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 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]-
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
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.
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
178
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].
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
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.
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.
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
180
[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].
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.
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.
27.
28.
29.
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Correspondence to:
Casper H.J. van Eijck
Department of Surgery, Room H 1049
Erasmus Medical Center Rotterdam
Dr Molenwaterplein 40
3015 GD Rotterdam, the Netherlands
E-mail: [email protected]