause hormone hypersecretion and associated symptoms. Most GEP-NETs overexpress receptors for somatostatins. Somatostatins inhibit the release of many hormones and other secretory proteins; their effects are mediated by G protein–coupled receptors that are expressed in a tissue-specific manner. Most GEP-NETs overexpress the somatostatin receptor SSTR2; somatostatin analogues are the best therapeutic option for functional neuroendocrine tumors because they reduce hormone-related symptoms and also have antitumor effects. Long-acting formulations of somatostatin analogues stabilize tumor growth over long periods. The development of radioactive analogues for imaging and peptide receptor radiotherapy has improved the management of GEP-NETs. Peptide receptor radiotherapy has significant antitumor effects, increasing overall survival times of patients with tumors that express a high density of SSTRs, particularly SSTR2 and SSTR5. The multi-receptor somatostatin analogue SOM230 (pasireotide) and chimeric molecules that bind SSTR2 and the dopamine receptor D2 are also being developed to treat patients with GEP-NETs. Combinations of radioactive labeled and unlabeled somatostatin analogues and therapeutics that inhibit other signaling pathways, such as mammalian target of rapamycin (mTOR) and vascular endothelial growth factor, might be the most effective therapeutics for GEP-NETs.

Keywords: Somatostatin Analogs, Somatostatin Receptors, Peptide Radio Receptor Therapy

Abbreviations used in this paper: DOTATOC, [DOTA0,Tyr3]-octreotide, DOTATATE, [DOTA0,Tyr3,Thr8]-octreotide, DTPA, diethylenetriaminepentaacetic acid, GEP-NET, gastroenteropancreatic neuroendocrine tumor, IFN, interferon, mTOR, mammalian target of rapamycin, PRRT, peptide receptor radionuclide therapy, SS, somatostatin, SSTR, somatostatin receptor

 

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) originate from the pancreas or the intestinal tract; some of these tumors grow slowly, others grow rapidly, and some cause hormone hypersecretion and associated symptoms. Most GEP-NETs overexpress receptors for somatostatins. Somatostatin was originally identified by Roger Guillemin and colleagues as a peptide hormone produced by the hypothalamus that inhibits release of growth hormone. It is also expressed in other parts of the brain and body, including the endocrine pancreas (by δ cells), the gastrointestinal tract, various endocrine organs, and even the immune system.1 Somatostatin acts as a neurotransmitter, an inhibitor of hormone and growth factor secretion, an immune regulator, and, under specific conditions, an inhibitor of proliferation2 (Supplementary Table 1). The somatostatin family of hormones comprises 14–amino acid (SS-14) and 28–amino acid forms (SS-28). Cortistatin, which has a high degree of homology with somatostatin (discovered in 1996 by L. de Lecea),3 comprises cortistatin-14, cortistatin-17, and cortistatin-29. Although corticostatin has many of the same endocrine functions as somatostatin, the role of cortistatin beyond that of immune regulation is not well understood.3

The actions of SS-14, SS-28, and cortistatins are mediated by a family of G protein–coupled SSTRs that are encoded by 5 genes (sst1 to sst5). In rodents, sst2 exists as an unspliced (sst2A) or spliced (sst2B) variant, characterized by distinct carboxyl termini. The 6 known SSTR proteins have been well characterized and are expressed in neuronal and nonneuronal tissues.4, 5 SS-14, SS-28, and the cortistatins all bind with high affinity to all SSTR subtypes.

Back to Article Outline

Expression Patterns 

Some tumor types overexpress somatostatin or SSTRs. Somatostatin-producing neuroendocrine tumors, also called somatostatinomas, are rare and represent a small fraction of gastrointestinal neuroendocrine tumors. They arise primarily in duodenum and pancreas and might be part of the neurofibromatosis syndrome; the tumor cells have a morphology like that of δ cells and produce high levels of somatostatin.6, 7 These tumors only rarely cause symptoms, such as somatostatinoma, which is characterized by steatorrhea, cholelithiasis, hyperglycemia, and weight loss. Medullary thyroid carcinoma, paraganglioma, pheochromocytoma, and some neuroendocrine tumors also produce moderate levels of somatostatin6 that do not cause symptoms. Cortistatin messenger RNAs (mRNAs) and protein have been detected in several human neuroendocrine tumors, including pheochromocytoma, medullary thyroid carcinoma, and parathyroid tumors,8 but expression does not seem to cause symptoms.

Tumors that express SSTRs are more prevalent and include growth hormone–producing pituitary tumors9; the incidence and density of receptors varies, but these are particularly high in neuroendocrine tumors and brain tumors.10

Several different in vitro techniques have been used to detect SSTRs in tumor and tissue samples. These involve quantification of receptor mRNA (usually by polymerase chain reaction), although this technique does not detect protein or altered cell morphology (unless in vitro hybridization is used). The optimal approach is to measure levels of SSTR protein or somatostatin-binding sites in samples, using assays that measure high-affinity binding of radiolabeled or nonradiolabeled somatostatin analogues.10 In vitro quantitative SSTR autoradiography on fresh-frozen tissue sections allows pathologists to determine cell morphology, detect binding site, and quantify receptors. Antibodies against the SSTRs, in particular sst2, can be used for immunohistochemical analysis of formalin-fixed tissues,11, 12, 13 but these antibodies do not necessarily detect the somatostatin binding site or quantify binding. Figure 1 shows an example of SSTR expression by receptor autoradiography and by immunohistochemistry. The existence of 5 SSTR subtypes in human tissues has made the evaluation of the SSTR profile complex; mRNA, autoradiography, and immunohistochemical analyses can detect each of the 5 SSTR subtypes. Unfortunately, not all antibodies against the SSTRs are of equal quality for immunohistochemical detection. The most frequently expressed SSTR (SST2) is normally detected at the cell surface (see Figure 1), but in patients who have received therapy with the somatostatin analogue octreotide, SST2 can be internalized by tumor cells14 (Figure 2).

  • View full-size image.
  • Figure 1. 

    Neuroendocrine tumors that overexpress SSTRs. In vitro receptor autoradiography shown on the left side reveals a high SSTR density in the whole tumor (a, H&E-stained section [bar = 1 mm]; b, autoradiogram showing total binding of 125I-Tyr3-octreotide; c, autoradiogram showing nonspecific binding). On the right side, immunohistochemical analysis of SSTR2 (R2-88 antibody) shows membrane-bound receptor in neuroendocrine tumor cells (bar = 0.01 mm).

  • View full-size image.
  • Figure 2. 

    Cell internalization of SSTR2. (A) In vitro SS-28–induced SSTR2 internalization in endosomes (HEK cells). Compare with the control (no peptide) on the left, showing membrane-bound SSTSR2. The application of 100 nmol/L SS-28 induced a complete internalization of SSTR2, which colocalized with the endosomal marker Transferrin-Alexa 594. (B) In vivo [Tyr3]-octreotate-induced sst2 internalization in rat AR42J tumors. Compared with the control (no peptide) on the left, showing membrane-bound SSTR2, the intravenous application of [Tyr3]-octreotate induced a complete SSTR2 internalization 10 minutes and 1 hour later, whereas an antagonist against SSTR2 was not internalized. Bar = 0.01 mm. (C) In vivo internalization of SSTR2 in the neuroendocrine tumor of a patient who had been treated with octreotide, compared with the membrane-bound SSTR2 in a neuroendocrine tumor of a patient who did not receive octreotide (left). SSTR2 was internalized in the neuroendocrine tumor of a patient who received an octreotide infusion during tumor resection. Bar = 0.01 mm.

SSTR incidence and density vary among tumors and with the methodology used in detection, although specific tumor types are associated with specific receptors (see Supplementary Table 2). Most human tumors that express SSTRs express SST2, the most frequently studied receptor subtype. Somatostatin analogues such as octreotide and lanreotide have high affinity for SST2.4 Neuroendocrine tumors that express high densities of SST2 include pituitary adenomas (in particular growth hormone– or thyroid-stimulating hormone–producing adenomas), gastroenteropancreatic and lung neuroendocrine tumors, pheochromocytomas, and paragangliomas.10 Tumors of the nervous system that express high densities of SST2 include medulloblastomas, meningiomas, and neuroblastomas.10 Some nonneural and nonneuroendocrine tumors express a lower incidence or density of SST2 and include breast and small cell lung tumors, lymphomas, and hepatocellular, renal cell, and gastric carcinomas.10 Tumors that express other SSTR subtypes, such as SST1, SST3, or SST5, include selected pituitary adenomas; adenomas that express growth hormone or adrenocorticotropic hormone most frequently express SST5, whereas many inactive adenomas express SST3. Many gastroenteropancreatic, lung neuroendocrine, and medullary thyroid tumors express multiple subtypes of SSTR. Furthermore, prostate tumors can express SST1, whereas gastric and thyroid carcinomas and some mesenchymal tumors express SST2 and other subtypes.10

Pancreatic neuroendocrine tumors (including gastrinomas, glucagonomas, vipomas) and gut neuroendocrine tumors (foregut, midgut, and hindgut tumors) express SSTRs in 80% to 100% of cases,15 compared with 50% to 70% of insulinomas. SSTRs are generally expressed homogeneously throughout GEP-NETs, making them good targets for therapeutics such as peptide receptor radiotherapy (PRRT). However, GEP-NET expression of SSTRs depends on their stage of differentiation; well-differentiated GEP-NETs express higher levels and more types of SSTRs (most frequently SST2, followed by SST1, SST5, and SST3) than undifferentiated tumors.16 Insulinomas often express SST1 and/or SST5 (Supplementary Table 2).

SSTR overexpression is not limited to tumor cells but also occurs in nonneoplastic cells, such as in vessels located within or near the tumor; this is particularly the case for colorectal cancers.17 Overexpression can be induced by the tumor itself or by the accompanying inflammation; in other pathologic, nonneoplastic conditions associated with chronic inflammation, such as Crohn's disease, colitis ulcerosa, or rheumatic arthritis, blood vessels have been observed to overexpress SSTRs.10, 18

Back to Article Outline

SSTR Biology 

SSTR signaling pathways are complex and vary among receptor, cell, and organ types. The complexity arises not only from the large number of SSTR subtypes and range of cell types that express them, but also because each receptor subtype signals through multiple pathways. This review focuses on their roles in regulation of hormone secretion, cell proliferation, and neoangiogenesis (Figure 3). Agonist-induced receptor internalization represents an attractive carrier system to transport somatostatin radioligands into the cell, such as with peptides that might be developed as therapeutics.

  • View full-size image.
  • Figure 3. 

    SRIF receptor-mediated modulation of signaling cascades leading to changes in hormone secretion, apoptosis, and cell growth. In most cells, SRIF inhibits hormone as well as other secretions. Increased secretion is observed, for example, in B cells. SRIF plays a role in the control of cell growth and apoptosis. In a G protein–dependent manner, PTPases, such as SHP-1, are activated, leading to dephosphorylation of signal transduction proteins. SRIF-induced inhibition of ERK1/2 blocks degradation of the cyclin-dependent kinase inhibitor p27kip1, leading to growth arrest. In rare cases, SRIF can stimulate proliferation. AC, adenylyl cyclase; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; Gά, Gβ, Gγ, G protein subunit; IP3, inositol triphosphate; PLC, phospholipase C; pHi, intracellular pH; PTPase, phosphotyrosine phosphatase.

Somatostatins receptors are Gi/Go proteins; ligand binding inhibits their adenylate-cyclase activity and regulates calcium and potassium channels.4, 19 SST2 and SST5 inhibit gastrointestinal hormones that include gastrin, cholecystokinin, serotonin, glucagon, vasoactive intestinal peptides, and others.

Somatostatin also directly and indirectly inhibits cell proliferation.2 Indirect inhibition occurs via suppression of synthesis and secretion of growth factors such as growth hormone and insulin-like growth factor 1. Somatostatins inhibit proliferation directly by regulating tyrosine kinase, tyrosine phosphatase, nitric oxide synthase, cyclic guanosine 3′,5′-cyclic monophosphate–dependent protein kinase, and RAS/extracellular signal–regulated kinase signaling pathways.2, 19 Their regulation of these pathways varies according to somatostatin subtype and the cell environment. Signaling via SST2 or SST3 has also been shown to result in apoptosis.20 Somatostatin can also inhibit angiogenesis in vitro and in vivo. Somatostatin inhibits proliferation of human umbilical vein endothelial cells21 and production of vascular endothelial growth factor and platelet-derived growth factor.22

Upon binding of somatostatins or other ligands, the SSTR-ligand complex is internalized by the cell; radiolabeled peptides have therefore been developed for diagnostic and therapeutic applications.10, 23, 24 Radioligand internalization by SSTR2-expressing tumor cells is used in imaging analyses of tumors in patients and for targeted radiotherapy.25, 26, 27 Most internalization studies have been performed in vitro, but Waser et al28 observed internalization of SSTR2 in vivo, in animal tumor models, after intravenous application of the somatostatin agonist [Tyr3]-octreotate. Agonist-induced internalization was rapid; almost all SSTR2 moved from the cell membrane to endosome-like cellular structures within the cytoplasm.28 SSTR2 is internalized by cells of gastrointestinal neuroendocrine tumors in patients who have received octreotide therapy; these tumors can therefore be used to study SSTR biology and trafficking and to confirm in vitro results (see Figure 2).14 In vitro data and biodistribution studies in animals have shown that somatostatin and agonists induce internalization of SSTR3.29 Agonist binding to SSTR5 induces mobilization of intracellular stores of the receptor to the cell membrane and then internalization of membrane SSTR5 following ligand binding.30

Back to Article Outline

Somatostatin Analogues 

Although SSTRs are good therapeutic targets, somatostatin is rapidly degraded, making it a challenge to develop as a therapeutic. However, synthetic analogues have been developed that are more stable and can be used in clinical applications. The analogues octreotide and lanreotide have been approved by the Food and Drug Administration for functioning neuroendocrine tumors with hormone-related symptoms, such as carcinoid syndrome, Verner–Morrison syndrome, and glucagonoma syndrome. They are more stable than natural somatostatin but have restricted receptor affinity profiles with high affinity for SSTR2 and lower affinities for SSTR3 and SSTR5.4 Rohrer et al have developed subtype-selective and multi-somatostatin nonpeptide somatostatin analogues31; these have not yet been tested in clinical trials. The multi-somatostatin analogue SOM230 (Pasireotide) has high affinity for SSTR1, SSTR2, SSTR3, and SSTR5; KE108 has high affinity for all 5 known SSTRs.4 SOM230 is in clinical trials for treatment of pituitary adenomas and octreotide-resistant carcinoids.4 Although multi-somatostatin analogues were designed to mimic the natural actions of somatostatins, SOM230 and KE108 have cell signaling properties distinct from those of somatostatin32; they mobilize calcium and induce phosphorylation of extracellular signal–regulated kinase, whereas somatostatin is an agonist in these pathways.32

Radioactive somatostatin-based ligands have been developed, primarily based on octreotide, to treat patients with cancer. The first commercially available agent was 111In-diethylentriaminepentaacetic acid (DTPA)0-octreotide (Supplementary Table 3), originally designed for scintigraphy. Further developments include the DOTA-coupled, somatostatin-based radiopeptides [DOTA0,Tyr3]-octreotide (DOTATOC) and [DOTA0,Tyr3,Thr8]-octreotide (DOTATATE), which have high affinity for SSTR2 and are used in nuclear medicine. Somatostatin-based radioligands that have broader affinities for receptor subtype profiles are being developed; these could not only extend the range of cancer therapies but also increase the net uptake by tumors, because many cancer cells express several receptor subtypes.10, 33 Several new compounds have been developed with high affinities for SSTR2, SSTR3, and SSTR5; the most effective contain the unnatural amino acids 1-naphtyl-alanine (1-Nal) (DOTA-NOC). Attempts have also been made to develop pan-somatostatin radioligands. KE108, modified by coupling DOTA to the N-terminus (In-KE-88),34 binds all SSTRs with high affinity. However, it is not effective for imaging studies because of its low level of internalization and uptake by tumors that express SSTR2.111,34

SSTR antagonists do not induce receptor internalization but can be used to visualize tumors in vivo.29 SSTR2- and SSTR3-selective somatostatin analogues bind to a larger number of receptor sites than agonists and have lower dissociation rates. This was shown in a pilot clinical trial with radiolabeled DOTA-linked SSTR2 antagonists, which confirmed studies in animal models.35 More potent SSTR2 antagonists are in development.36

Back to Article Outline

Somatostatin Analogues as Therapeutics 

Compared with somatostatin, octreotide contains 3 substituted amino acids (D-Phe, LThr[ol] D-Trp) that make it resistant to metabolic degradation and increase its in vivo half-life (see Figure 4).37 It was tested in clinical trials for patients with carcinoid syndrome and approved by the Food and Drug Administration for patients with hormone-producing neuroendocrine tumors such as carcinoid tumors as well as pancreatic tumors (glucagonoma, VIPoma) in 1987. Octreotide was originally formulated for subcutaneous injection, but the long-acting formulation (octreotide LAR) can be given as a monthly injection. This form is incorporated into microspheres of the biodegradable polymer poly (DL-lactide-co-glycolide-glucose) and undergoes slow release, which occurs by the cleavage of the polymer ester linkage, primarily through tissue fluid hydrolysis.38 Other analogues have been developed, such as lanreotide (BIM23014) and RC160 (Octastatin).39, 40 A long-acting form of lanreotide is Somatuline Autogel (IPSEN, Paris, France). SOM230 is a cyclohexapeptide with high affinity for SSTR1, SSTR2, SSTR3, and SSTR5 that is in clinical trials for patients with carcinoid tumors and the carcinoid syndrome.41

Limitations of peptide somatostatin analogues include lack of oral bioavailability, relatively short half-lives, immunogenicity, and tachyphylaxis.42 Strategies to optimize efficacy include optimization of the peptide structure and delivery mode as well as development of nonpeptide analogues, which might be synthesized to have more specific receptor binding, longer half-lives, and oral bioavailability and less immunogenecity.43 The most frequent adverse effects include abdominal pain with cramps, diarrhea, nausea, and pain at the injection site. Less frequent side effects include cholelithiasis, bradycardia, and diabetic glucose tolerance.44

GEP-NETs also overexpress dopamine receptor 2.45 BIM-23A760 is a chimeric molecule that has been developed to bind SSTR2 and dopamine receptor 2.46 It is in clinical trials in carcinoid tumors.

Back to Article Outline

Clinical Trial Data 

Numerous studies have shown that somatostatin analogues are effective in patients with hormone-producing GEP-NETs.44, 47, 48, 49 Pooled data of octreotide and lanreotide trials from the past 20 years, including more than 400 patients, show a mean symptomatic response rate of 73% (range, 50%–100%), with similar results for immediate-release forms and long-acting formulations. Biochemical response rates (partial plus complete responses) for chromogranin A and urinary 5-hydroxyindoleacetic acid for octreotide were 51% (range, 28%–77%), for octreotide LAR were 51% (range, 31.5%–100%), and for long-acting lanreotide were 39% (range, 18%–58%).50 The biochemical response rates to Somatuline Autogel and subcutaneous lanreotide are similar (59.3% and 55%, respectively).51 There has been controversy about the relative efficacies of octreotide and lanreotide, although most clinicians believe that the somatostatin analogues have similar efficacies to that of treatment of hormone-induced neuroendocrine symptoms52; tumors that are refractory to one analogue can respond to another.53 A phase 2, open-label, multicenter trial evaluated the efficacy and safety of SOM230 in 44 patients with metastatic GEP-NETs whose symptoms (diarrhea and flushed skin) were resistant to standard treatment with octreotide LAR. At subcutaneous doses up to 900 μg, SOM230 controlled these symptoms in up to 27% of patients with metastatic GEP-NETs.54

Carcinoid crisis is a severe condition that occurs in a subgroup of patients with carcinoid tumors, characterized by flushing, fluctuations in blood pressure, and bronchoconstriction. This condition is frequently observed during surgery and anesthetic induction, sometimes also during invasive radiological procedures.55, 56 Long-acting somatostatin analogues prevent carcinoid crisis. Carcinoid heart disease secondary to serotonin production of the tumor (liver metastases) was previously a common cause of death (30%) that has been significantly reduced (4%) by the introduction of somatostatin analogue therapy.

What are the effects of somatostatin therapies in patients with GEP-NETs that do not overproduce hormones but still progress? High doses of somatostatin analogues have been shown to slow tumor growth in some clinical studies; octreotide stabilized tumor growth in about 50% of patients.57, 58, 59, 60, 61 The PROMID phase 3 study showed that long-term administration of octreotide LAR inhibited tumor growth62 and more than doubled the time to tumor progression in patients with well-differentiated metastatic neuroendocrine midgut tumors (14.3 months) compared with placebo (6 months). After 6 months, 67% of patients who received octreotide LAR had stable disease compared with 37.2% of patients who received placebo. The greatest benefits were achieved in individuals who had limited liver metastases (less than 10% of the hepatic tumor load). The overall response (stable plus partial response) was 57% to 70% for octreotide and octreotide LAR and about 48% for lanreotide and 65% for long-acting lanreotide.50 A phase 3 clinical trial of Somatuline Autogel in patients with GEP-NETs that do not produce hormones is under way.

Back to Article Outline

Combination Therapies 

Several studies have evaluated the combined effects of somatostatin analogues and interferon alfa (IFN-α) in the management of GEP-NETs, although these studies were underpowered.63, 64, 65 Lanreotide and IFN-α were similarly effective in controlling the symptoms of the carcinoid syndrome; a combination of these reagents provided better control of symptoms and biochemical measures of disease but was also more frequently associated with side effects.65 A trial of patients with the carcinoid syndrome who were given octreotide alone or in combination with IFN-α after embolization of liver metastases reported that patients given combination therapy had a prolonged time to tumor progression.64 The combination of IFN-α and somatostatin analogues controls clinical symptoms better and for a longer time than either reagent alone and is well tolerated because somatostatin analogues can reduce side effects of IFN-α.

In a phase 2 study, the combination of octreotide and bevacizumab (a monoclonal antibody against vascular endothelial growth factor) improved progression-free survival compared with the combination of octreotide and pegylated IFN and increased the rate of partial remission.66 Phase 2 clinical studies of mammalian target of rapamycin (mTOR) inhibitors in patients with low-grade GEP-NETs showed a minimal tumor response rate. The activity of the oral inhibitor of mTOR (everolimus) in combination with octreotide LAR was recently studied in 60 patients with advanced low- to intermediate-grade neuroendocrine tumors. There were 22% partial responses, and 70% of patients developed stable disease.67 Partial remissions were more frequent in patients with endocrine pancreatic tumors compared with carcinoid tumors, and the overall median progression-free survival was 60 weeks. Reduced levels of chromogranin A, a tumor marker, during early stages of treatment indicated a better response to the combination of octreotide and everolimus.68

Back to Article Outline

SSTR Scintigraphy (Octreoscan) 

111Indium-DTPA-octreotide is regarded as the gold standard in nuclear imaging for patients with GEP-NETs. The optimal and recommended protocol for 111Indium-DTPA-octreotide scintigraphy is important to assure image quality and performance. The preferred administration activity of the tracer (with at least 10 μg of peptide) is about 200 MBq. Besides planar imaging, single photon emission computed tomography (SPECT) is recommended because of the increase in sensitivity and should be used in case of equivocal findings on planar imaging. The overall reported sensitivity is high, with 80% sensitivity for carcinoid tumors and 60% to 90% sensitivity for pancreatic neuroendocrine tumors, mostly depending on tumor type and lesion size. The sensitivity to detect insulinomas is lower than for most GEP-NETs, with a sensitivity of 20% to 60%. Currently, several 68Gallium-labeled somatostatin analogues have been evaluated for positron emission tomography scanning of GEP-NETs. 68Gallium is a generator-produced radionuclide that can be chelated with DOTA to form a stable complex with a somatostatin analogue. 68Gallium-DOTATOC and 68Gallium-DOTATATE have excellent image quality with better spatial resolution compared with imaging with the gamma-emitting analogues. Comparison between 68Gallium-labeled somatostatin analogues and 111Indium-DTPA-octreotide scintigraphy has shown higher sensitivity and specificity for the 68Gallium-based scanning; furthermore, in the next 5 years, it will replace Octreoscan (Covidien, Mansfield, MA) as a standard procedure for detection of and localization of GEP-NETs.69, 70

Back to Article Outline

Radionuclide Therapy 

Radiolabeled somatostatin analogues have been used since the 1990s to treat patients with inoperable and/or metastasized neuroendocrine tumors. PRRT unites the fields of endocrinology and nuclear medicine; the use of hormone receptors on neuroendocrine tumor cells to deliver radionuclides to kill tumor cells is similar to the use of the sodium iodine transporter to deliver radioactive iodine to the diseased thyroid, which was developed in the 1950s. PRRT involves binding of the radiolabeled hormone analogue with high specificity to SSTRs on tumor cells, the relatively fast clearance of residual radioactivity, and the long-term retention of the radioactivity in the tumor cells. PRRT has great advantages over external beam irradiation or systemic chemotherapy, because it is more effective at specifically killing tumor cells with fewer systemic side effects.

In the mid to late 1990s, high dosages of [111In-DTPA0]octreotide were used in PRRT. These initial studies showed reduced symptoms in patients with metastasized neuroendocrine tumors but did not result in many partial remissions.71, 72 This result was not surprising; 111In-coupled peptides are not ideal for PRRT because of their small range and penetration of tissue. The next generation of SSTR-mediated radionuclide therapy used a modified somatostatin analogue, [Tyr3]octreotide, that had a higher affinity for the SSTR2 and a different chelator (DOTA instead of DTPA) to increase binding stability of β-emitting radionuclide 90Yttrium. This compound (90Y-DOTA0,Tyr3 octreotide; OctreoTher, Novartis, Basel, Switzerland; Onalta, Molecular Insight Pharmaceuticals, Cambridge, MA) has been tested in phase 1 and 2 trials of patients with GEP-NETs.

Otte et al73 and Waldherr et al74, 75 reported that renal insufficiency developed in 4 of 29 patients in patients with GEP-NETs who were given 90Y-DOTA0,Tyr3 octreotide (renal protection with amino acid infusion was not performed in half of the patients). The overall response rate among patients with GEP-NETs who were treated with 5.9 GBq (160 mCi)/m2 or with 7.4 GBq (200 mCi)/m2 in 4 doses was 24% (Supplementary Table 3).74, 75 In a subsequent study, the same dose (7.4 GBq [200 mCi]/m2) administered in 2 sessions resulted in complete and partial remissions in 33% of the patients76 (Supplementary Table 3), although this was not a randomized trial that compared 2 dosing schemes.

Chinol et al77 reported no major acute reactions (no acute or delayed kidney failure) in patients with neuroendocrine tumors who were given doses of 5.6 GBq (150 mCi) per cycle of [90Y-DOTA0,Tyr3] octreotide, although the follow-up period was only 10 months. Partial and complete remissions occurred in 24 of 87 patients.78 Bodei et al79 later reported the results of a phase 1/2 study in 40 patients with SSTR-positive tumors (21 with GEP-NETs). Cumulative total treatment doses ranged from 5.9 to 11.1 GBq (160–300 mCi) and were given in 2 treatment cycles. Tumor regression occurred in 6 of 21 patients (29%), with a mean duration of response of 9 months.

In another study of [90Y-DOTA0,Tyr3]octreotide, 58 patients received increasing doses, up to 14.8 GBq (400 mCi)/m2 in 4 cycles or up to 9.3 GBq (250 mCi)/m2 in a single dose, without reaching the maximum tolerated single dose.80 The cumulative radiation dose to the kidneys was limited to 27 Gy. All patients received amino acids concomitant with [90Y-DOTA0,Tyr3]octreotide for kidney protection. One patient developed liver toxicity, 1 developed thrombocytopenia grade 4 (<25 × 109/L), and 1 developed myelodysplastic syndrome. Five of 58 patients (9%) had a partial response and 7 (12%) had a minor response (a 25%–50% reduction in tumor volume) (Supplementary Table 3). The median time to progression was 30 months.81 In a multicenter study of 90 patients with documented disease progression who were given a fixed dose of 3 × 4.4 GBq (3 × 120 mCi) [90Y-DOTA0,Tyr3]octreotide,82 4 patients had a partial response (4%) and 63 had stable disease (70%) (Supplementary Table 3). The median overall survival time was 27 months.

The somatostatin analogue [DTPA0,Tyr3]octreotate differs from [DTPA0,Tyr3]octreotide in that the carboxyl-terminal threoninol is replaced with threonine. Reubi et al83 reported that [DOTA0,Tyr3]octreotate had a 9-fold greater affinity for SSTR2 than [DOTA0,Tyr3]octreotide and the Yttrium-loaded counterpart had a 6- to 7-fold greater affinity.

Recent analyses of side effects and outcomes of [177Lu-DOTA0,Tyr3]octreotate therapies were described in studies of patients with GEP-NETs.84 Serious delayed toxicities were observed in 9 of 504 patients. There were 2 cases of renal insufficiency that were probably not related to treatment with [177Lu-DOTA0,Tyr3]octreotate. There were 3 patients with serious liver toxicity, 2 of which were probably treatment related. Myelodysplastic syndrome occurred in 4 patients (potentially treatment related in 3). In an analysis of 476 patients with GEP-NETs, 5 were hospitalized within 2 days of administration of the radiopharmaceutical because of hormone-related crises.85 All patients recovered after adequate care. Treatment responses at 3 months after the last therapy cycle were analyzed in 310 patients.84 Overall objective tumor response rate, comprising complete, partial, and minor response, was 46% (Supplementary Table 3). Prognostic factors that predicted response were high uptake on the Octreoscan and Karnofsky performance score >70. A small percentage of patients who had stable disease or a minor response, respectively, at their first 2 evaluations after therapy with the full dose had improvements in categorized tumor response after 6 and 12 months of follow-up (4% and 5% of patients, respectively). A typical response to PRRT is illustrated in Figure 5.

  • View full-size image.
  • Figure 5. 

    A patient with GEP-NET who received PRRT. Serial computed tomography scans (upper row) and octreoscans (second row) after PRRT with [177Lu-DOTA0,Tyr3]octreotate of a patient with a GEP-NET. PRRT (radioactivity symbol) and cycles (arrows; each 7.4 GBq) are indicated in the third row. The plot shows serum chromogranin A concentrations (red symbols, closed line) and the patient's weight (black symbols, dotted line). PR, partial remission; PD, progressive disease.

Three of 4 patients with neuroendocrine pancreatic tumors that did not produce symptoms but were inoperable before treatment and who had partial response underwent successful surgery 6 to 12 months after their last treatment with [177Lu-DOTA0,Tyr3]octreotate, whereas 1 died from postoperative complications. The median time to progression was 40 months from the start of treatment. The median overall survival time of 310 patients with GEP-NETs was 46 months (median follow-up time of 19 months, with 101 deaths). Among 167 patients with midgut carcinoid tumors, the overall survival time was 52 months; among 72 patients with pancreatic neuroendocrine tumors that did not produce symptoms, the overall survival time was 47 months. The median disease-related survival time of 310 patients with GEP-NETs was greater than 48 months (median follow-up time of 18 months, with 81 deaths).

Compared with patients given [DOTA0,Tyr3]octreotide, patients treated with [177Lu-DOTA0,Tyr3]octreotate have longer survival times from diagnosis (40–72 months) or referral, based on analyses of data from different epidemiologic studies that were limited to similar subgroups.84, 86, 87, 88, 89 (Figure 6). Comparisons with historical controls should be interpreted with caution, but many other reports using similar groups of patients have reported differences in survival times between patients given these therapeutics.

  • View full-size image.
  • Figure 6. 

    Results from PRRT clinical studies. Overall survival, in months since diagnosis, from observational and interventional studies (blue bars) of patients with similar tumor types and disease stages treated with [177Lu-DOTA0,Tyr3]octreotate (red bars). Patients treated with [177Lu-DOTA0,Tyr3]octreotate survived 40 to 72 months longer than patients treated with cytotoxics or biologicals (IFN-α, octreotide). Adapted from Kwekkeboom et al.84 WDEC, well-differentiated endocrine carcinoma; Dx, diagnosis; PNET, pancreatic neuroendocrine tumor.

Back to Article Outline

Management of Patients With GEP-NETs 

In patients treated with [177Lu-DOTA0,Tyr3]octreotate, the median overall survival time was shorter among those with a poor performance score or extensive liver involvement.84 Therefore, treatment with [177Lu-DOTA0,Tyr3]octreotate should be started during the earliest possible stage of disease progression. However, GEP-NETs can remain stable for years, so it is best to wait for signs of disease progression if the tumor load is moderate. These signs should not be restricted to tumor growth as assessed by computed tomography examination but also include increased serum levels of tumor markers, symptoms, or involuntary weight loss. In patients with limited tumor loads that might be cured, treatment should be initiated without further delay; the same holds true for patients with extensive tumor load, hepatomegaly, or significant weight loss. Waiting for formally assessed tumor progression would place these patients in an unfavorable starting position for treatment or might make them ineligible.

Can patients be successfully treated a second time if the first round of PRRT is ineffective? Among 33 patients who received 2 cycles of 7.4 GBq (200 mCi) of [177Lu-DOTA0,Tyr3]octreotate, 28 had a radiological response (at least a minor response) after treatment with usually 4 cycles of [177Lu-DOTA0,Tyr3]octreotate, and 5 had significant clinical improvement.90 All were found to have tumor progress, based on computed tomography analysis, before treatment was reinitiated. Seven patients (24%) had renewed reductions in tumor size and 7 (24%) had stable disease at follow-up. No major side effects were observed during a median follow-up of 16 months. It was concluded that in the absence of treatment alternatives, salvage therapy is safe and can be effective in certain patients.

Data from animal studies indicate that 90Y-labeled somatostatin analogues might be more effective for larger tumors, whereas 177Lu-labeled somatostatin analogues are effective for smaller tumors, but their combination could be the most effective approach.91 Therefore, apart from comparisons between radiolabeled octreotate and octreotide, and between somatostatin analogues labeled with 90Y or 177Lu, PRRT with combinations of 90Y- and 177Lu-labeled analogues should also be evaluated. Future directions to improve this therapy could include the use of radiosensitizing chemotherapeutical agents. With the combination of radiotherapy and capecitabine, an increased efficacy in terms of tumor growth control was reported if compared with radiotherapy as a single treatment modality for a variety of tumors.92 If capecitabine is used in relatively low doses (1600–2000 mg/m2/day), grade 3 hematologic or other toxicity is rare.92, 93 After proving the safety of the combined therapy,94 a randomized multicenter trial is under way to compare 177Lu-octreotate with and without capecitabine in patients with GEP-NETs.

Attempts to improve the results of this type of therapy may focus on further reducing the radiation absorbed dose to normal tissues and organs, like kidneys and bone marrow, or increasing the receptor density on the tumors, such as via receptor up-regulation. Either strategy could increase the therapeutic window. Individualization of dosimetry for each patient is important; radiation doses absorbed by the kidney and bone marrow vary widely among patients treated with [177Lu-DOTA0,Tyr3]octreotate.95, 96 Some patients are undertreated if fixed-dose schemes are used. Tailored dosimetry, based on analysis of urine samples, repeated imaging, and analysis of blood samples after therapy, is time consuming, but this calculation of the maximum cumulative doses is required for efficacy and safety of therapy.

Back to Article Outline

Conclusion 

Somatostatin analogues are the best therapeutics for reducing symptoms in patients with GEP-NETs. Long-acting formulations of somatostatin analogues have significantly improved the quality of life of these patients. The antiproliferative effects of somatostatin analogues require further investigation, as well as future studies to confirm the findings of the PROMID study. It will also be important to determine whether high-dose therapy with somatostatin analogues might increase the antiproliferative effects in tumor cells in clinical and in preclinical trials. The effects of combination of somatostatin analogues with drugs such as IFN-α, mTOR inhibitors, or vascular endothelial growth factor inhibitors must also be studied in prospected randomized clinical trials. Studies of pan-receptor analogues, such as pasireotide, might provide further insight into the antiproliferative effects of somatostatin analogues and provide better control of patients' symptoms. Clinical trials of chimeric molecules that bind SSTR2 as well as DR2 will provide information about the crosstalk between different G protein–coupled receptors in the development of neuroendocrine tumors. Further development of these types of drugs has the potential to improve the efficacy of neuroendocrine therapies and clarify the pathogenesis of these tumor types. PRRT is an effective treatment of GEP-NETs but needs to be further evaluated in randomized clinical trials.

Back to Article Outline

Acknowledgments 

All 4 authors contributed equally to this manuscript.

Back to Article Outline

Supplementary Material 

Supplementary Table 1. Somatostatin Actions (SSTR2 and SSTR5)
Inhibit secretionInsulin
Glucagon
Pancreatic polypeptide
Gastrin
Secretin
Vasoactive intestinal peptide (VIP)
Cholecystokinin (CCK)
GLP-1, GLP-2 (glucagon-like peptide)
Ghrelin
InhibitsPancreatic exocrine secretion and gastric acid secretion
ReducesSplanchnic blood flow, intestinal motility
IncreasesWater and electrolyte absorption
Supplementary Table 2. Expression of SSTRs in Gastroenteropancreatic Tumors and Signaling
CriteriaSstr1Sstr2Sstr3Sstr4Sstr5
Criteria
PancreaticX X(X)X
Intestinal carcinoidXXXXX
GastricXXX(X)X
Signaling
G protein couplingYesYesYesYesYes
Adenylyl cyclase activity
Phosphotyrosine phosphatase activity
Mitogen-activated protein kinase activity
K+ channels (GIRK)
Ca2+ channels
Na+/H+ exchanger
AMPA/kainate glutamate channels
Phospholipase C/inositol triphosphate activity
Phospholipase A2 activity
Table 3. PRRT Clinical Trials with 90Lu-labeled Somatostatin Analogs in Patients with GEP-NETs
ReferenceReported response
No. of evaluable patientsCRPRMRaSDPDCR + PRCriteriab
[90Y-DOTA0,Tyr3]octreotide
Otte et al. 19991601(6%)N/I14(88%)1(6%)1/16(6%)N/I
Waldherr et al. 2001371(3%)9(24%)N/I23(62%)4(11%)10/37(27%)WHO
Waldherr et al. 2002a371(3%)7(19%)N/I6(70%)3(8%)8/37(22%)WHO
Waldherr et al. 2002b362(6%)10(28%)N/I19(54%)4(12%)12/35(34%)WHO
Bodei et al. 20032106(29%)N/I11(52%)4(19%)6/21(29%)WHO
Valkema et al. 20065805(9%)7(13%)29(53%)14(25%)5/58(9%)SWOG
Bushnell et al. 20109004(4%)N/I63(70%)23(26%)4/90(4%)SWOG
[90Y-DOTA]Ianreotide
Virgolini et al. 200239008(20%)17(44%)14(36%)0/39(0%)WHO
[90Y-DOTA0,Tyr3]octreotate
Baum et al. 200475028(37%)N/I39(52%)8(11%)28/75(37%)N/I
[177Lu-DOTA0,Tyr3]octreotate
Kwekkeboom et al. 20083105(2%)86(28%)51(16%)107(35%)61(20%)91/310(29%)SWOG
Garkavij et al. 20101202(17%)3(25%)5(50%)2(17%)2/12(17%)RECIST

SWOG: PR (partial remission), ≥ 30% reduction of tumor size; MR (minor remission), 30% reduction or increase of SD (stable disease), < 30% reduction or increase of < 20% of tumor size; PD (progressive disease), ≥ 20% increase of tumor size or new lesion(s), measurements: bidimensional World Health Organization (WHO): PR, ≥ 50% reduction of tumor size; SD, < 50% reduction or increase of < 25% of tumor size; PD, ≥ 25% increase of tumor size or new lesion(s), measurements: bidimensional

Response Evaluation Criteria In Solid Tumors (RECIST): PR, ≥ 50% reduction of tumor size; SD, < 25% reduction or increase of tumor size; PD, 50% increase of tumor size, measurements: unidimensional; N/I, not indicated.

amodification of the Southwest Oncology Group (SWOG) criteria including MR (minor remission), between 25 and 50% reduction of tumor size.

bCriteria of Tumor Response:

Back to Article Outline

References 

  1. Guillemin R. Hypothalamic hormones a.k.a. hypothalamic releasing factors. J Endocrinol. 2005;184:11–28
  2. Pyronnet S, Bousquet C, Najib S, et al. Antitumor effects of somatostatin. Mol Cell Endocrinol. 2008;286:230–237
  3. de Lecea L, Castano JP. Cortistatin: not just another somatostatin analog. Nat Clin Pract Endocrinol Metab. 2006;2:356–357
  4. Weckbecker G, Lewis I, Albert R, et al. Opportunities in somatostatin research: biological, chemical and therapeutic aspects. Nat Rev Drug Discov. 2003;2:999–1017
  5. Olias G, Viollet C, Kusserow H, et al. Regulation and function of somatostatin receptors. J Neurochem. 2004;89:1057–1091
  6. DeLellis R, Lloyd R, Heitz PU, et al. World Health Organisation Classification of Tumors (Pathology and genetics: tumor of endocrine organs). In: Lyon Cedex 08, France: IARC Press; 2004;p. 185–190
  7. Garbrecht N, Anlauf M, Schmitt A, et al. Somatostatin-producing neuroendocrine tumors of the duodenum and pancreas: incidence, types, biological behavior, association with inherited syndromes, and functional activity. Endocr Relat Cancer. 2008;15:229–241
  8. Allia E, Tarabra E, Volante M, et al. Expression of cortistatin and MrgX2, a specific cortistatin receptor, in human neuroendocrine tissues and related tumours. J Pathol. 2005;207:336–345
  9. Reubi JC, Landolt AM. High density of somatostatin receptors in pituitary tumors from acromegalic patients. J Clin Endocrinol Metab. 1984;59:1148–1151
  10. Reubi JC. Peptide receptors as molecular targets for cancer diagnosis and therapy. Endocr Rev. 2003;24:389–427
  11. Korner M, Eltschinger V, Waser B, et al. Value of immunohistochemistry for somatostatin receptor subtype sst2A in cancer tissues: lessons from the comparison of anti-sst2A antibodies with somatostatin receptor autoradiography. Am J Surg Pathol. 2005;29:1642–1651
  12. Volante M, Brizzi MP, Faggiano A, et al. Somatostatin receptor type 2A immunohistochemistry in neuroendocrine tumors: a proposal of scoring system correlated with somatostatin receptor scintigraphy. Mod Pathol. 2007;20:1172–1182
  13. Fischer T, Doll C, Jacobs S, et al. Reassessment of sst2 somatostatin receptor expression in human normal and neoplastic tissues using the novel rabbit monoclonal antibody UMB-1. J Clin Endocrinol Metab. 2008;93:4519–4524
  14. Reubi JC, Waser B, Cescato R, et al. Internalized somatostatin receptor subtype 2 in neuroendocrine tumors of octreotide-treated patients. J Clin Endocrinol Metab. 2010;95:2343–2350
  15. Reubi JC, Waser B. Concomitant expression of several peptide receptors in neuroendocrine tumours: molecular basis for in vivo multireceptor tumour targeting. Eur J Nucl Med Mol Imaging. 2003;30:781–793
  16. Reubi JC, Kvols LK, Waser B, et al. Detection of somatostatin receptors in surgical and percutaneous needle biopsy samples of carcinoids and islet cell carcinomas. Cancer Res. 1990;50:5969–5977
  17. Reubi JC, Mazzucchelli L, Hennig I, et al. Local up-regulation of neuropeptide receptors in host blood vessels around human colorectal cancers. Gastroenterology. 1996;110:1719–1726
  18. Reubi JC, Mazzucchelli L, Laissue JA. Intestinal vessels express a high density of somatostatin receptors in human inflammatory bowel disease. Gastroenterology. 1994;106:951–959
  19. Schonbrunn A. Somatostatin receptors. In:  Lennarz V,  Lane M editor. Encyclopedia of biological chemistry. Volume 4:Oxford, England: Elsevier; 2004;
  20. Sharma K, Srikant CB. Induction of wild-type p53, Bax, and acidic endonuclease during somatostatin-signaled apoptosis in MCF-7 human breast cancer cells. Int J Cancer. 1998;76:259–266
  21. Woltering EA. Development of targeted somatostatin-based antiangiogenic therapy: a review and future perspectives. Cancer Biother Radiopharm. 2003;18:601–609
  22. Zatelli MC, Piccin D, Vignali C, et al. Pasireotide, a multiple somatostatin receptor subtypes ligand, reduces cell viability in non-functioning pituitary adenomas by inhibiting vascular endothelial growth factor secretion. Endocr Relat Cancer. 2007;14:91–102
  23. Bodei L, Paganelli G, Mariani G. Receptor radionuclide therapy of tumors: a road from basic research to clinical applications. J Nucl Med. 2006;47:375–377
  24. van Essen M, Krenning E, Kam B, et al. Peptide-receptor radionuclide therapy for endocrine tumors. Nat Rev Endocrinol. 2009;5:382–393
  25. Cescato R, Schulz S, Waser B, et al. Internalization of sst2, sst3, and sst5 receptors: effects of somatostatin agonists and antagonists. J Nucl Med. 2006;47:502–511
  26. Liu Q, Cescato R, Dewi DA, et al. Receptor signaling and endocytosis are differentially regulated by somatostatin analogs. Mol Pharmacol. 2005;68:90–101
  27. Ginj M, Chen J, Walter MA, et al. Preclinical evaluation of new and highly potent analogues of octreotide for predictive imaging and targeted radiotherapy. Clin Cancer Res. 2005;11:1136–1145
  28. Waser B, Tamma ML, Cescato R, et al. Highly efficient in vivo agonist-induced internalization of sst2 receptors in somatostatin target tissues. J Nucl Med. 2009;50:936–941
  29. Ginj M, Zhang H, Waser B, et al. Radiolabeled somatostatin receptor antagonists are preferable to agonists for in vivo peptide receptor targeting of tumors. Proc Natl Acad Sci U S A. 2006;103:16436–16441
  30. Stroh T, Jackson AC, Sarret P, et al. Intracellular dynamics of sst5 receptors in transfected COS-7 cells: maintenance of cell surface receptors during ligand-induced endocytosis. Endocrinology. 2000;141:354–365
  31. Rohrer SP, Birzin ET, Mosley RT, et al. Rapid identification of subtype-selective agonists of the somatostatin receptor through combinatorial chemistry. Science. 1998;282:737–740
  32. Cescato R, Loesch KA, Waser B, et al. Agonist-biased signaling at the sst2A receptor: the multi-somatostatin analogs KE108 and SOM230 activate and antagonize distinct signaling pathways. Mol Endocrinol. 2009;24:240–249
  33. Reubi JC, Maecke HR. Peptide-based probes for cancer imaging. J Nucl Med. 2008;49:1735–1738
  34. Ginj M, Zhang H, Eisenwiener KP, et al. New pansomatostatin ligands and their chelated versions: affinity profile, agonist activity, internalization, and tumor targeting. Clin Cancer Res. 2008;14:2019–2027
  35. Wild D, Fani M, Behe M, et al. First clinical evaluation of somatostatin receptor antagonist imaging. Presented at: 57th Annual Meeting of the Society of Nuclear Medicine; June 8, 2010; Salt Lake City, UT.
  36. Cescato R, Erchegyi J, Waser B, et al. Design and in vitro characterization of highly sst2-selective somatostatin antagonists suitable for radiotargeting. J Med Chem. 2008;51:4030–4037
  37. Bauer W, Briner U, Doepfner W, et al. SMS 201-995: a very potent and selective octapeptide analogue of somatostatin with prolonged action. Life Sci. 1982;31:1133–1140
  38. Lancranjan I, Bruns C, Grass P, et al. Sandostatin LAR: a promising therapeutic tool in the management of acromegalic patients. Metabolism. 1996;45:67–71
  39. Caron P, Morange-Ramos I, Cogne M, et al. Three year follow-up of acromegalic patients treated with intramuscular slow-release lanreotide. J Clin Endocrinol Metab. 1997;82:18–22
  40. Cai RZ, Szoke B, Lu R, et al. Synthesis and biological activity of highly potent octapeptide analogs of somatostatin. Proc Natl Acad Sci U S A. 1986;83:1896–1900
  41. Bruns C, Lewis I, Briner U, et al. SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. Eur J Endocrinol. 2002;146:707–716
  42. Hofland LJ, Lamberts SW. The pathophysiological consequences of somatostatin receptor internalization and resistance. Endocr Rev. 2003;24:28–47
  43. Lohof E, Planker E, Mang C, et al. Carbohydrate derivatives for use in drug design: cyclic alpha(v)-selective RGD peptides. Angew Chem Int Ed Engl. 2000;39:2761–2764
  44. Oberg K, Kvols L, Caplin M, et al. Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol. 2004;15:966–973
  45. Srirajaskanthan R, Watkins J, Marelli L, et al. Expression of somatostatin and dopamine 2 receptors in neuroendocrine tumours and the potential role for new biotherapies. Neuroendocrinology. 2009;89:308–314
  46. Jaquet P, Gunz G, Saveanu A, et al. BIM-23A760, a chimeric molecule directed towards somatostatin and dopamine receptors, vs universal somatostatin receptors ligands in GH-secreting pituitary adenomas partial responders to octreotide. J Endocrinol Invest. 2005;28:21–27
  47. Wood SM, Kraenzlin ME, Adrian TE, et al. Treatment of patients with pancreatic endocrine tumours using a new long-acting somatostatin analogue symptomatic and peptide responses. Gut. 1985;26:438–444
  48. Kvols LK, Moertel CG, O'Connell MJ, et al. Treatment of the malignant carcinoid syndrome (Evaluation of a long-acting somatostatin analogue). N Engl J Med. 1986;315:663–666
  49. Gorden P, Comi RJ, Maton PN, et al. NIH conference (Somatostatin and somatostatin analogue (SMS 201-995) in treatment of hormone-secreting tumors of the pituitary and gastrointestinal tract and non-neoplastic diseases of the gut). Ann Intern Med. 1989;110:35–50
  50. Modlin IM, Pavel M, Kidd M, et al. Somatostatin analogues in the treatment of gastroenteropancreatic neuroendocrine (carcinoid) tumours. Aliment Pharmacol Ther. 2010;31:169–188
  51. Bajetta E, Procopio G, Catena L, et al. Lanreotide autogel every 6 weeks compared with Lanreotide microparticles every 3 weeks in patients with well differentiated neuroendocrine tumors: a phase III study. Cancer. 2006;107:2474–2481
  52. Ricci S, Antonuzzo A, Galli L, et al. Long-acting depot lanreotide in the treatment of patients with advanced neuroendocrine tumors. Am J Clin Oncol. 2000;23:412–415
  53. Eriksson B, Oberg K. Summing up 15 years of somatostatin analog therapy in neuroendocrine tumors: future outlook. Ann Oncol. 1999;10(Suppl 2):S31–S38
  54. Kvols LK, Oberg K, Glusman JE, et al. The SOM230 Carcinoid Study Group. Safety and efficacy of pasireotide (SOM230) in patients with metastatic carcinoid tumors refractory or resistant to Octreotide LAR: results of a phase II study. Presented at: 42nd Annual Meeting of the American Society of Clinical Oncology; June 2–6, 2006; Atlanta, GA.
  55. Kinney MA, Warner ME, Nagorney DM, et al. Perianaesthetic risks and outcomes of abdominal surgery for metastatic carcinoid tumours. Br J Anaesth. 2001;87:447–452
  56. Kharrat HA, Taubin H. Carcinoid crisis induced by external manipulation of liver metastasis. J Clin Gastroenterol. 2003;36:87–88
  57. Saltz L, Trochanowski B, Buckley M, et al. Octreotide as an antineoplastic agent in the treatment of functional and nonfunctional neuroendocrine tumors. Cancer. 1993;72:244–248
  58. Plockinger U, Wiedenmann B. Neuroendocrine tumors (Biotherapy). Best Pract Res Clin Endocrinol Metab. 2007;21:145–162
  59. Welin SV, Janson ET, Sundin A, et al. High-dose treatment with a long-acting somatostatin analogue in patients with advanced midgut carcinoid tumours. Eur J Endocrinol. 2004;151:107–112
  60. Faiss S, Rath U, Mansmann U, et al. Ultra-high-dose lanreotide treatment in patients with metastatic neuroendocrine gastroenteropancreatic tumors. Digestion. 1999;60:469–476
  61. Granberg D, Jacobsson H, Oberg K, et al. Regression of a large malignant gastrinoma on treatment with Sandostatin LAR: a case report. Digestion. 2008;77:92–95
  62. Rinke A, Muller HH, Schade-Brittinger C, et al. Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group. J Clin Oncol. 2009;27:4656–4663
  63. Janson ET, Oberg K. Long-term management of the carcinoid syndrome (Treatment with octreotide alone and in combination with alpha-interferon). Acta Oncol. 1993;32:225–229
  64. Kolby L, Persson G, Franzen S, et al. Randomized clinical trial of the effect of interferon alpha on survival in patients with disseminated midgut carcinoid tumours. Br J Surg. 2003;90:687–693
  65. Arnold R, Rinke A, Klose KJ, et al. Octreotide versus octreotide plus interferon-alpha in endocrine gastroenteropancreatic tumors: a randomized trial. Clin Gastroenterol Hepatol. 2005;3:761–771
  66. Yao JC, Phan A, Hoff PM, et al. Targeting vascular endothelial growth factor in advanced carcinoid tumor: a random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alpha-2b. J Clin Oncol. 2008;26:1316–1323
  67. Duran I, Kortmansky J, Singh D, et al. A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas. Br J Cancer. 2006;95:1148–1154
  68. Yao JC, Lombard-Bohas C, Baudin E, et al. Daily oral everolimus activity in patients with metastatic pancreatic neuroendocrine tumors after failure of cytotoxic chemotherapy: a phase II trial. J Clin Oncol;28:69–76.
  69. Krenning EP, Kwekkeboom DJ, Bakker WH, et al. Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med. 1993;20:716–731
  70. Buchmann I, Henze M, Engelbrecht S, et al. Comparison of 68Ga-DOTATOC PET and 111In-DTPAOC (Octreoscan) SPECT in patients with neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2007;34:1617–1626
  71. Valkema R, De Jong M, Bakker WH, et al. Phase I study of peptide receptor radionuclide therapy with [In-DTPA]octreotide: the Rotterdam experience. Semin Nucl Med. 2002;32:110–122
  72. Anthony LB, Woltering EA, Espenan GD, et al. Indium-111-pentetreotide prolongs survival in gastroenteropancreatic malignancies. Semin Nucl Med. 2002;32:123–132
  73. Otte A, Herrmann R, Heppeler A, et al. Yttrium-90 DOTATOC: first clinical results. Eur J Nucl Med. 1999;26:1439–1447
  74. Waldherr C, Pless M, Maecke HR, et al. The clinical value of [90Y-DOTA]-D-Phe1-Tyr3-octreotide (90Y-DOTATOC) in the treatment of neuroendocrine tumours: a clinical phase II study. Ann Oncol. 2001;12:941–945
  75. Waldherr C, Pless M, Maecke HR, et al. Tumor response and clinical benefit in neuroendocrine tumors after 7.4 GBq (90)Y-DOTATOC. J Nucl Med. 2002;43:610–616
  76. Waldherr C, Schumacher T, Maecke HR, et al. Does tumor response depend on the number of treatment sessions at constant injected dose using 90Yttrium-DOTATOC in neuroendocrine tumors?. Eur J Nucl Med. 2002;29:100
  77. Chinol M, Bodei L, Cremonesi M, et al. Receptor-mediated radiotherapy with Y-DOTA-DPhe-Tyr-octreotide: the experience of the European Institute of Oncology Group. Semin Nucl Med. 2002;32:141–147
  78. Paganelli G, Bodei L, Handkiewicz Junak D, et al. 90Y-DOTA-D-Phe1-Try3-octreotide in therapy of neuroendocrine malignancies. Biopolymers. 2002;66:393–398
  79. Bodei L, Cremonesi M, Zoboli S, et al. Receptor-mediated radionuclide therapy with 90Y-DOTATOC in association with amino acid infusion: a phase I study. Eur J Nucl Med Mol Imaging. 2003;30:207–216
  80. Valkema R, Pauwels S, Kvols LK, et al. Survival and response after peptide receptor radionuclide therapy with [90Y-DOTA0,Tyr3]octreotide in patients with advanced gastroenteropancreatic neuroendocrine tumors. Semin Nucl Med. 2006;36:147–156
  81. Valkema R, Pauwels S, Kvols L, et al. Long-term follow-up of a phase 1 study of peptide receptor radionuclide therapy (PRRT) with [90Y-DOTA0,Tyr3]octreotide in patients with somatostatin receptor positive tumours. Eur J Nucl Med Mol Imaging. 2003;30:232
  82. Bushnell DL, O'Dorisio TM, O'Dorisio MS, et al. 90Y-edotreotide for metastatic carcinoid refractory to octreotide. J Clin Oncol. 2010;28:1652–1659
  83. Reubi JC, Schar JC, Waser B, et al. Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur J Nucl Med. 2000;27:273–282
  84. Kwekkeboom DJ, de Herder WW, Kam BL, et al. Treatment with the radiolabeled somatostatin analog [177Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol. 2008;26:2124–2130
  85. de Keizer B, van Aken MO, Feelders RA, et al. Hormonal crises following receptor radionuclide therapy with the radiolabeled somatostatin analogue [177Lu-DOTA0,Tyr3]octreotate. Eur J Nucl Med Mol Imaging. 2008;35:749–755
  86. Clancy TE, Sengupta TP, Paulus J, et al. Alkaline phosphatase predicts survival in patients with metastatic neuroendocrine tumors. Dig Dis Sci. 2006;51:877–884
  87. Janson ET, Holmberg L, Stridsberg M, et al. Carcinoid tumors: analysis of prognostic factors and survival in 301 patients from a referral center. Ann Oncol. 1997;8:685–690
  88. Quaedvlieg PF, Visser O, Lamers CB, et al. Epidemiology and survival in patients with carcinoid disease in The Netherlands (An epidemiological study with 2391 patients). Ann Oncol. 2001;12:1295–1300
  89. Mazzaglia PJ, Berber E, Milas M, et al. Laparoscopic radiofrequency ablation of neuroendocrine liver metastases: a 10-year experience evaluating predictors of survival. Surgery. 2007;142:10–19
  90. van Essen M, Krenning EP, Kam BL, et al. Salvage therapy with (177)Lu-octreotate in patients with bronchial and gastroenteropancreatic neuroendocrine tumors. J Nucl Med;51:383–390.
  91. De Jong M, Valkema R, Jamar F, et al. Somatostatin receptor-targeted radionuclide therapy of tumors: preclinical and clinical findings. Semin Nucl Med. 2002;32:133–140
  92. Rich TA, Shepard RC, Mosley ST. Four decades of continuing innovation with fluorouracil: current and future approaches to fluorouracil chemoradiation therapy. J Clin Oncol. 2004;22:2214–2232
  93. Dunst J, Reese T, Sutter T, et al. Phase I trial evaluating the concurrent combination of radiotherapy and capecitabine in rectal cancer. J Clin Oncol. 2002;20:3983–3991
  94. van Essen M, Krenning EP, Kam BL, et al. Report on short-term side effects of treatments with 177Lu-octreotate in combination with capecitabine in seven patients with gastroenteropancreatic neuroendocrine tumours. Eur J Nucl Med Mol Imaging. 2008;35:743–748
  95. Kwekkeboom DJ, Bakker WH, Kooij PP, et al. [177Lu-DOTAOTyr3]octreotate: comparison with [111In-DTPAo]octreotide in patients. Eur J Nucl Med. 2001;28:1319–1325
  96. Forrer F, Krenning EP, Kooij PP, et al. Bone marrow dosimetry in peptide receptor radionuclide therapy with [177Lu-DOTA(0),Tyr(3)]octreotate. Eur J Nucl Med Mol Imaging. 2009;36:1138–1146

 Conflicts of interest The authors disclose the following: Dr Öberg is a member of advisory boards for Novartis and Ipsen. Drs Kwekkeboom and Krenning are stockholders in Bio Synthema. Dr Reubi discloses no conflicts.

PII: S0016-5085(10)01037-1

doi:10.1053/j.gastro.2010.07.002

Gastroenterology
Volume 139, Issue 3 , Pages 742-753.e1, September 2010

Article Tools

* Image Usage & Resolution