Somatostatin receptor imaging and therapy of pancreatic endocrine tumors

Somatostatin receptor imaging and therapy of pancreatic endocrine tumors

Annals of Oncology 10 Suppl. 4: S177-S181,1999. © 1999 Kluwer Academic Publishers. Printed in the Netherlands. Review Somatostatin receptor imaging a...

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Annals of Oncology 10 Suppl. 4: S177-S181,1999. © 1999 Kluwer Academic Publishers. Printed in the Netherlands.

Review Somatostatin receptor imaging and therapy of pancreatic endocrine tumors C.H.J. van Eijck,1 M. de Jong,2 W.A.P. Breeman,2 G.D. Slooter,' R.L. Marquet1 & E.P. Krenning2>3 Departments of 'Surgery, 2Nuclear Medicine, and 'internal Medicine 111, Erasmus Medical Center Rotterdam, The Netherlands

Summary

Somatostatin receptor expression and subtypes Somatostatin (SS) is a small regulatory peptide, produced by degradation of a precursor protein [1]. SS is widely distributed in the human body and is located in the pancreas in the D cells at the periphery of the islets of Langerhans [2]. Its main function is the inhibition of secretion of various hormones and it may act as neurotransmitter in the CNS [3]. A number of observations have also suggested an antiproliferative effect of SS and its stable analogues [4-6]. Critical to these actions is the presence of somatostatin receptors (SS-Rs), which like other membrane receptors subserve two functions: (1) to recognize the ligand and bind it with high affinity and specificity, and (2) to generate a transmembrane signal that evokes a biological response. Large number of SS-Rs were found on most tumors with amine precursor uptake and decarboxilation (APUD) characteristics and neuroendocrine properties, as well as on breast and brain tumors [7-9] At least five different human SS-R subtypes have been cloned [10]. All subtypes bind SS with high affinity, while their affinity for the SS analogue, octreotide, differs considerably. Octreotide binds with high affinity to subtype 2 (ss^) and ssts, to a lesser degree sst3, while no binding to sst, and sst4 occurs. Endocrine pancreatic tumors do have APUD characteristics and neuroendocrine properties, which can be confirmed using combinations of the immunocytochemical staining with chromogranin A, neuro specific enolase and the Grimelius silver staining. After SS-Rs have been detected on the normal endocrine islet cells (A, B and D cells possess such receptors [11]), Reubi et al. demonstrated that most hormone producing endocrine pancreatic tumors also express a high density of SS-Rs [7]. Later on it was observed that these receptors were functional, because a positive correlation existed between SS-R expression of hormone producing endocrine pancreatic tumors and the beneficial effect of octreotide on hormone release and tumor growth of these tumors during therapy [12] Somatostatin receptor mRNA subtypes are widely expressed in endocrine pancreatic tumors, but their distribution is not correlated with SS-R

Key words: pancreatic endocrine tumors, radionuclide therapy, somatostatin analogues, somatostatin receptor scintigraphy

subtype expression. The majority of human endocrine pancreatic tumors such as gastrinomas, glucagonomas, VIPomas and "non-functioning" islet cells tumors express sstj. In vitro studies have shown that 72% of the insulinomas express SS-Rs, however, these receptors are mainly sst3, which has low affinity for octreotide [13,14]. Although SSRs have been demonstrated on exocrine pancreatic cells in experimental animals, mainly in the acinar cells, neither SSRs nor neuroendocrine properties could be confirmed on human exocrine pancreatic adenocarcinomas [15].

Somatostatin receptor scintigraphy For the visualization of SS-R-positive tumors somatostatin receptor scintigraphy (SRS) with ["'ln-DTPA°]octreotide (Octreoscan®) (DTPA = diethylenetriaminopentaaceticacid) is used, since there are several arguments that this technique represents SS-R imaging [16]. First of all pretreatment with high doses of unlabeled octreotide prevents tumor uptake of ['"In-DTPA°] octreotide in rats bearing SS-R- positive tumors. Autoradiographically the radioligand showed specific binding to the anterior lobe of the rat pituitary, which is the only part of this organ with SSRs. Finally the specific SS-R-like biologic effect of this radioligand was proven by the inhibition of growth hormone secretion by cultured rat pituitary cells in dose-dependent fashion. The efficacy SRS of ['"in-DTPA^octreotide was evaluated in an European multicenter trial in 350 patients with histologically or biochemically proven endocrine pancreatic tumors or carcinoids [17]. The highest success rates of SRS were obserevd with glucanomas (100%), vipomas (88%), gastrinomas (73%) and 'non-functioning' islet cell tumors (82%). The low detection rate (46%) noted for insulinomas is related to the lower incidence of sstjon insulinoma cells. Data combined from different scanning protocols show an estimated sensitivity for gastrinomas of 79%, insulinomas of47%, glucagonomas of 100% and other endocrine pancreatic tumors of 84% [18]. However the lower sensitivity found in several studies may be related to

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Somatostatin receptors (SS-Rs) have been found on a variety of neuroendocrine tumors like carcinoids, paragangliomas, as well as on brain and breast tumors. SS-Rs are also present on most pancreatic endocrine tumors, while previous in vitro studies indicate the absence of these receptors on pancreatic duct cancers. Somatostatin receptor scintigraphy with a radionuclide labeled somatostatin analogue, ['"In-DTPA0]-

octreotide, is a sensitive and specific technique to visualize in vivo the presence of SS-Rs on various tumors. The purpose of this article is to review the somatostatin receptor imaging of pancreatic endocrine tumors and to illustrate the impact of SS-R expression for therapeutic strategies.

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We and the Swedish group of Ahlman evaluated intraoperative localization of SS-R- positive endocrine pancreatic tumors using a hand-held scintillation detector [23]. Laparotomy was performed 3 to 5 days after the injection of at least 200 MBq ['"in-DTPA^octreotide. In most cases, however, in situ measurements added little information to the preoperative SRS and surgical findings. Tumor to normal tissue '"In radioactivity ratios ex vivo were high in all patients. So in patients with SS-R-positive endocrine pancreatic tumors the hand-held probe could be used in stead of frozen sections to confirm if an endocrine lesion was resected. Furthermore the very high tumor to blood ratios of radioactive concentrations found in some endocrine pancreatic tumors seem promising for future SS-R-mediated radionuclide therapy. Since sensitivity for the detection of insulinomas is low, SRS is not recommended as a diagnostic procedure in the preoperative work-up. Patients with biochemically proven insulinomas, without liver metastases should be explored with intraoperative ultrasound available. If radiolabeled somatostatin analogues with high affinity for the ss^receptor become available, a highly sensitive scintigraphic detection of insulinomas might be expected. However, in patients with metastatic disease SRS should be performed in order to determine whether octreotide therapy could be administered. Octreotide therapy in these patients may produce severe hypoglycemia if the secretion of insulin is not affected

because of the lack of SS-Rs with octreotide affinity, while the release of glucagon and growth hormone is suppressed by octreotide [24]. In patients with metastatic disease from endocrine pancreatic tumors, SRS has been shown to be essential for planning therapeutic strategies. Chemoembolization or even liver transplantation for small liver metastases should only be considered if no extrahepatic disease is present [22]. On the other hand systemic therapy differs considerably between patients with SS-R- positive (5fluorouracil, streptozotocin, folinic acid) and SS-R- negative (cisplatin, etoposide) metastases as has been shown by Moertel et al [25]. Finally, the difference in SS-R expression between islet cell tumors and pancreatic duct cancers offers the possibility to differentiate between these tumors preoperatively [26]. This is important, as palliative surgery in patients with islet cell tumors is not only of value to relieve clinical symptoms, but also because a decrease in tumor burden might enhance the effect of medical treatment, resulting in a better clinical condition and a longer survival. Therefore SRS has a place in the preoperative differential diagnosis of endocrine pancreatic tumors, especially "nonfunctioning" islet cell tumors, and pancreatic ductal cancers. If metastases occur more than 3 years after resection of a pancreatic tumor, SRS should be performed since these metastases are likely to express SS-Rs and therapeutic options might be available.

Clinical use of somatostatin analogues Most endocrine pancreatic tumors, with the exception of insulinomas, are malignant and have already metastasized at the time of diagnosis. These tumors are in general slow growing and most of the clinical distress is related to the hypersecretion of hormones which often incapacitates them and causes long and repeated hospital stay. The clinical use of the somatostatin analogue octreotide in this type of patients is of considerable help in controlling symptomatology. Debilitating diarrhoea, dehydration and hypokalemia (VIPoma), peptic ulceration (gastrinoma), lifethreatening attacks of hypoglycemia (insulinoma) and necrolytic skin lesions (glucagonoma) can be well controlled during chronic treatment with octreotide. There is no doubt that octreotide therapy is of great benefit for most of these patients and improves their quality of life dramatically [27]. Clinical studies in patients with hormone producing islet cell tumors showed a close parallel between the presence of SSRs on the tumors and the in vivo and in vitro suppressive effects of octreotide on hormone release [12]. This indicates that SRS can predict a possible suppressive effect of octreotide on hormonal hypersecretion by endocrine pancreatic tumors. Although octreotide may not be considered as a substitute for proton-pump inhibitors, like omeprazole, its specific properties may also be of therapeutic benefit in some Zollinger-Ellison syndrome patients. Even during chronic treatment of octreotide few allergic reactions have been reported and the most common side effect is the development of gallbladder stones due to the inhibitory effects on cholecystokinin release. Since it was demonstrated that octreotide interferes with growth factors and might have antiproliferative effect on tumor cells by inhibition of angiogenesis, modulation of immunological activity or a

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important differences in scanning procedures such as the amount of radioligand administered, the duration of the acquisition and the use of single photon emission computed tomography (SPECT). The fact that abdominal SPECT was not systematically performed in all patients with gastrinomas in the European multicenter trial may explain that only 73% of gastrinoma patients had a positive scan compared to the 90-100% sensitivity reported in other studies. In a prospective study Gribil et al compared the sensitivity of SRS with that of CT-scanning, MRI, ultrasonography and selective angiography in the detection of primary and metastatic gastrinomas [19]. They also investigated the effect of SRS on clinical management. Since this technique altered management of 47% of the patients, they concluded that SRS should be the initial imaging modality for patients with gastrinomas, also because of its superior sensitivity, high specificity, simplicity and cost-effectiveness. Mignon et al compared the results of SRS with those of conventional imaging techniques including endoscopic ultrasonography, and with surgical findings in 21 consecutive patients with Zollinger-Ellison syndrome [20]. None of their patients had pancreatic gastrinoma, only duodenal and/or peripancreatic lymph node gastrinomas were found at surgical exploration. Even a duodenal gastrinoma of 3 mm was localized by SRS. The SRS added complementary information to other imaging techniques including echoendoscopy and improved the preoperative detection of extrapancreau'c gastrinomas. By combining SRS with echoendoscopy they were able to detect 90% of the tumors in the upper duodenopancreatic area. SRS identified metastatic disease in 20-30% of patients after all other imaging techniques had failed [21]. In their prospective study concerning 160 patients with neuroendocrine gastroenteropancreatic tumors including pancreatic islet cell tumors, SRS changed the surgical therapeutic strategy in 40 (25%) patients [22].

179 direct antimitotic effect via SS-Rs, several reports were published about an oncological application of octreotide [46]. However octreotide alone or in combination with interferon-a has failed to control neoplastic growth [28]. Currently other somatostatin analogues like lanreotide are being studied in different doses and modes of administration. Preliminary results do not appear to be better than those achieved with standard doses of octreotide. However tumor biopsies before and during treatment indicated apoptosis in responding patients [29]. This phenomenon was never reported with regular doses of octreotide and warrant further investigations of these analogues in association with interferon-a.

Table /.Effect of PRRT on SS-R-positive liver metastases, given at different times and after pHx Treatment Number of animals with Oto 100 metastases 0 1-20 21-100 >100 Controls PRRT day 1 PRRT day 8 PRRT day 1&8

In order to optimalize scintigraphy and therapy of endocrine pancreatic tumors we briefly will describe some new developments.

pHx (70%) Controls PRRT day 1&8 Abbreviations: PRRT - peptide receptor radionuclide therapy; SS-R somatostatin receptor; pHx - 70% partial hepatectomy The effect of all treatment schedules was significantly different (p < 0.01) from that of 0.5 jig cold [DTPA°]octreotide on days 1 and 8 in both experiments with control groups.

New Analogues Recently we have evaluated and compared different '"inchelator-peptide constructs with regard to binding to octreotide receptors on mouse pituitary tumor cell membranes and internalization in rat pancreatic tumor cells. Furthermore, biodistribution in tumor-bearing rats was investigated in vivo. The analogs tested were

Future aspect

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The major finding from these experiments was that PRRT with [" 'ln-DTPA°]octreotide leads to a marked inhibition of intrahepatic growth of SS-R-positive tumor cell colonies (Table 1). In repeated experiments, most treated animals showed none or few SS-R-positive tumor colonies, an outcome that was not observed in earlier experiments using high doses of non-radioactive octreotide [34]. Furthermore, blocking the SS-Rs by pre-treatment with cold octreotide substantially decreased the efficacy of PRRT and no effect of treatment was observed using SS-R -negative tumor cells. This indicates the essential presence of SS-Rs and that PRRT is SS-R-mediated. In addition, three experimental studies demonstrated tumor growth inhibitory effects on solid subcutaneous tumors by radiolabeled SS analogues in animal models [35-37]. Either by intra-tumor or intraperitoneal injection, all resulted in significant decrease Somatostatin receptor radionuclide therapy in tumor size. To demonstrate the presence of SS-Rs in vivo peptide In 1995 we started a phase 1 clinical study in order to receptor scintigraphy has been proven to be a sensitive and investigated the side effects and anti-proliferative effect of specific technique. After injection of ['"In- high, multiple radiotherapeutic doses of ["'inDTPA°]octreotide, SS-R-positive tumors show uptake of DTPA°]octreotide in twenty end-stage patients with mainly radioactivity due to the high affinity of octreotide for sst^ a high tumor load of progressing neuroendocrine tumors which can be visualized with a gamma camera [16]. '"in including pancreatic cell tumors. After scoring tumor emits not only gamma rays, which can be visualized, but radioactivity uptake using scintigrams obtained 24 hr after also internal-conversion and Auger electrons with a medium the injection of a diagnostic dose (220 MBq) of ["'Into short tissue penetration (200-550 um, 0.02-10 urn) [30]. DTPA°]octreotide treatment was initiated. All patients In vivo '"in is internalized and transported into the received a dose of 6000-7000 MBq '"in incorporated in 40lysosomes of SS-R- positive cells after administration of 50 ug [DTPA°]octreotide with at least 2 weeks intervals ['"ln-DTPA0]octreotide with a long residence time in the between administrations. A total of 8 injections was aimed tumor cells (biological half-life >700hr [31,32]. The at with extension to 12 -14 administrations. Sixteen out of internalization by tumor cells of the radioligand is apart from these 20 patients received a total cumulative dose of at least the high affinity of ['"ln-DTPA0']octreotide for sstj in vivo 20 GBq ['"ln-DTPA°]octreotide. Four patients treated with an important aspect of peptide receptor radionuclide therapy a total dose lower than 20 GBq, showed progressive disease (PRRT). Internalization by receptor-mediated endocytosis despite PRRT. High, multiple radiotherapeutic doses were may bring the radionuclide closer to its target, the DNA of give to 16 patients up to cumulative of 27 to 74 GBq per the tumor cell. We investigated the anti-proliferative effect patients. Except for a transient decline in platelets counts and of ['"in-DTPA^octreotide on SS-R-positive and -negative lymphocyte subsets occurred in a few patients, no major tumor cells in a rat liver metastases model [33]. The clinical side effects after up to 2 years of treatment, with a development of hepatic metastases was determined 21 days longest follow-up of 26 months. Of. the 16 patients who after direct injection of SS-R-positive pancreatic CA20948 received a cumulative dose of more than 20 GBq, 5 patients tumor cells or SS-R-negative CC-531 colon adenocarcinoma showed reduction in size of the tumors and 5 other patients cells on day 0. In order to accelerate tumor growth of SS-R- stable disease. In these patients beneficial effects on positive cells a 70% partial hepatectomy (pHx) was also hormone production and clinical symptoms were found. performed in a parallel experiment . On day 1 and/or 8 There was a tendency towards better results in patients animals were treated with 370 MBq (0.5 ug) ['"In- whose tumors had a higher accumulation of the radioligand DTPA°]octreotide. on their scoring scintigram, from which the uptake was graded. So a high expression of SS-Rs was correlated with a better result of PRRT.

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New peptides Receptors for Vasoactive Intestinal Peptide (VIP), a 28 aminoacid neuroendocrine mediator, have been found in many primary tumours and metastases [39]. On the basis of these data, VIP receptor scintigraphy might become a sensitive tool for both the detection of the primary tumor and its metastases. VIP receptor scintigraphy with 123I-VIP has been reported for pancreatic duct carcinomas as well as endocrine pancreatic tumors [40,41]. The theoretical application of VIP receptor scintigraphy on the basis of results of autoradiography studies is very broad. However, some reservation with regard to its possible use for peptide receptor scintigraphy is the in-house labeling with 123I (costs, logistics, manpower) and the intense accumulation of 123IVIP in the lung for the first hours after injection.

Furthermore, as long as there is no chelated VIP analog available that enables easier labeling with a radionuclide and that might be used in the future for peptide receptor radionuclide therapy, if ever possible because of the high accumulation in the lung, the available alternatives in nuclear medicine, namely e.g. MIBI, FDG and SRS will in our view prevail for the near future. Substance P receptor scintigraphy with'' 'In-labeled DTPAchelated substance P analogue has been performed predominantly in patients with autoimmune diseases [42]. Substance P, an undecapeptide, belongs to the family of tachykinins. This peptide acts as a neurotransmitter in the central nervous system, has vasodilator potency and increases vascular permeability. Furthermore, it affects the immune response and angiogenesis. Receptor autoradiography studies with radiolabeled substance-P have shown a sporadic positivity for the presence of substance P receptors in pancreatic cancer tumor samples [43]. In most of the tumours the distribution of substance P receptors was non-homogeneous. The role of substance P receptors in pancreatic cancer and the application of radiolabeled substance-P ligands have yet to be established. Other interesting peptide receptors for nuclear medicine are cholecystokinin-B (CCK-B), gastrin orbombesin [44]. The use of radiolabeled radioligands for binding to these receptors in pancreatic endocrine tumors however might be of minor importance. PRRT developments For radiotherapeutic applications, besides '"In also other radionuclides have been proposed and investigated for coupling to octreotide-analogues. '"Y is a 8-particle emitter, the maximum energy of the electrons is 2.3 MeV, their mean range is a few mm in tissue. '"Y shows dissociation from DTPA-conjugated peptides in serum, resulting in hematopoietic toxicity in vivo, therefore, Tyr3-octreotide, which has a higher binding affinity for sstj than octreotide itself, has been derivatized with the chelator DOTA enabling stable radiolabeling with both '"Y and' "in. It is to be expected that the radiotherapeutic use of '"Y leads to higher radiation doses in a larger part of the tumor, also because of their more appropriate particle ranges or tissue penetration [45, 46] The first two radionuclide therapy trials with f°YDOTA°,Tyr3]-octreotide have started recently. Based on the assumptions described in Materials and Methods and on a similar biodistribution of '"In- and ^ - l a b e l e d peptide the estimated tumor radiation dose after an administered dose of 3.7 GBq "Y-labeled peptide will be 16.500 cGy (10 gr., 1 % uptake) -1800 cGy (100 gr., 1 % uptake). Estimated tissue doses are 2400 cGy for the kidneys, 1500 cGy for the liver, and 1400 cGy for the spleen. Thus, tumors with an inhomogeneous cellular distribution of SS-Rs may then respond in a favorable way to this kind of treatment because the better cross-fire. A problem during radionuclide-therapy may arise because of the high uptake of ^ - l a b e l e d peptide in the kidneys, causing a high dose to the kidneys, thereby reducing the possibilities for radionuclide-therapy. We showed that the renal uptake of radiolabeled octreotide-analogues in rats could be reduced about 50 % by single intravenous administration of 400 mg/kg L- or D-lysine [47,48] The high tissue penetration of'"Y localized in tubular cells may affect the glomeruli and eventually induce glomerular fibrosis.

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[DTPA°]octreotide, [DTPA 0 ,Tyr 3 ]octreotide and [DTPA^Tyr'fcctreotate. ([DTPA^Tyi^Joctreotide and [DTPA^Tyr^octreotate were synthesized at Mallinckrodt Medical, St. Louis, Mo). Phe-residues were replaced with Tyr to increase the hydrophylicity of the peptides. Furthermore, [DTPA°,Tyr3] octreotate, with the C-terminal threonine, was synthesized to investigate the effects of an additional negative charge on clearance and cellular uptake. In addition, [DOTA°,Tyr3] octreotide (DOTA = tetraazacyclododecanetetraacetic acid) was synthesized (by Prof. Macke, Basel, Switzerland) and tested, as this compound enables stable radiolabeling with both '"In and the B' particle-emitting radionuclide 90 Y. Radiolabeling with '"In and quality control procedures were mostly as described for [DTPA°]octreotide, for radiolabeling of [DOTA°,Tyr3] octreotide, the mixture was heated for 25 min at 100 C. In in vitro receptor binding studies, all unlabeled compounds showed high and specific binding for the SS-Rs, with IC^, values in the low nanomolar range. [DOTA^Tyr^octreotide showed the highest affinity of the compounds tested [38]. Comparison of specific intemalization of the '"in-labeled compounds in two SS-R-positive cell lines, showed that internalized radioactivity was by far the highest after incubation with [l"ln-DTPA°,Tyr3]octreotate. Also in biodistribution experiments in ss^-positive CA20948 tumor bearing rats, uptake in the ss^-expressing organs and tumor of '"In-labeled [DTPA^Tyr^octreotide, [DOTA^Tyr3]octreotide and [DTPA^Tyr^octreotate was significantly higher than that of [" 'ln-DTPA°]octreotide at the time points tested. ["1In-DTPA°,Tyr3]octreotate showed the highest uptake in the ssVpositive organs of the '"In-labeled peptides tested, also in accordance with the in vitro intemalization studies. Uptake of this '"In-labeled peptide in the ss^-positive target organs represented mostly specific binding to this octreotide preferring SS-R, as uptake was decreased to less than 7 % of control by pretreatment of the rats with 0.5 mg unlabeled octreotide. Clearance from the blood was rapid. Furthermore, the low uptake of ['"InDTPA°,Tyr3]-octreotate in the liver is worth mentioning, which is favorable especially in combination with the rapid blood clearance and high uptake of this compound in the target organs. We concluded that '"In-labeled [DTPA°,Tyr3]-octreotide, but especially [DTPA^Tyr3] octreotate and their DOTA-coupled counterparts are most promising for scinti-graphy and, after coupling to therapeutic radionuclides, for radionuclide therapy of SS-R-positive tumors in humans [38].

181 Measures have to be taken in order to decrease the renal accumulation of 8-emitting peptides when used for radionuclide therapy, e.g. with lysine infusions.

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