scispace - formally typeset
Search or ask a question
Journal ArticleDOI

Peptide receptor radionuclide therapy

TL;DR: A variety of other peptide-based radioligands, such as bombesin and NPY(Y(1)) analogues, receptors for which are expressed on common cancers such as prostate and breast cancer, are currently under development and in different phases of (pre)clinical investigation.
Abstract: Peptide receptor radionuclide therapy is a new treatment modality for patients with inoperable or metastasised neuroendocrine gastroenteropancreatic tumours. After the successful implementation of somatostatin receptor scintigraphy in daily clinical practice, the next logical step was to increase the radiation dose of the administered radiolabelled somatostatin analogue in an attempt to induce tumour shrinkage. Since then, an increasing number of patients has been successfully treated with this approach, resulting in a substantial numbers of patient with objective tumour shrinkage. Serious side-effects have been rare. This article reviews the effectiveness of the different radiolabelled somatostatin analogues used, the currently known side-effects and the survival data available. Furthermore, clinical issues, including indication and timing of therapy, are discussed. Finally, important directions for future research are briefly mentioned to illustrate that, although the currently available results already suggest a favourable outcome compared with other systemic therapies, new strategies are being developed to increase efficacy.

Summary (3 min read)

RADIONUCLIDES AND SOMATOSTATIN ANALOGUES IN PEPTIDE RECEPTOR RADIONUCLIDE THERAPY

  • Several radiolabelled somatostatin analogues are currently used to treat patients with SSTR-positive metastasised GEP tumours.
  • Radionuclides emitting b-radiation have greater therapeutic potential since the emitted particle range exceeds the cell diameter.
  • SSTR2 remains the receptor subtype for which [111In-DTPA0]octreotide has the highest affinity.
  • Radiolabelled somatostatin analogues that had a higher affinity for SSTR2 than did 111In-octreotide, and were therefore potentially more effective for therapy, thus became available.

CLINICAL STUDIES

  • The outcome of several phase I and phase II PRRT studies, in which different radiolabelled somatostatin analogues were used, has been published.
  • Patients with stable disease and minor remission (17 out of 26; 65%) were considered to have shown a beneficial therapeutic effect as all patients had documented progressive disease at study entry.
  • And as a consequence a decrease in the number of therapeutic injections, could be more beneficial, it must be stressed that this was not a randomised controlled trial and the number of treated patients was low.
  • The reported results of therapy in terms of complete and partial remission percentages, ranging up to 37% (Table 4), indicated an improvement in therapeutic effectiveness compared with the studies with 111In-labelled octreotide.
  • The effect of 177Lu-DOTATATE therapy on tumour size, uptake on post-therapy scintigraphy, liver enzymes and the tumour marker chromogranin A in a patient who showed partial remission is shown in Figure 2.

Comparison of the different treatments

  • Treatment with 90Y- and 177Lu-labelled somatostatin analogues is very encouraging in terms of tumour shrinkage.
  • Direct comparison to evaluate the optimal treatment remains difficult.
  • Differences in treatment protocol, such as administered doses, dosing schemes and the tumour response criteria used, can be responsible for the observed differences in treatment outcome.
  • Therefore, randomised controlled trials are necessary to define the optimal PRRT and treatment scheme.

SIDE-EFFECTS AND RADIATION TOXICITY

  • Adverse reactions observed after PRRT can be divided into direct side-effects and the more delayed effects of radiotoxicity.
  • Direct effects commonly mentioned during and after therapy are nausea, vomiting and abdominal pain.
  • In general, these sideeffects occur in a minority of patients and are easily treated with anti-emetics or pain medication.
  • Mild hair loss was observed in patients treated with 177Lu-DOTATATE, but hair growth had normalised at follow-up 3–6 months after the last administration.
  • 17 Beside these mild side-effects, more serious toxicity may occur, especially to the bone marrow, kidneys and liver.

Haematological toxicity

  • In general, the decrease in blood cell count was transient, and transfusion was only occasionally needed.
  • More serious side-effecs were reported from a clinical trial in which 50 patients were treated with 111In-octreotide.
  • The other two patients, who had had no previous cytotoxic therapy, developed myelodysplastic syndrome after more than 3 years.
  • In the report by Kwekkeboom et al,45 who studied the patients treated with 177Lu-DOTATATE as PRRT, one patient in the whole group of patients who had been treated or were being treated up to that time (201 patients, 637 administrations) developed myelodysplastic syndrome.

Renal toxicity

  • Chelated somatostatin analogues are cleared predominantly by the kidneys.
  • 49 Because of the rapid clearance, [111In-DTPA0]octreotide can be safely applied for diagnostic use without any damage to the kidneys.
  • Some years later, a case report of a patient who developed late-onset renal insufficiency with a total cumulative dose of less than 7.4 GBq/m2 indicated that even less radiation can cause renal damage at a later time point.
  • Two recent studies in which patients were treated with 90Y-DOTATOC provided more insight into individual kidney dosimetry and its importance in PRRT.
  • Preclinical studies have shown that the infusion of positively charged amino acids, mainly L-lysine and L-arginine, are able to reduce the tubular reabsorption of radiolabelled somatostatin analogues in rats.

Liver toxicity

  • Most patients treated with PRRT in the clinical trials studied had liver metastases.
  • It is therefore not unlikely that PRRT can induce hepatocellular radiation injury.
  • In the group of patients treated with 177Lu-DOTATATE, significantly increased liver function parameters (grade 4 liver toxicity) was evident in two patients after the first cycle of treatment (D.J. Kwekkeboom, personal communication, 2004).
  • One patient, who suffered from a rapidly growing neuroendocrine tumour with extensive liver involvement, clinically progressed to liver failure within 3 weeks and died shortly thereafter.
  • Gradually, the liver function parameters and hyperbilirubinaemia returned to pre-therapy levels.

CLINICAL PRACTICE

  • In patients with metastasised GEP tumours, for whom surgery is no longer an option, PRRT can be an effective alternative therapeutic modality with limited side-effects.
  • PRRT has not been widely recognised as alternative systemic therapy.
  • Indications for peptide receptor radionuclide therapy Candidates for PRRT are those patients with inoperable GEP tumours who have progressive disease or symptomatology that is difficult to manage with medication.
  • 10 High uptake during 111In-octreotide scintigraphy has been shown to be correlated with tumour regression after PRRT.17 Additionally, because of the radiation to the bone marrow and the risk of temporary bone marrow suppression, patients need to fulfil certain minimal haematological criteria.
  • Kidney function has to be determined before therapy to exclude patients with signs of impending renal failure (glomerular filtration rate !40 ml/minute).

Timing of therapy

  • There is currently no consensus about when to start PRRT in patients with GEP tumours.
  • In a recent report in which the relationship between delay of diagnosis, extent of disease and survival in 115 patients with carcinoid was studied, a mean delay in the diagnosis of 66 months was found.
  • Strikingly, the delay of the diagnosis did not correlate with the extent of the disease.
  • In the multicentre trial with 111In-octreotide,6 it was reported that PRRT for end-stage patients with a higher tumour burden was less likely to have a favourable outcome than for patients with lower tumour burden or in a better general condition.
  • The combined results suggest that patients may experience a clinical benefit from PRRT.

FUTURE DEVELOPMENTS

  • It might therefore be a promising analogue to be used for treatment of patients with tumours that not bear only SSTR2, but also express SSTR3 and/or SSTR5.
  • In vitro and in vivo studies show that the irradiation of neuroendocrine AR42J (rat pancreatic tumour) cells can upregulate the expression of SSTR2 and gastrin receptors.
  • Most research in PRRT is focused on the different SSTR subtypes.

SUMMARY

  • Using radiolabelled peptides, which bind with high affinity to specific receptors on cancer cells, it is possible to target the cancer efficiently.
  • In GEP tumours, radiolabelled somatostatin analogue therapy has been proven to be effective.
  • Dose-limiting organs are the bone marrow and the kidneys.
  • With the currently used maximum allowed dose, PRRT is relatively safe, and serious side-effects are rare.

Did you find this useful? Give us your feedback

Figures (8)

Content maybe subject to copyright    Report

8
Peptide receptor radionuclide therapy
Jaap J.M. Teunissen
*
MD
Dik J. Kwekkeboom
MD, PhD
Marion de Jong
PhD
Jan-Paul Esser
MD
Roelf Valkema
MD, PhD
Eric P. Krenning
MD, PhD
Professor and Head of the Department of Nuclear Medicine
Department of Nuclear Medicine, Erasmus MC,
Dr Molewaterplein 40, 3015 Rotterdam GD, The Netherlands
Peptide receptor radionuclide therapy is a new treatment modality for patients with inoperable or
metastasised neuroendocrine gastroenteropancreatic tumours. After the successful implementation
of somatostatin receptor scintigraphy in daily clinical practice, the next logical step was to increase
the radiation dose of the administered radiolabelled somatostatin analogue in an attempt to induce
tumour shrinkage. Since then, an increasing numberof patients has been successfully treated with this
approach, resulting in a substantial numbers of patient with objective tumour shrinkage. Serious side-
effects have been rare. This article reviews the effectiveness of the different radiolabelled
somatostatin analogues used, the currently known side-effects and the survival data available.
Furthermore, clinical issues, including indication and timing of therapy, are discussed. Finally,
important directions for future research are briefly mentioned to illustrate that, although the
currently available results already suggest a favourable outcome compared with other systemic
therapies, new strategies are being developed to increase efficacy.
Key words: neuroendocrine tumours; carcinoid tumour; somatostatin receptors; radiotherapy;
radionuclides.
Best Practice & Research Clinical Gastroenterology
Vol. 19, No. 4, pp. 595–616, 2005
doi:10.1016/j.bpg.2005.04.001
available online at http://www.sciencedirect.com
1521-6918/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved.
*
Corresponding author. Address: Department of Nuclear Medicine, Erasmus MC, Dr Molewaterplein 40,
3015 GD Rotterdam, The Netherlands. Tel.: C31 10 463 4889; Fax: C31 10 463 5997.
E-mail addresses: j.teunissen@erasmusmc.nl (J.J.M. Teunissen), d.j.kwekkeboom@erasmusmc.nl (D.
J. Kwekkeboom), m.hendriks-dejong@erasmusmc.nl (M. de Jong), j.esser@erasmusmc.nl (J.-P. Esser),
r.valkema@erasmusmc.nl (R. Valkema), e.p.krenning@erasmusmc.nl (E.P. Krenning).

Somatostatin receptor (SSTR) scintigraphy, which was developed in the late 1980s, has
become an important image modality in patients with SSTR-positive tumours.
1,2
This is
not only because of its high sensitivity for visualising somatostatin-positive tumours and
thereby its ability to localise otherwise undetectable disease, but also because of the
selection of known metastatic disease for peptide receptor radionuclide therapy
(PRRT) with radiolabelled somatostatin analogues. This new modality of targeted
therapy is very promising, especially in patients with inoperable or metastatic
gastroenteropancreatic (GEP) tumours (i.e. gastrointestinal carcinoids and functioning
and non-functioning pancreatic endocrine tumours).
RADIONUCLIDES AND SOMATOSTATIN ANALOGUES IN PEPTIDE
RECEPTOR RADIONUCLIDE THERAPY
Several radiolabelled somatostatin analogues are currently used to treat patients with
SSTR-positive metastasised GEP tumours. These conjugates all consist of a
somatostatin analogue, such as octreotide or octreotate, a complexing moiety (or
chelator) and a radionuclide. The chelator, which is attached to the somatostatin
analogue, allows a stable connection between the analogue and the radionuclide. The
basic principle of tumour-targeting after systemic administration of the conjugate
involves binding to SSTRs, which are expressed on the cell surface of the tumour cell,
followed by effective internalisation of the radionuclide-peptide complex.
3–5
The
emitted radiation can damage the DNA, which may subsequently lead to the induction
of cell death. In clinical practice, different combinations of radionuclides and
somatostatin analogues are used to target the SSTR-positive tumour. These analogues
differ from each other in their affinity for the various SSTR subtypes. This variable
affinity is important because it can have great influence on the clinical effectiveness of
the radiolabelled somatostatin analogue. The available radionuclides and somatostatin
analogues used will be discussed.
Radionuclides in peptide receptor radionuclide therapy
Indium (
111
In), yttrium (
90
Y) and lutetium (
177
Lu) have been the most frequently used
radionuclides for targeted radiotherapy in the various clinical trials over the past
decade. Differences in the physical properties of these radionuclides, which are
important for the effectiveness of the therapy, relate to, for example, emitted particles,
particle energy and tissue penetration range (Ta b l e 1 ).
111
In, coupled via the chelator
DTPA to D-Phe
1
-octreotide ([
111
In-DTPA
0
]octreotide;
111
In-octreotide), was used in
the first clinical trials in which patients with metastasised GEP tumours were
treated with radiolabelled somatostatin analogues.
6–8
Besides g-radiation, which makes
111
In a suitable radionuclide for imaging, it emits both Auger and conversion electrons
with a medium-to-short tissue penetration range (0.02–10 and 200–500 mm,
respectively). In vitro PRRT studies with [
111
In-DTPA
0
]octreotide showed that the
therapeutic effect was dependent on internalisation, which enables the Auger electrons
to reach the nucleus.
9
These results suggest that the Auger electrons and not the
conversion electrons can be held responsible for the reported tumour responses with
111
In-labelled somatostatin analogues.
In an attempt to increase the efficacy of PRRT, clinical trials that followed used
b-emitting radionuclides, such as
90
Yor
177
Lu. Radionuclides emitting b-radiation have
596 J. J. M. Teunissen et al

greater therapeutic potential since the emitted particle range exceeds the cell
diameter.
10–12
Furthermore, the ability to irradiate neighbouring cells is an advantage
with tumours, such as breast carcinomas, that are characterised by a heterogeneous
SSTR tissue distribution, with regions of high density next to regions that lack receptor
expression.
13
As expected, the clinical and preclinical studies in which
90
Y- o r
177
Lu-
coupled somatostatin analogues were used demonstrated more effectiveness in
terms of tumour shrinkage than was reported with somatostatin analogues coupled to
111
In.
14–17
O’Donoghue et al,
12
who used a mathematical model to examine tumour
curability and its relationship to tumour size for 22 b-emitting radionuclides, calculated
an optimal tumour diameter for cure of 34 and 2 mm for
90
Y and
177
Lu, respectively.
With respect to these calculations, the preclinical studies by de Jong et al,
14,18
in
which Lewis rats bearing SSTR-positive pancreatic CA20948 tumours of different
sizes (0.1–15 cm
2
) were treated with [
177
Lu-DOTA
0
,Tyr
3
]octreotate (
177
Lu-DOTA-
TATE) and [
90
Y-DOTA
0
,Tyr
3
]octreotide (
90
Y-DOTATOC) are of special interest.
After treatment with
177
Lu-DOTATATE (total cumulative dose 555 MBq, maximum
estimated tumour dose 60 Gy), a higher cure rate was observed in the group of rats
bearing small tumours (%1cm
2
) than in the rats bearing larger tumours (R1cm
2
,
mean approximately 5 cm
2
). In contrast, treatment with a single dose of 370 MBq
90
Y-DOTATOC, leading up to a maximum of 60 Gy in the medium-sized (3–9 cm
2
)
tumours, showed less cure within the group of rats bearing small (%1cm
2
) tumours
compared with the rats bearing medium-sized tumours (Figure 1).
19
These results
suggested that treatment with a combination of
90
Y- and
177
Lu-labelled somatostatin
analogues can be more effective in the treatment of multiple tumours that differ in size
than can one of the analogues separately. Recently, de Jong et al
20
reported the
results of such a combination versus single analogue therapy. In rats bearing both a small
(!0.5 cm
2
) and a large tumour (7–9 cm
2
), significantly better survival was observed
after PRRTwith the combination of 185 MBq (half-dose)
90
Y-DOTATOC and 278 MBq
(half-dose)
177
Lu-DOTATATE than after a single full dose of 370 MBq
90
Y-DOTATOC or
555 MBq
177
Lu-DOTATATE.
To translate these results to the clinical setting with patients with GEP tumours,
90
Y-labelled somatostatin analogues may be more effective in larger tumours, whereas
177
Lu-labelled somatostatin analogues may be more effective in smaller tumours, with
the combination of both radionuclides as the most suitable therapy for the clinical
Table 1. Physical characteristics of the radionuclides used in peptide receptor radionuclide therapy.
Radionuclides
Emitted
particle
Particle energy
(mean keV)
Maximum tissue penetration
range (approximate number
of cells
a
) Half-life (days)
Indium (
111
In) Auger
electrons
3 and 19 keV 10 mm(!1) 2.8
g-radiation 171 and
245 keV
Yttrium (
90
Y) b-radiation 935 keV 12 mm (approximately 600) 2.7
Lutetium (
177
Lu) b-radiation 130 keV 2 mm (approximately 100) 6.7
g-radiation 113 and
208 keV
a
Number of cells based on an average tumour cell size of 20 mm.
Peptide receptor radionuclide therapy 597

situation in which most patients have tumour metastases varying in size. Unfortunately,
randomised controlled clinical studies comparing the therapeutic efficacy of
90
Y and
177
Lu somatostatin analogues or combination-based regimens are still lacking.
Somatostatin analogues in peptide receptor radionuclide therapy
The various
111
In-,
90
Y- o r
177
Lu-labelled somatostatin analogues differ in their affinity
for the expressed SSTRs. Five human SSTR subtypes (SSTR1–SSTR5) that bind native
human somatostatin (SS14) and its high-affinity 28 amino acid precursor (SS28) have
been cloned.
21–23
However, their affinities for synthetic somatostatin analogues differ
considerably. The ‘cold’ analogue octreotide, which is frequently used to control
symptoms related to hormone overproduction by GEP tumours, binds with high affinity
to SSTR2 and with low affinity to SSTR3 and SSTR5, whereas it does not bind to SSTR1
and SSTR4.
24,25
Furthermore, autoradiography studies by Reubi et al
26
demonstrated
that, after labelling octreotide, via DTPA, with
111
In, the affinities to SSTR2 and SSTR5
were diminished (Ta bl e 2). However, despite the change in affinities, SSTR2
[
90
Y-DOTA
0
, Tyr
3
]octreotide
< 1 cm
2
3-9 cm
2
0
25
50
75
100
CR
PR
percentage (%)
[
177
Lu-DOTA
0
, Tyr
3
]octreotate
< 1 cm
2
> 1 cm
2
0
25
50
75
100
C
R
PR
percentage (%)
Figure 1. Cure rate (expressed as percentage of cured rats) found in groups of rats bearing CA20948
tumours of different indicated sizes after treatment with 370 MBq[
90
Y- D OTA
0
,Tyr
3
]octreotide or
555 MBq[
177
Lu-DOTA
0
,Tyr
3
]octreotate (maximum estimated tumour dose of 60 Gy for both treatments).
CR, complete response; PR, partial response. (Modified from de Jong et al.
14
).
598 J. J. M. Teunissen et al

remains the receptor subtype for which [
111
In-DTPA
0
]octreotide has the
highest affinity. Hofland et al
27
demonstrated that the uptake of [
111
In-DTPA
0
]octreo-
tide in the SSTR-positive organs of mice was predominantly determined by SSTR2.
Moreover, John et al
28
demonstrated that a positive [
111
In-DTPA
0
]octreotide
scintigram in patients with neuroendocrine tumours is mainly the result of
SSTR2 expression, whereas SSTR1, SSTR3, SSTR4 and probably SSTR5 are less
important.
Radiolabelled somatostatin analogues that had a higher affinity for SSTR2 than did
111
In-octreotide, and were therefore potentially more effective for therapy, thus
became available. Small structural changes in the radioligand molecule, for example a
different radionuclide, chelator or peptide, revealed distinct differences in the
binding properties of the analogue for the various SSTR subtypes (Table 2).
26
In
animal experiments, several
111
In-labelled somatostatin analogues showed a higher
specific uptake than
111
In-labelled [DTPA
0
]octreotide in SSTR-positive organs.
5
Furthermore, the analogue [DOTA
0
,Tyr
3
]octreotate has a ninefold higher affinity for
SSTR2 compared with [DOTA
0
,Tyr
3
]octreotide, whereas the affinities for SSTR3
and SSTR5 were found to be lower.
26
In line with the higher affinity for SSTR2,
biodistribution studies on
111
In-octreotide and
177
Lu-DOTATATE scintigraphy
showed a three- to fourfold higher tumour uptake in four out of five patients
with somatostatin-positive tumours, of whom three had GEP tumours.
29
As most
GEP tumours are known to predominantly express SSTR2, all clinical studies
selected a radiolabelled somatostatin analogue for PRRT with at least a high affinity
for SSTR2.
Table 2. Affinity profiles (IC
50
)
a
for human somatostatin receptors SSTR1–SSTR5 (hSSTR1–hSSTR5) of a
series of somatostatin analogues.
Peptides hSSTR1 hSSTR2 hSSTR3 hSSTR4 hSSTR5
Somatostatin-28 5.2G0.3 (19) 2.7G0.3 (19) 7.7G0.9 (19) 5.6G0.4 (19) 4.0G0.3 (19)
Octreotide O10,000 (5) 2.0G0.7 (5) 187G55 (3) O1,000 (5) 22G6 (5)
DTPA-octreotide O10,000 (6) 12G2 (5) 376G84 (5) O1,000 (5) 299G50 (6)
111
In-octreotide O10,000 (5) 22G3.6 (5) 182G13 (5) O1,000 (5) 237G52 (5)
DOTATOC O10,000 (7) 14G2.6 (6) 880G324 (4) O1,000 (6) 393G84 (6)
90
Y- DOTATOC O10,000 (4) 11G1.7 (6) 389G135 (5) O10,000 (5) 114G29 (5)
DOTALAN O10,000 (7) 26G3.4 (6) 771G229 (6) O10,000 (4) 73G12 (6)
90
Y-DOTALAN O10,000 (3) 23G5 (4) 290G105 (4) O10,000 (4) 16G3.4 (4)
DOTA-OC O10,000 (3) 14G3 (4) 27G9 (4) O1,000 (4) 103G39 (3)
90
Y-DOTA-OC O10,000 (5) 20G2 (5) 27G8 (4) O10,000 (4) 57G22 (4)
DTPA-Tyr
3
-
octreotate
O10,000 (4) 3.9G1 (4) O10,000 (4) O1,000 (4) O1,000 (4)
111
In-DTPA-Tyr
3
-
octreotate
O10,000 (3) 1.3G0.2 (3) O10,000 (3) 433G16 (3) O1,000 (3)
DOTA-Tyr
3
-
octreotate
O10,000 (3) 1.5G0.4 (3) O1,000 (3) 453G176 (3) 547G160 (3)
90
Y-DOTA-Tyr
3
-
octreotate
O10,000 (3) 1.6G0.4 (3) O1,000 (3) 523G239 (3) 187G50 (3)
Modified from Reubi et al.
26
a
All values are IC
50
GSEM in nM. The number of experiments is in parentheses.
Peptide receptor radionuclide therapy 599

Citations
More filters
Journal ArticleDOI
TL;DR: To improve outcome from GEP NETs, a better understanding of their biology is needed, with emphasis on molecular genetics and disease modeling, and more-reliable serum markers, better tumour localisation and identification of small lesions, and histological grading systems and classifications with prognostic application are needed.
Abstract: Gastroenteropancreatic (GEP) neuroendocrine tumours (NETs) are fairly rare neoplasms that present many clinical challenges. They secrete peptides and neuroamines that cause distinct clinical syndromes, including carcinoid syndrome. However, many are clinically silent until late presentation with mass effects. Investigation and management should be highly individualised for a patient, taking into consideration the likely natural history of the tumour and general health of the patient. Management strategies include surgery for cure (which is achieved rarely) or for cytoreduction, radiological intervention (by chemoembolisation and radiofrequency ablation), chemotherapy, and somatostatin analogues to control symptoms that result from release of peptides and neuroamines. New biological agents and somatostatin-tagged radionuclides are under investigation. The complexity, heterogeneity, and rarity of GEP NETs have contributed to a paucity of relevant randomised trials and little or no survival increase over the past 30 years. To improve outcome from GEP NETs, a better understanding of their biology is needed, with emphasis on molecular genetics and disease modeling. More-reliable serum markers, better tumour localisation and identification of small lesions, and histological grading systems and classifications with prognostic application are needed. Comparison between treatments is currently very difficult. Progress is unlikely to occur without development of centers of excellence, with dedicated combined clinical teams to coordinate multicentre studies, maintain clinical and tissue databases, and refine molecularly targeted therapeutics.

1,494 citations

Journal ArticleDOI
TL;DR: The two most common functional p-NETs (gastrinomas, insulinomas) are considered separately, whereas the other well-described and possible rarefunctional p- NETs are considered together as a group called rare functional rFTs (RFTs).
Abstract: Pancreatic endocrine tumors (p-NETs) include both pancreatic neuroendocrine tumors (p-NETs) associated with a functional syndrome (functional p-NETs) or those associated with no distinct clinical syndrome (non-functional p-NETs) [1,2,3,4]. Non-functional p-NETs frequently secrete pancreatic polypeptide, chromogranin A, neuron-specific enolase, human chorionic gonadotrophin subunits, calcitonin, neurotensin or other peptides, but they do not usually produce specific symptoms and thus are considered clinically to be non-functional tumors [2,3,5,6,7]. Only the functional p-NETs will be considered in this section. The two most common functional p-NETs (gastrinomas, insulinomas) are considered separately, whereas the other well-described and possible rare functional p-NETs are considered together as a group called rare functional p-NETs (RFTs) (table ​(table1)1) [1,2,3,4]. Table 1 Functional pancreatic endocrine tumor (PET) syndromes Gastrinomas are neuroendocrine neoplasms, usually located in the duodenum or pancreas, that secrete gastrin and cause a clinical syndrome known as Zollinger-Ellison syndrome (ZES). ZES is characterized by gastric acid hypersecretion resulting in severe peptic disease (peptic ulcer disease (PUD), gastroesophageal reflux disease (GERD)) [8,9,10]. In this section, ZES due to both duodenal and pancreatic gastrinomas will be covered together because clinically they are similar [8,10]. Specific points related to gastrinomas associated with the genetic syndrome of Multiple Endocrine Neoplasia type 1 (MEN1) (25% of cases) will also be mentioned [11,12]. Insulinomas are neuroendocrine neoplasms located in the pancreas that secrete insulin, which causes a distinct syndrome characterized by symptoms due to hypoglycemia [2,13,14,15]. The symptoms are typically associated with fasting and the majority of patients have symptoms secondary to hypoglycemic central nervous system (CNS) effects (headaches, confusion, visual disturbances, etc.) or due to catecholamine excess secondary to hypoglycemia (sweating, tremor, palpitations, etc.) [2,3,13,14,15]. RFTs can occur in the pancreas or in other locations (VIPomas, somatostatinomas, GRHomas, ACTHomas, p-NETs causing carcinoid syndrome or hypercalcemia (PTHrp-omas)) (table ​(table1)1) [1,2,3,4,5,7]. Each of the established RFT syndromes is associated with a distinct clinical syndrome reflecting the actions of the ectopically secreted hormone. Other RFTs are listed as causing a possible specific syndrome either because there are too few cases or there is disagreement about whether the described features are actually a distinct syndrome (table ​(table1)1) [1,2,3,4,5,7].

502 citations

Journal ArticleDOI
01 Oct 2008-Cancer
TL;DR: The study of PETs in these uncommon disorders has provided valuable insights that, in many cases, are applicable to the general group of patients with sporadic PETs and the controversies that exist in their management are summarized briefly and discussed.
Abstract: Pancreatic endocrine tumors (PETs) can occur as part of 4 inherited disorders, including Multiple Endocrine Neoplasia type 1 (MEN1), von Hippel-Lindau disease (VHL), neurofibromatosis 1 (NF-1) (von Recklinghausen disease), and the tuberous sclerosis complex (TSC). The relative frequency with which patients who have these disorders develop PETs is MEN1>VHL>NF-1>TSC. Over the last few years, there have been major advances in the understanding of the genetics and molecular pathogenesis of these disorders as well in the localization and the medical and surgical treatment of PETs in such patients. The study of PETs in these disorders not only has provided insights into the possible pathogenesis of sporadic PETs but also has presented several unique management and treatment issues, some of which are applicable to patients with sporadic PETs. Therefore, the study of PETs in these uncommon disorders has provided valuable insights that, in many cases, are applicable to the general group of patients with sporadic PETs. In this article, these areas are reviewed briefly along with the current state of knowledge of the PETs in these disorders, and the controversies that exist in their management are summarized briefly and discussed.

422 citations


Cites methods from "Peptide receptor radionuclide thera..."

  • ...are similar to those used in patients with malignant sporadic PETs and have been covered in several recent reviews.(8,18,154,291-295)...

    [...]

Journal ArticleDOI
TL;DR: The utility of chromogranin A (CgA) measurement in the diagnosis of neuroendocrine tumors has been discussed in this paper, where the utility of CgA measurement is discussed.
Abstract: Neuroendocrine tumors (NETs) are a form of cancer that differ from other neoplasia in that they synthesize, store, and secrete peptides, e.g., chromogranin A (CgA) and amines. A critical issue is late diagnosis due to failure to identify symptoms or to establish the biochemical diagnosis. We review here the utility of CgA measurement in NETs and describe its biological role and the clinical value of its measurement. Literature review and analysis of the utility of plasma/serum CgA measurements in NETs and other diseases. CgA is a member of the chromogranin family; its transcription and peptide processing are well characterized, but its precise function remains unknown. Levels are detectable in the circulation but vary substantially (~25%) depending on which assay is used. Serum and plasma measurements are concordant. CgA is elevated in ~90% of gut NETs and correlates with tumor burden and recurrence. Highest values are noted in ileal NETs and gastrointestinal NETs associated with multiple endocrine neoplasia type 1. Both functioning and nonfunctioning pancreatic NETs have elevated values. CgA is more frequently elevated in well-differentiated tumors compared to poorly differentiated NETs. Effective treatment is often associated with decrease in CgA levels. Proton pump inhibitors falsely increase CgA, but levels normalize with therapy cessation. CgA is currently the best available biomarker for the diagnosis of NETs. It is critical to establish diagnosis and has some utility in predicting disease recurrence, outcome, and efficacy of therapy. Measurement of plasma CgA is mandatory for the effective diagnosis and management of NET disease.

307 citations

Journal ArticleDOI
TL;DR: Key recommendations include the evaluation of pancreatic NET separately from NETs of other sites and the exclusion of patients with poorly differentiated histologies from trials focused on low-grade histologies.
Abstract: Neuroendocrine tumors (NETs) arise from a variety of anatomic sites and share the capacity for production of hormones and vasoactive peptides. Because of their perceived rarity, NETs have not historically been a focus of rigorous clinical research. However, the diagnosed incidence of NETs has been increasing, and the estimated prevalence in the United States exceeds 100,000 individuals. The recent completion of several phase III studies, including those evaluating octreotide, sunitinib, and everolimus, has demonstrated that rigorous evaluation of novel agents in this disease is both feasible and can lead to practice-changing outcomes. The NET Task Force of the National Cancer Institute GI Steering Committee convened a clinical trials planning meeting to identify key unmet needs, develop appropriate study end points, standardize clinical trial inclusion criteria, and formulate priorities for future NET studies for the US cooperative group program. Emphasis was placed on the development of well-designed clinical trials with clearly defined efficacy criteria. Key recommendations include the evaluation of pancreatic NET separately from NETs of other sites and the exclusion of patients with poorly differentiated histologies from trials focused on low-grade histologies. Studies evaluating novel agents for the control of hormonal syndromes should avoid somatostatin analog washout periods when possible and should include quality-of-life end points. Because of the observed long survival after progression of many patients, progression-free survival is recommended as a feasible and relevant primary end point for both phase III studies and phase II studies where a delay in progression is expected in the absence of radiologic responses.

291 citations

References
More filters
Journal ArticleDOI
TL;DR: The updated information on tolerance of normal tissues of concern in the protocols of this contract, based on available data, is presented, with a special emphasis on partial volume effects.
Abstract: The importance of knowledge on tolerance of normal tissue organs to irradiation by radiation oncologists cannot be overemphasized. Unfortunately, current knowledge is less than adequate. With the increasing use of 3-D treatment planning and dose delivery, this issue, particularly volumetric information, will become even more critical. As a part of the NCI contract N01 CM-47316, a task force, chaired by the primary author, was formed and an extensive literature search was carried out to address this issue. In this issue. In this manuscript we present the updated information on tolerance of normal tissues of concern in the protocols of this contract, based on available data, with a special emphasis on partial volume effects. Due to a lack of precise and comprehensive data base, opinions and experience of the clinicians from four universities involved in the contract have also been contributory. Obviously, this is not and cannot be a comprehensive work, which is beyond the scope of this contract.

4,133 citations

Journal ArticleDOI
TL;DR: The successful application of radiolabelled octreotide in scintigraphy indicates the possible usefulness of other radiolABelled peptides, either native peptides or derivatives of these, in, for example, nuclear oncology.
Abstract: Various tumours, classically specified as either neuroendocrine or non-neuroendocrine, contain high numbers of somatostatin receptors, which enable in vivo localization of the primary tumour and its metastases by scintigraphy with the radiolabelled somatostatin analogue octreotide. In addition granulomas and autoimmune processes can be visualized because of local accumulation of somatostatin receptor-positive activated mononuclear leucocytes. In many instances a positive scintigram predicts a favourable response to treatment with octreotide. It is tempting to speculate that octreotide labelled with an appropriate radionuclide might be used in cancer therapy. The successful application of radiolabelled octreotide in scintigraphy indicates the possible usefulness of other radiolabelled peptides, either native peptides or derivatives of these, in, for example, nuclear oncology. The small size of these peptides, e.g. bombesin and substance P, is of the utmost importance for a relatively fast blood clearance, thus leading to low background radioactivity. In this way peptides are powerful alternatives to (fragments of) monoclonal antibodies, the application of which to scintigraphic localization of specific cell surface antigen-bearing tumours is plagued by slow blood clearance and, hence, high background levels.

1,498 citations

Journal ArticleDOI
TL;DR: In vivo somatostatin receptor scintigraphy using Octreoscan is a valuable method for the visualisation of human endocrine tumours and their metastases and small structural modifications, chelator substitution or metal replacement were shown to considerably affect the binding affinity.
Abstract: In vivo somatostatin receptor scintigraphy using Octreoscan is a valuable method for the visualisation of human endocrine tumours and their metastases. Recently, several new, alternative somatostatin radioligands have been synthesised for diagnostic and radiotherapeutic use in vivo. Since human tumours are known to express various somatostatin receptor subtypes, it is mandatory to assess the receptor subtype affinity profile of such somatostatin radiotracers. Using cell lines transfected with somatostatin receptor subtypes sst1, sst2, sst3, sst4 and sst5, we have evaluated the in vitro binding characteristics of labelled (indium, yttrium, gallium) and unlabelled DOTA-[Tyr3]-octreotide, DOTA-octreotide, DOTA-lanreotide, DOTA-vapreotide, DTPA-[Tyr3]-octreotate and DOTA-[Tyr3]-octreotate. Small structural modifications, chelator substitution or metal replacement were shown to considerably affect the binding affinity. A marked improvement of sst2 affinity was found for Ga-DOTA-[Tyr3]-octreotide (IC50 2.5 nM) compared with the Y-labelled compound and Octreoscan. An excellent binding affinity for sst2 in the same range was also found for In-DTPA-[Tyr3]-octreotate (IC50 1.3 nM) and for Y-DOTA-[Tyr3]-octreotate (IC50 1.6 nM). Remarkably, Ga-DOTA-[Tyr3]-octreotate bound at sst2 with a considerably higher affinity (IC50 0.2 nM). An up to 30-fold improvement in sst3 affinity was observed for unlabelled or Y-labelled DOTA-octreotide compared with their Tyr3-containing analogue, suggesting that replacement of Tyr3 by Phe is crucial for high sst3 affinity. Substitution in the octreotide molecule of the DTPA by DOTA improved the sst3 binding affinity 14-fold. Whereas Y-DOTA-lanreotide had only low affinity for sst3 and sst4, it had the highest affinity for sst5 among the tested compounds (IC50 16 nM). Increased binding affinity for sst3 and sst5 was observed for DOTA-[Tyr3]-octreotide, DOTA-lanreotide and DOTA-vapreotide when they were labelled with yttrium. These marked changes in subtype affinity profiles are due not only to the different chemical structures but also to the different charges and hydrophilicity of these compounds. Interestingly, even the coordination geometry of the radiometal complex remote from the pharmacophoric amino acids has a significant influence on affinity profiles as shown with Y-DOTA versus Ga-DOTA in either [Tyr3]-octreotide or [Tyr3]-octreotate. Such changes in sst affinity profiles must be identified in newly designed radiotracers used for somatostatin receptor scintigraphy in order to correctly interpret in vivo scintigraphic data. These observations may represent basic principles relevant to the development of other peptide radioligands.

1,022 citations

Journal ArticleDOI
TL;DR: The cloning, functional expression, and tissue distribution of two different somatostatin receptors (SSTRs) are reported, showing that SSTR1 and SSTR2 are expressed at highest levels in jejunum and stomach and in cerebrum and kidney, respectively.
Abstract: Somatostatin is a tetradecapeptide that is widely distributed in the body. It acts on multiple organs including brain, pituitary, gut, exocrine and endocrine pancreas, adrenals, thyroid, and kidneys to inhibit release of many hormones and other secretory proteins. In addition, it functions as a neuropeptide affecting the electrical activity of neurons. Somatostatin exerts its biological effects by binding to specific high-affinity receptors, which appear in many cases to be coupled to GTP-binding proteins. Here we report the cloning, functional expression, and tissue distribution of two different somatostatin receptors (SSTRs). SSTR1 and SSTR2 contain 391 and 369 amino acids, respectively, and are members of the superfamily of receptors having seven transmembrane segments. There is 46% identity and 70% similarity between the amino acid sequences of SSTR1 and SSTR2. Stably transfected Chinese hamster ovary cells expressing SSTR1 or SSTR2 exhibit specific somatostatin binding, with an apparently higher affinity for somatostatin-14 than somatostatin-28, and NH2-terminally extended form of somatostatin-14. RNA blotting studies show that SSTR1 and SSTR2 are expressed at highest levels in jejunum and stomach and in cerebrum and kidney, respectively. A SSTR1 probe hybridized to multiple DNA fragments in EcoRI digests of human and mouse DNA, indicating that SSTR1 and SSTR2 are members of a larger family of somatostatin receptors. Thus, the biological effects of somatostatin are mediated by a family of receptors that are expressed in a tissue-specific manner.

768 citations

Journal ArticleDOI
TL;DR: Treatment with 177Lu-octreotate results in tumor remission in a high percentage of patients with GEP tumors, and results are better in patients with a limited tumor load.
Abstract: Purpose There are few treatment options for patients with metastasized or inoperable endocrine gastroenteropancreatic (GEP) tumors. Chemotherapy can be effective, but the response is usually less than 1 year. Here, we present the results of treatment with a radiolabeled somatostatin analog, [177Lu-DOTA0,Tyr3]octreotate (177Lu-octreotate). Patients and Methods One hundred thirty-one patients with somatostatin receptor-positive tumors were treated with up to a cumulative dose of 600 to 800 mCi (22.2 to 29.6 GBq) of 177Lu-octreotate. Results One patient developed renal insufficiency, and another patient developed hepatorenal syndrome. Creatinine clearance did not change significantly in the other patients. WHO hematologic toxicity grade 3 or 4 occurred after less than 2% of the administrations. We observed complete remission in three patients (2%), partial remission in 32 patients (26%), minor response (tumor diameter decrease of 25% to 50%) in 24 patients (19%), stable disease (SD) in 44 patients (35%), and...

621 citations

Related Papers (5)
Frequently Asked Questions (2)
Q1. What have the authors contributed in "Peptide receptor radionuclide therapy" ?

This article reviews the effectiveness of the different radiolabelled somatostatin analogues used, the currently known side-effects and the survival data available. Furthermore, clinical issues, including indication and timing of therapy, are discussed. Finally, important directions for future research are briefly mentioned to illustrate that, although the currently available results already suggest a favourable outcome compared with other systemic therapies, new strategies are being developed to increase efficacy. 

A direction of future research to improve current PRRT for GEP tumours includes the development of new stable somatostatin analogues with a high affinity for the different SSTR subtypes. 69 The concomitant expression of these receptors could be used in the future in a multireceptor PRRT to target more efficiently GEP tumours in each patient individually. 70 Although the patients were treated with external radiotherapy, gemcitabine and other radiosensitising agents with concurrent PRRT might prove effective in the future. It might therefore be a promising analogue to be used for treatment of patients with tumours that not bear only SSTR2, but also express SSTR3 and/or SSTR5.