Radiolabelled somatostatin analogue(s) for peptide receptor scintigraphy and radionuclide therapy
Radiolabelled somatostatin analogue(s) for peptide receptor scintigraphy and radionuclide therapy
E. P. Krenning 2
M. de Jong 2
P. P. M. Kooij 2
W. A. P. Breeman 2
W. H. Bakker 2
W. W. de Herder 1
C. H. J. van Eijck 0
D. J. Kwekkeboom 2
0 Surgery, University Hospital and Erasmus University Rotterdam (EUR) , The Netherlands
1 Department of Internal Medicine III
2 Department ofNuclear Medicine
3 Department of Nuclear Medicine, Catholic University ofLouvain , Brussels , Belgium
Summary two years treatment, except that in a few patients a transient decline in platelets counts and lymphocyte subsets occurred. Background: Peptide receptor scintigraphy with the radioactive Promising beneficial effects on clinical symptoms, hormone somatostatin analogue, [mIn-DTPA0]octreotide, is a sensitive production and tumour proliferation were found. Of the 21 and specific technique to show in vivo the presence and abun- patients who received a cumulative dose of more than 20 GBq, dance of somatostatin receptors on various tumours. eight patients showed stabilisation of disease and six other Aim: With this technique primary tumours and metastases patients a reduction in size of tumours. There is a tendency of neuroendocrine cancers as well as of many other cancer-types towards better results in patients whose tumours have a higher can be localised. This technique is currently used to assess accumulation of the radioligand. the possibility of peptide receptor radionuclide therapy Conclusions: PRRT is feasible, also with m I n as radio(PRRT) with repeated administrations of high doses of [luIn- nuclide. Depending on the homogeneity of distribution of DTPA°]octreotide. '"in emits Auger and conversion electrons tumour cells expressing peptide receptors and the size of the having a tissue penetration of 0.02-10 urn and 200 to 500 urn, tumour, P-emitting radionuclides, e.g., 90Y, labelled to DOTArespectively. chelated peptides, are also attractive candidates for PRRT. The Patients and methods: Thirty end-stage patients with mostly first PRRT trials with [90Y-DOTA°,Tyr3]octreotide started neuroendocrine progressing tumours were treated with [ulIn- recently. DTPA°]octreotide, up to a maximal cumulative patient dose of about 74 GBq, in a phase I trial. Key words: octreotide, peptide, radionuclide, scintigraphy, Results: There were no major clinical side effects after up to somatostatin, therapy
The inhibitory effect of somatostatin on hormone
secretion of various glands led to the concept of beneficial
effects of somatostatin in the treatment of diseases,
based on gland hyperfunction or overproduction of
hormones by endocrine-active tumours. However, the
tetradecapeptide SSj4 itself is unsuitable for routine
treatment, because of its very short half-life of « 3 minutes in
man after intravenous injection due to rapid enzymatic
degradation and because of its diversity of action, such
as lowering insulin levels. Successful efforts have been
undertaken to synthesise somatostatin analogues that
are more resistant to enzymatic degradation.
Introduction of D-amino acids and shortening of the molecule
to the bioactive core sequence resulted in the eight
amino acids-containing somatostatin-analogue
octreotide (Figure 1).
Somatostatin receptors are structurally related
integral membrane glycoproteins. Recently, five different
human somatostatin receptor types have been cloned.
All subtypes bind SS!4 and SS2s (a polypeptide of 28
amino acids with SSi4 making up the C-terminus) with
high affinity, while the affinity of numerous somatostatin
analogues for the five different subtypes differs
]. Octreotide binds with high affinity to the
sst2 (human somatostatin receptor subtype 2), while this
analogue has a relatively low affinity for sst3 and sst5
and shows no binding to sstl and sst4 [
scintigraphy is, therefore, based on the visualisation of
(an) octreotide-binding somatostatin receptor(s), most
probably the sst2 and sst5.
Peptide receptor scintigraphy with the radioactive
somatostatin analogue, [mIn-DTPA°]octreotide (Figure 1),
is a sensitive and specific technique to show in vivo the
presence and abundance of somatostatin receptors on
various tumours. In general, mapping of the presence of
various peptide receptors on the cell membrane by
peptide receptor scintigraphy (PRS) may become an
attractive, non-invasive, harmless, easy-to-perform tool
for an individual therapeutic approach of the cancer
]. Also the detection of heterogeneous
metastases (with regard to the expression of different
peptide receptors or the accumulation of other
radiolabeled ligands) becomes possible if a combination of
radiolabeled peptides or of radiolabeled peptides with
other radioligands (all labelled with different
radionuclides) can be used. At the moment, examples of this
approach are the use of 1) octreotide and MIBG
scintigraphy in patients with metastasised pheochromocytoma
and 2) octreotide and radioiodine scintigraphy in
patients with metastasised differentiated thyroid cancer.
One of the therapeutic options for patients with
endocrine cancers is the use of non-radioactive peptides (or
antagonists) but application of radiolabeled peptides for
therapeutic use, possibly in combination with other
radiolabeled ligands (e.g., MIBG or radioiodine) may
become a new alternative or adjunct as well.
A new and fascinating application is the use of
radiolabeled peptides for PRRT. The success of the
therapeutic strategy relies upon the amount of radioligand, which
can be concentrated within tumour cells and the rates of
internalization, degradation and recycling of both ligand
and receptor will among other things determine this.
Binding of several peptide hormones to specific surface
receptors is generally followed by internalization of the
ligand receptor complex via invagination of the plasma
]. The resulting intracellular vesicles,
termed endosomes, rapidly acidify, which causes the
ligand to dissociate from the receptor. The ligand may
be delivered to the lysosome  and the receptor
recycles back to plasma membrane. The whole process
takes approximately 15 min [
], and a single receptor
can deliver numerous ligand molecules to the lysosomes.
We have studied internalization and degradation of
radiolabeled [DTPA°]octreotide in the somatostatin
receptor positive rat pancreatic tumour cell lines CA20948
and AR42J and in the somatostatin receptor negative
human anaplastic thyroid tumour cell line ARO. We
detected internalization of the radiopharmaceutical in
vitro, in accordance with the findings of Andersson et al.
], and found that this process was receptor specific
and temperature dependent [
internalization of [inIn-DTPA0]octreotide will most
probably result in degradation to "'in-DTPA-D-Phe,
this metabolite is not capable passing the lysosomal
For radiotherapeutic applications several
radionuclides have been proposed and investigated for coupling
to [DTPA°]octreotide. 90Y, a suitable (3-emitting
radionuclide, shows dissociation from this chelated peptide in
serum, '"in labelled [DTPA°]octreotide has an
appropriate distribution profile in humans for PRS and PRRT
]. nlIn emits Auger- and conversion-electrons and
can therefore be used to investigate its antiproliferative
effect in cancer.
Scintigraphy with [l"ln-DTPA°]octreotide
The efficacy of PRS with [ulIn-DTPA°]octreotide was
evaluated in a European multicenter trial (EMT) in 350
patients with a histologically or biochemically proven
GEP tumour [
]. Tumour sites were detected by
conventional imaging methods (CIM) in 88%, whereas
somatostatin receptor scintigraphy was positive in 80%. The
highest success rates of somatostatin receptor
scintigraphy were observed with glucagonomas (100%), vipomas
(88%), carcinoids (87%) and non-functioning islet cell
tumours (ICT; 82%). The low detection rate (46%) noted
for insulinomas is related to the lower incidence of sst2
somatostatin receptors on insulinoma cells. However,
the overall 80% sensitivity found is somewhat lower
than the 88% obtained at the Erasmus University
Rotterdam (EUR) in 130 patients with GEP tumours. This
may be related to important differences in scanning
procedures such as the amount of radioligand
administered (minimal dose of '"in of 200 MBq and at least 10
ug of peptide at EUR), the duration of the acquisition
and the use of single photon emission computed
tomography (SPECT, with a triple head camera at EUR). The
fact that abdominal SPECT was not systematically
performed in all patients of the EMT may explain that
only 73% of gastrinoma patients had a positive scan
compared to the 90%-100% sensitivity reported in other
studies. In the EMT, a total of 388 sites were visualized
with CIM in 308 out of the 350 patients. In addition to
297 known localisations, somatostatin receptor
scintigraphy revealed another 166 unsuspected lesions. Forty
percent of these unsuspected lesions were subsequently
confirmed as true positive findings based on the results
of additional imaging procedures or histology obtained
during the one-year follow-up period. The clinical
relevance of detecting additional tumour localizations is
very dependent on the clinical status of the patient. The
demonstration of an unsuspected lesion in a patient with
known metastatic spread usually has little impact on the
management. In contrast, the detection of unsuspected
tumour sites in patients with a single known lesion or
without any known lesion is important in that it may
affect the selection for curative surgery, which remains
the treatment of choice of patients with this type of
tumours. In the cohort of 350 patients studied, 42 had
no lesion detected by CIM and 178 were known to have
a single tumour localisation prior to the study.
Somatostatin receptor scintigraphy was positive in 11 of the 42
patients (25%) and 12 of 16 lesions revealed by
somatostatin receptor scintigraphy were further confirmed as
true positive. Somatostatin receptor scintigraphy
demonstrated multiple tumour sites in 62 of the 178 patients
(35%), 60% of these lesions were confirmed by follow-up
(one year) procedures. A reply to an impact questionnaire
was obtained for 235 patients. Overall, the scintigraphic
findings led to management changes in 40% of the 235
Gibril et al. compared in a prospective study the
sensitivity of somatostatin receptor scintigraphy with that
of CT, MRI, ultrasonography and selective angiography
in the detection of primary and metastatic gastrinomas
]. Their conclusion is that somatostatin receptor
scintigraphy is the single most sensitive method for imaging
either primary or metastatic liver lesions in patients with
Zollinger-Ellison syndrome. The same group studied
the effect of somatostatin receptor scintigraphy on
clinical management based on the data of this comparative
]. Since this technique altered management
of 47% of the patients, they concluded that somatostatin
receptor scintigraphy should be the initial imaging
modality for patients with gastrinomas, also because of
its superior sensitivity, high specificity, simplicity and
cost-effectiveness. Furthermore, "it is likely that the
conclusion drawn from this study can also be extended
to other pancreatic endocrine tumour syndromes except
After internalization of the radiopharmaceutical in
tumour cells, the radioactive ligand is close to the nucleus.
Since '"in emits not only gamma-rays, which are
visualized during PRS, but also short-ranged Auger-electrons,
an effect on tumour cell proliferation could be expected,
as the radiotoxicity of Auger electrons is very high if
their target, the DNA of the cell, is within the particle
We performed PRRT studies in rats using
['"in-DTPA0]octreotide. To investigate receptor dependence of the
therapeutic effects, we compared the effect of PRRT in
animals inoculated with the somatostatin receptor
positive CA20948 tumour cells in the portal vein of the liver
and the somatostatin receptor negative CC531 tumour
cells. Other groups of rats were co-injected with 1 mg
octreotide, to investigate the effect of excess unlabeled
peptide. All rats were sacrificed 21 days after inoculation
of tumour cells and tumour growth was determined by
counting the number of metastases on the surface of
the liver lobes.
The side-effects and antiproliferative effect of high,
multiple radiotherapeutic doses of [IMIn-DTPA0]octreotide,
using the Auger- and conversion-electrons emitted by
'"in, are being investigated in patients and reported
here preliminarily [
14, 15, 21
]. In this phase I study of
therapy with [lllIn-DTPA°]octreotide we included
endstage patients with mainly a high tumour load of
progressing neuroendocrine tumours.
Patients and methods
PTPA°]octreotide and mlnCl3 (DRN 4901, 370 MBq/ml in HC1, pH
= 1.5-1.9) were obtained from Mallinckrodt Medical BV (Petten, The
Netherlands). [DTPA°]octreotide was labelled with '"in as has been
described previously [
Rats in the experimental groups were injected with 370 MBq (0.5 ug)
[mIn-DTPA°]octreotide i.v. on day 1 and/or 8 after injection of
tumour cells into the portal vein. Tumour inoculated rats in the control
groups were injected with 0.5 ug unlabeled [DTPA°]octreotide i.v.
according to the same schedule.
Since 1995, the typical doses per administration are 6000-7000 MBq
'"in incorporated in 40-50 ug [DTPA°]octreotide within 24 hours
after production of '"in. It is given with at least two weeks intervals
between administrations and a total of eight administrations is aimed
at with extensions to 12-14 administrations. PRRT with
['"in-DTPA0]octreotide was applied after witnessed informed consent by the patient
and approval by the medical ethics committee of our hospital. The
following measurements, carried out prior to and between all
administrations, served as parameters of possible side-effects: the usual
hematological and chemical analyses of bone-marrow, liver, kidney
and endocrine pancreatic (glucose or Hb Alc) function. Pituitary
function (FreeT4, post-menopausal women: LH and FSH, men:
testosterone) was assessed prior to and four weeks after the 4th and 8th
administration of ["'ln-DTPA°]octreotide: at these time points also
possible effects on 1) the endocrine activity of the tumours and/or their
production of specific serum markers, and 2) tumour-size (CTor MR!)
were investigated. Pituitary-adrenal-axis function testing (metyrapone
test) prior to and after eight administrations as well as long-term
followup with three to four months' intervals was also investigated, if feasible.
Dosimetry of (l"ln-DTPA°|octreotide accumulation
Scoring of tumour radioactivity uptake in patients prior to the start of
treatment with ['"ln-DTPA°]octreotide was done visually by using
scintigrams obtained 24 hours after injection of a diagnostic dose (220
MBq) of ["'ln-DTPA°]octreotide. The scoring grades used were 4 =
intense, 3 = clear (higher than liver uptake), 2 = clear but faint (lower
than or equal to liver uptake), 1 = equivocal and 0 = no accumulation.
Patients were also scanned three and seven days after each
administration of the radiotherapeutical dose. Percentage uptake of the
administered dose in total body and in the most prominent tumour was
calculated (data not shown). Uptakes decreased slowly or remained the
same if the interval between the successive administrations was less
than one month. In patients who had 6 or more administrations of
6000 to 7000 MBq of ['"ln-DTPA°]octreotide with intervals of
maximally one month between administrations, uptake in the tumour was
still clearly visible after the last administration. Typical radiation doses
to tissues with administered doses of 6000-7000 MBq
['"in-DTPA0]octreotide are: kidneys 300 - 1400 (depending on the relative
biological effectiveness (RBE 1-20) for Auger electrons) cGy, spleen 200
cGy, liver 50 cGy, bone marrow 13 cGy (target organ for gamma
photons), thyroid gland 25 cGy and pituitary 70 cGy [
]. Thus the
critical organs are kidneys and spleen. With these administered doses
the estimated tumour radiation doses are for a 10 gram tumour
(assumptions: 1% uptake; effective half-life is equal to the physical
half-life) 1700 and 6700 cGy (RBE for Auger electrons 1 and 20,
respectively) and for a 100 gram tumour (1% uptake) 250 and 750
Pre >20 >50
CUMULATIVE DOSE (GBq) of
Pre >20 >50
CUMULATIVE DOSE (GBq) of
PRRT with administrations of 370 MBq
[U1ln-DTPA0]octreotide on day 1 and /or day 8 induced a significant
(p<0.01) decrease in the number of hepatic metastases Figure 2. Course of haemoglobulin and blood cells during peptide
21 days after intraportal injection of CA20948 pancre- r[e'"clnep-DtoTrPraAd°i]ooncutcreliodteidtere.aNtmisenntuwmibtherthoef ipnadtiiecnattesd( Mcum±uSlaEtMive).doses of
atic somatostatin receptor positive tumour cells. PRRT
in rats with somatostatin receptor-negative liver
metastases did not induce a difference in the number of liver Figure 2 shows the course of blood cells and platelets
tumour colonies. Furthermore, pre-treatment with 1 mg counts. PRRT with [luIn-DTPA°]octreotide may
(tranoctreotide, resulting in a saturation of somatostatin siently) effect the number of white blood cells and to an
receptors, led to a diminished therapeutic effect of even higher extent that of platelets.
PRRT. The results of these experiments indicate that the Renal function was monitored by measurements of
effect on tumour growth be due to specific binding of the serum creatinine and creatinine clearance (Figure 3). If
radiolabel to somatostatin receptors (manuscript sub- there is any effect on the kidney function it is of no
mitted for publication). clinical relevance so far. Remarkable is that the average
kidney function of the seven patients with creatinine
Clinical clearances between 21 and 80 ml/min prior to the start
Thirty end-stage patients with mainly neuroendocrine of PRRT did not significantly change after
administratumours have been treated with [mIn-DTPA0]octreotide tions of cumulative doses of 20 to 30 GBq (« = 4) and 50
in Rotterdam [
] and Brussels [
] (Table 1). Twenty-one to 60 GBq (« = 3) with a maximum follow up period of
out of these thirty patients received a total cumulative two years.
dose of at least 20 GBq [inIn-DTPA°]octreotide. Of the It is well known that the pituitary and pancreatic islet
nine patients treated with a total dose lower than 20 cells express somatostatin receptors. Endocrine
paramGBq, seven had to stop prematurely because of too eters of pituitary and pancreatic function during
treatprogressive disease despite the treatment with [mIn- ment cycles and follow up after treatment with
[inInDTPA°]octreotide and 2 did not conclude yet the first DTPA°]octreotide did not change either (data not
course of four administrations. The tumour uptake shown).
scores in the seven patients with very progressive disease Impressive, though in a number of patients
tempovaried between 2 (n = 3), 3 (n = 2) and 4 (w = 2). High, rary because of end-stage disease, effects on the clinical
multiple radiotherapeutic doses of ['"ln-DTPA0]octreo- condition of the patient and on hormone or tumour
tide were given to 21 patients up to total cumulative marker production (overall data not shown; Figure 4)
doses of 22 to 30 GBq and 12 patients 50 to 60 GBq per were observed after administration of multiple, high
patient. Three patients received maximum doses of doses of ['"in-DTPA^octreotide. Also,
anti-proliferaabout 75 GBq. No major side effects were noticed in the tive effects have been noticed (Figures 5 and 6). All
first treated patient after a cumulative dose of 25 GBq twenty-one patients who received a total cumulative
and a follow-up interval of two years, which is so far the dose of at least 20 GBq "'in-labelled
[DTPA°]octreolongest follow-up period. In the other patients no major tide, had progressive disease, i.e., unequivocal increase
clinical side effects were observed either. in tumour volume according to CT or MRI prior to the
start of ['"ln-DTPA0]octreotide therapy. In eight
patients this treatment resulted in stable disease and in
another six patients in actual tumour shrinkage. Thus,
six out of 21 patients with progressive disease, who
received an adequate dose of at least 20 GBq
[H1InDTPA°]octreotide, showed an antiproliferative effect.
So far, it can be concluded that a response to treatment
with ['"Tn-DTPA^octreotide, based on antiproliferative
•VOLUME — GLUCAGON •mln-Octreotlde -tgammaQT
8 10 12 2 4 6 S 10 12 2 4 6 8 9 11 1 3 5 7 9 12
90 | 91 | 92 | 93 94,
effects and a lowering of tumour markers in serum
and/or urine, has been obtained if 1) the cumulative
therapeutic dose of [luIn-DTPA°]octreotide was at least
about 20 GBq and 2) tumour uptake was at least grade 2
in order to get a stabilisation of disease and grade 3 or 4
for reduction in size of tumours (Table 1).
The observed responses to this PRRT are in agreement
with internalization of [luIn-DTPA°]octreotide into
tumour cells [because of the abundance of Auger and
conversion electrons with a (very) short particle range
or tissue penetration] and, with an antiproliferative effect
induced by these electrons. Since it is at present not
exactly known to what extent the radionuclide is
localised intracellularly after administration of high amounts
of [luIn-DTPA°]octreotide, measurements of the actual
radiation doses are not possible.
It is to be expected that the radiotherapeutic use of
radionuclides, such as 90Y, emitting the higher energies
of (3-particles, coupled to (small) DOTA-chelated
peptides, leads to higher radiation doses in a larger part
of the tumour, also because of their more
appropriate particle ranges or tissue penetration [
contrast to [90Y-DTPA°]octreotide, 90Y labelled to
[DOTA0,Tyr3]octreotide shows no dissociation from this
DOTA chelated peptide in serum. The first two PRRT
trials with [90Y-DOTA°,Tyr3]octreotide started recently
[26; Krenning, Kvols, Pauwels in Novartis B151 trial].
Based on the same assumptions as in section 3.1. and a
similar biodistribution ('"in and 90Y labelled peptide)
the estimated tumour radiation dose after an
administered dose of 3.7 GBq 90Y-labelled peptide will be 16.500
cGy (10 g, 1% uptake) and 1800 cGy (100 g, 1% uptake).
Estimated tissue doses are 2400 cGy for the kidneys, 150
cGy for the liver, and 1400 cGy for the spleen. Thus,
tumours with an inhomogeneous distribution of cells
expressing peptide receptors may then respond in a
favourable way to this kind of treatment because of the
A problem during PRRT may be caused by the high
uptake of 90Y-labelled peptide in the kidneys; small
peptides in the blood plasma are filtered through the
glomerular capillaries in the kidneys and subsequently
reabsorbed almost completely (^90%) by the proximal
tubular cells by carrier-mediated endocytosis. After the
subsequent degradation process that takes place in the
lysosomes of the tubular cells, their labeled degradation
products are 'trapped' in the lysosomes [
]. This will
cause a high dose of radioactivity in the kidneys, thereby
reducing the possibilities for PRRT. We showed that the
renal uptake of [niIn-DTPA°]octreotide in rats could be
reduced about 50% by single intravenous administration
of 400 mg/kg L- or D-lysine [
]. The membranes of
renal tubular cells contain negatively charged sites, to
which positively charged residues of peptides or proteins
are thought to bind . An inhibition of this binding
process may explain the effects by administration of
the positively charged amino acid lysine (both D- and
L-lysine) on lnIn-DTPA-octreotide re-uptake [
The high tissue penetration of 90Y localised in
tubular cells may affect the glomeruli and eventually induce a
glomerular fibrosis. Measures have to be taken in order
to decrease the renal accumulation of beta-emitting
peptides when used for PRRT, e.g., with lysine infusions
]. In this study, in which [mIn-DTPA°]octreotide
was used, no special precautions were taken to lower
In this phase I study of therapy with
[1HIn-DTPA0]octreotide we only included end-stage patients with
(neuroendocrine) tumours expressing a (rather) homogeneous
distribution of somatostatin receptors and preferably
high or modest accumulation of the radioligand. Based
on our results with [mIn-DTPA°]octreotide scintigraphy
and given a relatively high accumulation of the
radioligand in the tumour it is anticipated that patients with
the following tumours might be candidates for this kind
of treatment: most of (metastasised) GEP-tumours and
paragangliomas, and 30% and 40% of malignant
lymphomas and small-cell lung cancers, respectively.
E. P. Krenning, MD, PhD
Department of Nuclear Medicine
University Hospital Rotterdam
3015 G D Rotterdam
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