imaging and treatmen

SUPPLEMENT PAPEREndocrine-Related Cancer (2011) 18 S27–S51

Nuclear medicine techniques for thet of neuroendocrine

tumours

Jaap J M Teunissen1, Dik J Kwekkeboom1, R Valkema1 and Eric P Krenning1,2

Departments of 1Nuclear Medicine and 2Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands

(Correspondence should be addressed to J J M Teunissen; Email: j.teunissen@erasmusmc.nl)

Abstract

Nuclear medicine plays a pivotal role in the imaging and treatment of neuroendocrine tumours(NETs). Somatostatin receptor scintigraphy (SRS) with [111In-DTPA0]octreotide has proven itsrole in the diagnosis and staging of gastroenteropancreatic NETs (GEP-NETs). New techniques insomatostatin receptor imaging include the use of different radiolabelled somatostatin analogueswith higher affinity and different affinity profiles to the somatostatin receptor subtypes. Most ofthese analogues can also be labelled with positron-emitting radionuclides that are being used inpositron emission tomography imaging. The latter imaging modality, especially in the combinationwith computed tomography, is of interest because of encouraging results in terms of improvedimaging quality and detection capabilities. Considerable advances have beenmade in the imagingof NETs, but to find the ideal imaging method with increased sensitivity and better topographiclocalisation of the primary and metastatic disease remains the ultimate goal of research. Thisreview provides an overview of the currently used imaging modalities and ongoing developmentsin the imaging of NETs, with the emphasis on nuclear medicine and puts them in perspective ofclinical practice. The advantage of SRS over other imaging modalities in GEP-NETs is that it canbe used to select patients with sufficient uptake for treatment with radiolabelled somatostatinanalogues. Peptide receptor radionuclide therapy (PRRT) is a promising new tool in themanagement of patients with inoperable or metastasised NETs as it can induce symptomaticimprovement with all Indium-111, Yttrium-90 or Lutetium-177-labelled somatostatin analogues.The results that were obtained with [90Y-DOTA0,Tyr3]octreotide and [177Lu-DOTA0,Tyr3]octreotate are even more encouraging in terms of objective tumour responses with tumourregression and documented prolonged time to progression. In the largest group of patientsreceiving PRRT, treated with [177Lu-DOTA0,Tyr3]octreotate, a survival benefit of several yearscompared with historical controls has been reported.

Endocrine-Related Cancer (2011) 18 S27–S51

Introduction

The first description of the in vivo visualisation of

somatostatin receptor-positive tumours in patients was

based on the use of a radioiodine (123I) labelled

somatostatin analogue (Krenning et al. 1989). In the

years that followed an Indium-111 (111In) labelled

This paper forms part of a special issue of Endocrine-Related

Cancer on neuroendocrine tumours. Novartis Pharmaceuticals

Corporation has supported the publication of this special issue.

Logistical support during development and submission of this

article was provided by Springer Healthcare LLC. This support

was funded by Novartis.

Endocrine-Related Cancer (2011) 18 S27–S51

1351–0088/11/018–S27 q 2011 Society for Endocrinology Printed in Great

somatostatin analogue, chelated with diethylenetria-

minepentaaceticacid (DTPA), was successfully

developed. Subsequently, [111In-DTPA0]octreotide

(OctreoScan, Covidien, Petten, The Netherlands),

was introduced worldwide and became commercially

available. Despite the development of several radio-

labelled somatostatin analogues for scintigraphy,

[111In-DTPA0]octreotide is the only registered radio-

pharmaceutical for somatostatin receptor scintigraphy

(SRS) of gastroenteropancreatic neuroendocrine

tumours (GEP-NETs).

In the last decade, with the increasing use of positron

emission tomography (PET) imaging, somatostatin

Britain

DOI: 10.1530/ERC-10-0282

Online version via http://www.endocrinology-journals.org

J J M Teunissen et al.: Imaging and treatment of NET

analogues have been labelled with various positron-

emitting isotopes, such as Gallium-68 (68Ga) and

Copper-64 (64Cu) (Lewis et al. 1999, Schottelius et al.

2004, Gabriel et al. 2007). Scintigraphy with these

investigational compounds display encouraging good

imaging quality that might result in an improved

sensitivity in tumour site detection compared with

[111In-DTPA0]octreotide scintigraphy. Also, other

PET radiopharmaceuticals were developed, such as18F-dihydroxy-phenyl-alanine (18F-DOPA) and 11C-

labelled 5-hydroxytryptophan (11C-5-HTP) with

encouraging results in terms of visualisation of GEP-

NETs (Koopmans et al. 2008).

After the successful introduction of SRS in the

diagnosis and staging of NETs, the next logical step

was to increase the administered activity so that the

radiopharmaceutical can induce tumour shrinkage in

patients who had inoperable and/or metastasised NETs.

Therefore, the first peptide receptor radionuclide

therapy (PRRT) was performed with high administered

activity of [111In-DTPA0]octreotide (Krenning et al.

1994a). However, besides encouraging results with

regard to symptom relief, the reported number of

objective responses was rather disappointing with

relative low number of patients with tumour shrinkage.

To make significant advancements in the treatment

of somatostatin receptor-positive metastatic disease,

more efficient radiolabelled somatostatin analogues

were developed with higher affinity to the somatostatin

receptor. Also, more stable conjugation with high-

energy b-emitters, such as Yttrium-90 (90Y) and

Lutetium-177 (177Lu), was made possible with the

introduction of the chelator 1,4,7,10-tetraazcyclodode-

cane-1,4,7,10-tetraacetic acid (DOTA). These

developments, together with the introduction of

protective measures to limit the radiation dose to the

kidneys and maximisation of the total cumulative

administered activity respecting the currently inter-

national accepted dose limit to the bone marrow, were

important to make PRRT a valuable therapeutic

modality in the complete arsenal of treatment options

in patients with encouraging results in terms of tumour

shrinkage, quality of life (QoL) and survival.

This review covers the whole spectrum of the imaging

of GEP-NETs with the emphasis on somatostatin

receptor imaging and summarises the results of the

therapeutic options within the field of nuclear medicine.

Imaging

To detect the exact location and subsequent staging

of GEP-NETs, which is crucial for further patient

management, a sensitive imaging modality is important.

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Commonly used imaging modalities include conven-

tional radiology (computed tomography (CT), mag-

netic resonance imaging (MRI) and transabdominal

ultrasonography (US)), selective angiography, nuclear

imaging techniques (e.g. somatostatin receptor

imaging) and endoscopic US (EUS). In most patients,

however, more than one modality is needed to gather

enough information to establish the exact localisation

of the often small biochemically active tumours.

Beside the increasing number of interesting new

modalities, modalities are combined to increase the

overall sensitivity and specificity.

Conventional imaging

The exact localisation of the primary tumour in

patients diagnosed with a GEP-NET, especially

gastrinomas and carcinoids of the small intestine, is

often difficult to establish. The detection frequency

with the conventional imaging modalities CT and

MRI in pancreatic NETs is about 22–45%, which is

higher than the reported sensitivity of abdominal US

(13–27%; Modlin et al. 2008). For endoscopic US the

percentages are mostly dependent on suspected tumour

localisation with detection of 45–60% of the duodenal

lesions and 90–100% of the pancreatic lesions

(Anderson et al. 2000).

As most NETs are already metastasised at diagnosis,

imaging of (liver) metastases is important. To visualise

these metastases the use of specific acquisition

protocols for CT and MRI is of vital importance.

Owing to variability of appearance it is recommended

to use a triple-phase (early/late arterial and portal

venous) CT and a multiphasic (arterial, portal venous

and delayed) dynamic and T2 weighted MRI protocol

(Sheth & Fishman 2002). Even when these protocols

are followed, the reported detection rate varies widely.

For identification of metastasised disease, reported

sensitivities of the modalities ranges from 60 to 80%

visualisation with CT, 55–70% for MRI and 14–63%

for US (Sugimoto et al. 1995, Gibril et al. 1996, Gibril

& Jensen 2004, Tamm et al. 2007).

Somatostatin receptor-based radionuclide

imaging

All somatostatin receptor-based radionuclide imaging is

based on the principle of the binding of a radiolabelled

ligand to the somatostatin receptor. Somatostatin

receptors, which are structurally related membrane

glycoproteins, are expressed in various normal tissues,

including central nervous system (CNS), anterior

pituitary, thyroid, pancreas, gastrointestinal tract, spleen

and adrenals (Kwekkeboom et al. 2009).

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Endocrine-Related Cancer (2011) 18 S27–S51

The first report of overexpression of somatostatin

receptors on tumour tissue was published in 1984.

(Reubi & Landolt 1984) High density of somatostatin

receptors on pituitary tumours in acromegaly patients

was demonstrated. Five different subtypes of somato-

statin receptors (sst1–sst5) are currently known and

characterised (Rohrer et al. 1993, Patel & Srikant

1994). However, the expression of the various subtypes

and their density on the tumour cell surface differs

among the various tumours. Reubi et al. (2001), who

used autoradiography to study the sstr subtype profile

of numerous human tumours, reported a predominance

of sst2 and/or somatostatin sst1 in GEP-NETs. The first

report of the in vivo imaging of these NETs expressing

somatostatin receptors with 123I-labelled [Tyr3]octreo-

tide was published in 1989 (Krenning et al. 1989).

However, an important drawback considering routine

use of this compound for scintigraphy was the

relatively high non-receptor-based uptake in the liver

and intestinal uptake, which both can obscure occult

pathology. Therefore, a radiolabelled somatostatin

analogue with better characteristics, [111In-DTPA0]oc-

treotide, was developed. Since then, [111In-DTPA0]oc-

treotide is regarded as the gold standard in nuclear

imaging for patients with GEP-NETs (Krenning et al.

1993). The somatostatin analogue octreotide binds

with high affinity to receptor subtypes 2 and 5. Several

authors demonstrated that a positive [111In-DTPA0]oc-

treotide scintigraphy is mainly due to the sst2, whereas

sst1–sst5 are less important. Therefore, the presence of

sst2 is essential for imaging tumours with SRS (John

et al. 1996, Hofland et al. 2003).

The use of an optimal protocol for [111In-DTPA0]

octreotide scintigraphy in the diagnosis of GEP-NETs

is important to ensure good image quality and per-

formance (Kwekkeboom et al. 2009). The preferred

administered activity of [111In-DTPA0]octreotide (with

at least 10 mg of the peptide) is about 200 MBq.

Besides planar imaging, single photon emission

computed tomography (SPECT) has to be included

because of the increased sensitivity compared with

planar imaging and should, be performed of the upper

abdomen, including the liver, and of other regions with

suspicion of disease. Also, besides increased sensi-

tivity, SPECT imaging allows better anatomical

delineation than planar views. If available, it is

recommended to use hybrid SPECT/CT imaging for

even better anatomical delineation. Timing and

sufficient counts per view are also important acqui-

sition characteristics. Any change in the protocol might

influence the quality and therewith the sensitivity of the

SRS performed. In more detail, these recommen-

dations are available as procedure guidelines for

www.endocrinology-journals.org

somatostatin receptor imaging, published by the

Society of Nuclear Medicine (SNM; Balon et al.

2001). Furthermore, the most important acquisition

protocol recommendations have also been adapted

by the European Association of Nuclear Medicine

(EANM) and European Neuroendocrine Tumour Society

(ENETS; Bombardieri et al. 2010, Kwekkeboom

et al. 2009).

Normal scintigraphic findings with SRS with

[111In-DTPA0]octreotide include visualisation of

thyroid, spleen, liver, kidneys and in a proportion of

patients the adrenals and/or pituitary gland. Also, the

urinary bladder and the bowel are usually visualised to

a variable degree (Krenning et al. 1992, Jacobsson

et al. 2003). The visualisation of the pituitary, thyroid,

adrenals and spleen is due to receptor binding. The

uptake in the kidneys is mainly due to reabsorption of

the radiolabelled somatostatin analogue in the renal

tubular cells after glomerular filtration. Clearance of

the radiopharmaceutical is primarily via the kidneys

and some clearance is via the hepatobiliary pathway.

Because of the latter, the use of laxatives and 48 h

scanning is sometimes necessary to differentiate

between non-specific bowel uptake and somatostatin

receptor-positive abdominal pathology. Also, because

of possible competition between cold octreotide and

radiolabelled octreotide at the receptor site, temporary

discontinuation of the therapeutic use of somatostatin

analogues is recommended before imaging; at least

24 h in case of short-acting somatostatin analogues

and 6 weeks when long-acting forms of somatostatin

analogues are used. Unwanted competition may

negatively affect the sensitivity for the detection of

somatostatin receptor-positive pathological lesions,

and therewith can results in false negatives.

Imaging results of [111In-DTPA0]octreotide

scintigraphy

The sensitivity of somatostatin receptor imaging with

[111In-DTPA0]octreotide scintigraphy for detecting

NETs, including NETs of the pancreas (functioning

and non-functioning) and carcinoids, has been well-

documented. The overall reported sensitivity is high

with 80% to almost 100% sensitivity for carcinoids and

60–90% for pancreatic NETs, mostly depending on

tumour type and lesion size (Krenning et al. 1993,

Kwekkeboom et al. 1993, Westlin et al. 1993, de

Kerviler et al. 1994, Kalkner et al. 1995, Gibril et al.

1996, Zimmer et al. 1996, Lebtahi et al. 1997,

Virgolini et al. 2005).

The sensitivity of histologically or biochemically

proven neuroendocrine pancreatic tumours or

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J J M Teunissen et al.: Imaging and treatment of NET

carcinoids was evaluated in a European multi-centre

trial (Krenning et al. 1995). The highest success rates

were observed with glucagonomas (100%), VIPomas

(88%), gastrinomas (72%), non-functioning islet cell

tumours (82%) and carcinoids (87%). These excellent

imaging characteristics have made [111In-DTPA0]oc-

treotide scintigraphy essential in the clinical work-up

of GEP-NETs.

In contrast, the sensitivity to detect insulinomas with

[111In-DTPA0]octreotide scintigraphy is lower than for

most GEP-NETs with a sensitivity of 20–60%

(Krenning et al. 1993, Schillaci et al. 2000, Vezzosi

et al. 2005, de Herder et al. 2006). The variability in

sensitivity may be caused by the low number of patients

included in each study and an inferior scanning

protocol, such as low administered activity or short

acquisition time (Schillaci et al. 2000). Furthermore, in

malignant insulinomas, the expression and density of

somatostatin receptor subtypes is different from benign

insulinomas so that a higher rate of scan positivity with

[111In-DTPA0]octreotide scintigraphy can be expected

in malignant insulinomas (Bertherat et al. 2003). Most

of the reported patients with malignant insulinoma who

had an [111In-DTPA0]octreotide scintigram, demon-

strated uptake in the primary and metastatic lesions

(Bokenkamp et al. 2003, Hirshberg et al. 2005, Vezzosi

et al. 2005, Baldelli et al. 2007). However, the reported

numbers of patients within these studies are to low

to establish a reliable sensitivity of [111In-DTPA0]

octreotide scintigraphy in malignant insulinoma.

Of interest for the detection of insulinomas is the

recently introduced 111In-labelled (Lys40(Ahx-DOTA)

NH2)exendin-4 (111In-DOTA-exendin-4) which

displays a high sensitivity for insulinomas. It targets

specifically the glucagon-like peptide 1 receptor

(GLP1R), which is expressed in very high density in

almost all insulinomas (Christ et al. 2009). Although

the results with this compound are promising, most of

the insulinomas are benign and localised (90%).

Therefore, the need for staging with GLP1R imaging

in the preoperative setting for benign insulinoma

is questionable. Also, because of the already proven

high sensitivity of endoscopic ultrasound (de Geus-Oei

et al. 2002) in these tumours (Zimmer et al. 1996), the

need for this new imaging modality in clinical practice

warrants further studies.

[111In-DTPA0]octreotide scintigraphy versus

conventional imaging

Conventional imaging (including abdominal CT,

US and MRI) if compared with the combination of

planar and SPECT SRS has a lower sensitivity in the

S30

detection of GEP-NETs (Schillaci 2004) However,

with the recently introduced improved techniques in

conventional imaging, such as multi-detector CT

imaging, new MRI sequences and EUS, the accuracy

of these modalities is increasing (Kaltsas et al. 2004).

Unfortunately, studies in which direct comparison of

these improved imaging techniques with SRS are

performed, are limited and the studied population often

small. In one series of ten gastrinoma and ten

insulinoma patients reported sensitivities (per-lesion-

based analysis) for EUS were 79%, 86% for SRS and

29% for the combined conventional imaging of CT, US

and MRI. In the insulinoma patients, eight benign and

two malign, the reported sensitivities were 93% with

EUS, 14% with SRS, 21% with CT and 7% with US

and MRI (Zimmer et al. 1996). In another study by

Gibril et al. (1996), 80 consecutive patients with the

Zollinger–Ellison syndrome had conventional tumour

localisations studies and SRS. SRS localised a primary

gastrinoma in 56% of patients and had greater

sensitivity than any conventional study including

angiography, and was equal in sensitivity to all

conventional imaging studies combined.

[111In-DTPA0]octreotide scintigraphy versus

other radiolabelled somatostatin receptor

analogues

After the successful introduction of [111In-DTPA0]

octreotide scintigraphy developments focused on

new analogues that would have a better affinity profile

with higher sensitivity or a wider somatostatin

receptor subtype affinity profile compared with

[111In-DTPA0]octreotide. Some of the newly

developed 111In-labelled somatostatin analogues use

the macrocyclic chelator DOTA instead of DTPA. The

most important advantage of the use of DOTA is the

stable conjugation with the b-emitting radionuclides

such as 90Y and 177Lu, which are used in PRRT.

DTPA-labelled counterparts are not stable enough

in vivo to be used in a therapeutical setting (de Jong

et al. 2002a). Therefore, in view of selecting patients

for PRRT with diagnostic scintigraphy, the use of the

same (DOTA conjugated) somatostatin analogue is

preferable. Examples of such analogues that are used

in clinical studies include [111In-DOTA]lanreotide

(Virgolini et al. 2002) and [111In-DOTA0]octreotide

(Kwekkeboom et al. 1999, Gabriel et al. 2007).

Furthermore, the somatostatin analogues [111In-DOTA

[1-NaI3]octreotide (111In-DOTANOC; Wild et al.

2003), [111In-DOTA[NaI8Thr8]octreotide (111In-

DOTANOCATE) and [111In-DOTA0,BzThi3,Thr8]

octreotide (111In-DOTABOCATE) demonstrated

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Table 1 111In- and 99mTc-radiolabelled somatostatin analogues compared with [111In-DTPA0]octreotide for scintigraphy

Radioligand (references) Setting

Comparison with

[111In-DTPA0]octreotide Other reported results Comments

[111In-DOTA0,Tyr3]octreotide

(Kwekkeboom

et al. 1999)

Clinical Yes; equal to [111In-DTPA0]

octreotide

Higher background

radioactivity

Scan protocol adequate

[111In-DOTA0,Tyr3]octreotide

(Gabriel et al. 2007)

Clinical Not performed Inferior to

[68Ga-DOTA0,Tyr3]

octreotide

[111In-DOTA]lanreotide

(Virgolini et al. 2002)

Clinical Not performed Inferior to [111In-DOTA0]

octreotide

[111In-DOTA[1-NaI3]

octreotide (Wild et al. 2003)

Preclinical Not performed High affinity to hsst2, 3

and 5

No clinical studies

published

[111In-DOTA[NaI8Thr8]

octreotide (Ginj et al. 2005)

Preclinical Not performed High affinity to hsst2, 3

and 5

No clinical studies

published

Superior to [111In-DOTA0]

octreotide

[111In-DOTA0,BzThi3,Thr8]

octreotide (Ginj et al. 2005)

Preclinical Not performed High affinity to hsst2, 3

and 5

No clinical studies

published

Superior to [111In-DOTA0]

octreotide99mTc-depreotide (Lebtahi

et al. 2002)

Clinical Yes; inferior to [111In-DTPA0]

octreotide

High lung and bone

marrow uptake

Both registered radio-

pharmaceuticals

Scan protocol adequate

[99mTc-EDDA/HYNIC0,Tyr3]

octreotate (Hubalewska-

Dydejczyk et al. 2006)

Clinical Yes; superior to [111In-DTPA0]

octreotide

No 24/48 h p.i. imaging

possible

Scan protocol inadequate

[99mTc-EDDA/HYNIC0,Tyr3]

octreotide (Gabriel et al.

2003)

Clinical Yes; superior to [111In-DTPA0]

octreotide

No 24/48 h p.i.

imaging possible

Scan protocol inadequate

[99mTc-EDDA/HYNIC0,Tyr3]

octreotide (Bangard et al.

2000)

Clinical Yes; equal to [111In-DTPA0]

octreotide: liver lesions

superior to [111In-DTPA0]

octreotide: extrahepatic

No 24/48 h p.i.

imaging possible

Scan protocol inadequate

NA, not applicable; hsst2, human somatostatin receptor subtype 2; p.i., post-injection.

Endocrine-Related Cancer (2011) 18 S27–S51

promising affinity profile characteristics (Table 1; Ginj

et al. 2005). [111In-DOTA]lanreotide is a somatostatin

receptor imaging agent with a slightly different affinity

profile than [111In-DTPA0]octreotide (Reubi et al.

2000). In comparison with [111In-DTPA0]octreotide,

it has a lower sensitivity to demonstrate NETs.

However, the use of [111In-DOTA]lanreotide may

have advantages in other tumours, for instance in

differentiated thyroid carcinoma (Virgolini et al.

2002). In a direct comparison with [111In-DTPA0]oc-

treotide, [111In-DOTA0,Tyr3]octreotide demonstrated

a distribution and excretion pattern that resembled that

of [111In-DTPA0]ctreotide. However, the interstitial

background was higher, which could be disadvanta-

geous in therapy, thereby exposing a higher absorbed

dose to the dose-limiting organs (Kwekkeboom

et al. 1999). Although 111In-DOTANOC, 111In-DO-

TATATE, 111In-DOTANOCATE and 111In-DOTA-

BOCATE are promising analogues in terms of

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biodistribution and receptor affinity profile, in vivo

human studies are scarce.

Besides the various 111In-labelled somatostatin

analogues, metastable Technetium-99 (99mTc) has

been coupled to somatostatin analogues for imaging.

The most important advantages of the use of 99mTc

compared with 99mTc-labelled based somatostatin

analogues includes no expense of producing 111In in

a cyclotron and no need to wait 24–48 h after injection

for optimal detection of tumours. 99mTc-labelled

somatostatin analogues used in a clinical setting

include [99mTc-EDDA–HYNIC-D-Phe1,Tyr3]octreo-

tide (99mTc-HYNIC-TOC; Gabriel et al. 2005, 2007),

[99mTc-EDDA/HYNIC0,Tyr3]octreotate (99mTc-HYNIC-

TATE; Hubalewska-Dydejczyk et al. 2006) and99mTc-Depreotide (Lebtahi et al. 2002). As

[111In-DTPA0]octreotide scintigraphy is regarded as

the gold standard in SRS, several of these new

somatostatin analogues have been compared with

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J J M Teunissen et al.: Imaging and treatment of NET

[111In-DTPA0]octreotide in patients with GEP-NETs

(Table 1). Most important advantages in imaging

characteristics compared with [111In-DTPA0]octreo-

tide reported, included superior imaging capabilities of

the extrahepatic lesions, increased sensitivity with

more and new metastases and better individual

separation. However, these results have to be inter-

preted with caution since most of these reported

comparisons did not use the imaging protocols for

[111In-DTPA0]octreotide scintigraphy according to

the international guidelines, including those from the

EANM, ENETS and SNM (Balon et al. 2001,

Kwekkeboom et al. 2009, Bombardieri et al. 2010).

Especially the scanning time and the amount of

radiopharmaceutical injected formulated in these

guidelines are important to obtain an adequate image

with good sensitivity.

In general, the studies with the new 99mTc-labelled

somatostatin analogues show feasibility for imaging.

However, [111In-DTPA0]octreotide scintigraphy,

despite minor disadvantages, still remains the imaging

method of choice in SRS.

Furthermore, these studies illustrate that comparison

between compounds in a clinical setting is difficult

to interpret even in a single centre. To follow the

international guidelines is essential not only to guarantee

optimal acquisition protocols leading to optimal imaging

and diagnostic assessment of the patient, but also in

conducting a valid comparative study.

Imaging results of metaiodobenzylguanidine

scintigraphy

Metaiodobenzylguanidine (MIBG) is an arkyl-guani-

dine derivative, structurally similar to noradrenaline,

which utilises the vesicular monoamine transporters

and is incorporated into vesicles or neurosecretory

granules in the cytoplasm of neureoendocrine cells

(Wafelman et al. 1994). However, it is not significantly

metabolised. MIBG shows little binding to post-

synaptic receptors and causes little or no pharma-

cological response (Sisson & Wieland 1986).123I radiolabelled MIBG has been used for many

years to visualise carcinoid tumours as it is concen-

trated in endocrine cells (Hoefnagel et al. 1987). The

use of radiolabelled MIBG was initially concentrated

on detecting tumours arising from chromaffin cells

such as phaeochromocytomas, paraganglioma and

neuroblastoma with overall reported high sensitivity

of w90% and specificity as high as 99% (Hoefnagel

et al. 1987, Shapiro 1995). Although with lower

sensitivity, MIBG scintigraphy was thereafter utilised

to detect NETs. MIBG scintigraphy in carcinoid

S32

tumours, including the diagnostic scintigraphy with131I-labelled MIBG, has shown lower sensitivity than

the more frequently used [111In-DTPA0]octreotide

scintigraphy. In a review of 10 years experience with

MIBG, including MIBG scintigraphy, a median

detection rate and sensitivity of 50 and 76%,

respectively, was reported (Modlin et al. 2006). In

contrast, the largest review, that included pooled

imaging data from 35 centres with in total more than

1200 patients with carcinoid tumours, [111In-DTPA0]

octreotide scintigraphy demonstrated a higher sensi-

tivity of 84% (57–93%; Modlin et al. 2005).

Furthermore, imaging with 123I-MIBG has a poor

sensitivity in identifying islet cell tumours (Kaltsas

et al. 2001a). Interestingly, within the few studies that

compared 123I-MIBG and [111In-DTPA0]octreotide

scintigraphy in carcinoid tumours, despite the in

general lower uptake of 123I-MIBG, a complementary

role of 123I-MIBG scintigraphy has been noted as either

a different intensity or a different pattern of uptake in

non-octreotide avid regions (Taal et al. 1996a, Kaltsas

et al. 2001a). In one report in which a direct

comparison between these two imaging modalities

was performed, comparable results with sensitivities of

about 84% were demonstrated, whereas the com-

bination of these scans increased the sensitivity to 95%

(Taal et al. 1996a).

Considering these two imaging modalities, it was

concluded that [111In-DTPA0]octreotide scintigraphy

is more sensitive in detecting metastatic lesions from

GEP-NETs than with 123I-MIBG scintigraphy, with the

latter imaging modality useful in the occasional patient

who has MIBG-avid lesions, which do not show up

with the initially performed [111In-DTPA0]octreotide

scintigraphy (Kaltsas et al. 2001b). Also, differential

uptake of 123I-MIBG and [111In-DTPA0]octreotide in

different metastases within one subject has been

reported and may be important in view of further

clinical management (Quigley et al. 2005).

Imaging results of PET

PET using 18F-fluorodeoxyglucose (18F-FDG) is a

powerful functional modality for oncological imaging,

especially in tumours with high proliferative activity

and low differentiation grade. Unfortunately, since

most GEP-NETs are well-differentiated, 18F-FDG is

not accumulated in GEP-NETs except in the case of

less differentiated tumours with high proliferative

activity (Adams et al. 1998). Therefore, in general, it

is not used as the initial imaging modality in the early

diagnostic phase. However, a recently published study

reported a negative correlation of 18F-FDG uptake and

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Endocrine-Related Cancer (2011) 18 S27–S51

the prognosis of the disease (Binderup et al. 2010a).

Furthermore, in a recent study by the same group, the

combination of [111In-DTPA0]octreotide scintigraphy

and 18F-FDG PET yielded an overall sensitivity of 96%

compared with 89% with [111In-DTPA0]octreotide

scintigraphy alone, indicating that 18F-FDG PET

provides complementary diagnostic information

(Binderup et al. 2010b). 18F-FDG PET was especially

of value in GEP-NET patients with negative

[111In-DTPA0]octreotide scintigraphy or a high

proliferation index (Ki-67O15%). Also, in pathology

proven NETs that do not visualise on somatostatin

receptor imaging, it is recommended to perform

FDG-PET in staging, since these tumours show often

more aggressive behaviour and faster growth. (Belho-

cine et al. 2002).

Other PET radiopharmaceuticals are also used to

visualise these relatively slow growing tumours. In line

with the commonly used [111In-DTPA0]octreotide

scintigraphy, somatostatin analogues labelled with a

positron-emitting radionuclide are the most obvious

radiopharmaceuticals to use for imaging.

Currently, several 68Ga labelled somatostatin

analogues have been evaluated. 68Ga is a generator-

produced radionuclide that can be chelated with DOTA

to form a stable complex with somatostatin analogues.

[68Ga-DOTA0,Tyr3]octreotide (68Ga-DOTATOC) was

the first 68Ga-labelled somatostatin analogue that was

studied in patients. The results were promising

(Hofmann et al. 2001, Maecke et al. 2005, Gabriel

et al. 2007). Consequently, other clinically applicable68Ga-labelled somatostatin analogues were developed

to increase their sensitivity or widen their affinity

profile, including 68Ga-DOTANOC (Wild et al. 2005,

Ambrosini et al. 2008, Fanti et al. 2008, Krausz et al.

Table 2 Results of 68Ga labelled positron emission tomography liga

Radioligand (references) Compared with

[68Ga-DOTA0,Tyr3]octreotide

(Hofmann et al. 2001)

[111In-DTPA0]octreotide

[68Ga-DOTA0,Tyr3]octreotide

(Buchmann et al. 2007)

[111In-DTPA0]octreotide

[68Ga-DOTA,1-nal3]octreotide

(Fanti et al. 2008)

CT

[68Ga-DOTA,1-nal3]octreotide

(Ambrosini et al. 2008)

18F-DOPA

[68Ga-DOTA,1-nal3]octreotide

(Wild et al. 2005)

[111In-DOTA0]octreotide

[68Ga-DOTA0,Tyr3]octreotate

(Kayani et al. 2008)

18F-FDG

[68Ga-DOTA,1-nal3]octreotide

(Krausz et al. 2010)

[111In-DTPA0]octreotide

www.endocrinology-journals.org

2010) and [68Ga-DOTA0,Tyr3]octreotate (68Ga-

DOTATATE; Kayani et al. 2008).

All these positron-emitting radionuclide labelled

somatostatin analogues share the excellent image

quality with better spatial resolution compared with

the imaging with the g-emitting analogues. Compari-

son of 68Ga-labelled somatostatin analogues with

[111In-DTPA0]octreotide scintigraphy and other

imaging modalities has been performed in several

studies (Table 2; Hofmann et al. 2001, Buchmann et al.

2007, Ambrosini et al. 2008, Fanti et al. 2008, Krausz

et al. 2010). Unfortunately, however, inadequate

protocols for [111In-DTPA0]octreotide scintigraphy

were used in many studies and therefore the

comparison often inappropriate.

In clinical practice, PET imaging with the 68Ga-

labelled somatostatin analogues has some more

advantages compared with [111In-DTPA0]octreotide

scintigraphy besides the already mentioned higher

spatial resolution with excellent image quality. These

advantages include the easy accessibility and avail-

ability of the 68Ga generator, favourable acquisition

protocol, with relative short scanning time, and low

radiation exposure to the patient (Krausz et al. 2010). It

is likely that, if available, PET/CT with 68Ga-labelled

somatostatin analogues will become the image

modality to be used for SRS in the future.

Also in SRS with the use of 68Ga-labelled

somatostatin analogues in GEP-NET patients,18F-FDG PET might have its place in the diagnostic

work up with an increased overall sensitivity of 92%

with the combination of 68Ga-DOTATATE PET/CT

and 18F-FDG PET/CT especially in intermediate- and

high-grade NET (Kayani et al. 2008).

nds in clinical imaging compared with other imaging modalities

Reported results Comments

Superior Scan protocol [111In-DTPA0]

octreotide inadequate

Superior to SPECT Scan protocol [111In-DTPA0]

octreotide inadequate

Useful additional information No comparison with other

radioligands

Superior

Superior Case report

Superior: low-grade tumours

Inferior: high/intermediate-

grade tumours

Comparable, if not superior

S33

J J M Teunissen et al.: Imaging and treatment of NET

Besides, the 68Ga-labelled somatostatin analogues,

a glycosylated 18F-labelled somatostatin analogue,

Na-(1-deoxy-D-fructosyl)-N3-(2-[18F]fluoropropionyl)-

Lys0-Tyr3-octreotate (Gluc-Lys([18F]FP)-TOCA),

has been introduced for PET with a diagnostic

performance superior to [111In-DTPA0]octreotide

scintigraphy and probably comparable with 68Ga-

DOTATOC (Meisetschlager et al. 2006). However,

the preparation of Gluc-Lys([18F]FP)-TOCA requires a

time-consuming multistep synthesis that will probably

hamper its future clinical use.

Other interesting, not somatostatin analogue-based,

PET imaging agents in GEP-NETs include 18F-DOPA

and 11C-5-HTP.

PET with 18F-DOPA is based on the fact that DOPA

is a catecholamine precursor, which is taken up by

neuroendocrine cells (Becherer et al. 2004), whereas

5-HTP is a direct precursor for the serotonin pathway

and therefore a potentially sensitive universal method

for NET detection (Orlefors et al. 2005).

In a recent comparison on the diagnostic sensitivity

of PET scanning with both 11C-5-HTP and 18F-DOPA

as tracers, it was concluded that 18F-DOPA PET is an

ideal imaging modality for staging in carcinoid patients

and 11C-5-HTP PET in patients with NET in the

pancreas. Furthermore, the anatomical information

obtained by the (almost) simultaneously performed

CT increases the sensitivity of the PET in both studies

even more (Koopmans et al. 2008). Examples of18F-DOPA PET and 11C-5-HTP images in the same

patient are shown in Figs 1 and 2.

Both new tracers, especially in combination, are

promising for more accurate staging of patients with

NETs. However, for selecting patients for PRRT, the

radiopharmaceutical for imaging has to be of the same

family as for PRRT and therefore SRS the imaging

method of choice.

Therapy

Peptide receptor scintigraphy is important in staging as

it may detect resectable GEP-NETs that could be

missed with conventional imaging techniques. Further-

more, it may prevent surgery in patients whose tumours

have metastasised to a greater extend than could be

detected with conventional imaging alone. Besides

staging it may also be used to select patients for PRRT

with 111In-, 90Y- or 177Lu-labelled peptide analogues.

The outcome of several phases 1 and 2 PRRT studies

have been published in which different somatostatin

analogues labelled with on of these three radionuclides

were used (Tables 3 and 4).

S34

[111In-DTPA0]octreotide

The initial studies on radiolabelled somatostatin

analogue therapy in GEP-NET patients were per-

formed in the early 1990s and were based on the

administration of high administered activities of

[111In-DTPA0]octreotide (Krenning et al. 1994b).

At that time no other chelated analogue was available

for therapeutic purposes (Table 3; Anthony et al. 2002,

Valkema et al. 2002, Buscombe et al. 2003,

Delpassand et al. 2008). Overall, the reported outcome

of these treatments was encouraging in terms of

reduced symptomatology and biochemical response.

Despite reported partial remissions (PRs) were few,

patients with stable disease (SD) and minor remission

might be considered to have had a beneficial

therapeutic effect as 92% or more patients had

documented progressive disease at study entry.

Recently, a study reported high-activity PRRT with

cumulative administered activities up to 37.3 GBq

given in two cycles (Delpassand et al. 2008). On an

intention to treat basis, two out of 29 (7%) patients had

PR, 16/29 (55%) had SD and 11/29 (37%) of the

patients were either deceased (nZ4) or withdrawn

from the study without any clear reason mentioned

(nZ7). Eighteen out of 29 (62%) patients had the

intended therapy of two cycles of [111In-DTPA0]

octreotide. In this group, 2/18 (11%) had PR and 16/18

(89%) had SD 3 months after the last therapy.

Although the number of PRs was few, the remainder

of patients (nZ16) that could be analysed had SD. In

addition, a significant decrease in the tumour marker

chromogranin A (CgA) or hormone levels from

pretreatment observations was observed with a 50%

reduction from pretreatment levels in CgA or at least

one hormone in eight patients (44%). Change of

biomarkers, such as CgA in GEP-NETs might, besides

objective responses, be important in these relative

indolent growing tumours as morpholigical assessment

alone might underestimate the therapeutic efficacy.

Unfortunately, biomarkers as secondary outcome

parameters are often not available and moreover

difficult to compare with other studies.

When therapeutic toxicity of PRRT is considered,

transient bone marrow suppression was the most often

encountered toxicity after [111In-DTPA0]octreotide

therapy. More serious side effects included leukaemia

and myelodysplastic syndrome (MDS), which were

discovered during follow-up in three out of six patients

who had received more than a total administered

activity of 100 GBq with estimated bone marrow

radiation dose of more than 3 Gy (Valkema et al.

2002). One of the patients had chemotherapy before

www.endocrinology-journals.org

A B18F-DOPA 11C-HTP

C 18F-DOPA PET/CT

PET CT PET/CT

Figure 1 (a) 18F-dihydroxy-phenyl-alanine (18F-DOPA, 180 MBq) positron emission tomography (PET) of a 64-year-old male patientdiagnosed with carcinoid disease with multiple abdominal lesions and one possible small lesion in the supraclavicular region (blackarrows). (b) 11C-5-hydroxy-tryptophan (11C-5-HTP, 200 MBq) PET in the same patient with almost similar uptake pattern. 18F-DOPAPET in this patient appears to be slightly more sensitive, with a better tumour-to-background ratio and a possible left supraclavicularlesion. Note also the clearance of both radiopharmaceuticals via the kidneys. (c) From left to right: coronal thoracoabdominal imagesof 18F-DOPA PET, CT and 18F-DOPA PET/CT in the same patient.

Endocrine-Related Cancer (2011) 18 S27–S51

www.endocrinology-journals.org S35

A B18F-DOPA 11C-HTP

Figure 2 (a) 18F-dihydroxy-phenyl-alanine (18F-DOPA) positron emission tomography (PET) of a 56-year-old female patientdiagnosed with an endocrine tumour of the pancreas extending towards the spleen with liver metastases. Note the knownphysiological uptake in the gallbladder (Balan 2005). (b) 11C-5-hydroxy-tryptophan (11C-5-HTP) PET in the same patient indicatingmore tumour mass and a higher number of liver metastasis in comparison with the 18F-DOPA PET. Note also the clearance of bothradiopharmaceuticals via the kidneys.

J J M Teunissen et al.: Imaging and treatment of NET

[111In-DTPA0]octreotide therapy, which could have

contributed or caused this severe complication.

Renal insufficiency was reported by Anthony et al.

(2002) in one patient and was probably related to

retroperitoneal fibrosis already present before therapy.

Three patients with tumour replacement of more than

75% of their hepatic parenchyma and with treatment-

associated necrosis on CT experienced transient grade

4 hepatic toxicity.

From the clinical studies with [111In-DTPA0]

octreotide, it can be concluded that [111In-DTPA0]

octreotide therapy is not the ideal radiolabelled peptide

for PRRT, at least not for metastatic GEP-NETs.

Experimental data in rats have shown that high

absorbed doses of [111In-DTPA0]octreotide can inhibit

the growth of liver metastases after injection of

somatostatin receptor sst2 tumour cells into the portal

vein. Therefore, 111In-based PRRT might be effica-

cious in the treatment of micro-metastases or in the

prevention of metastatic spread during initial surgery

(Slooter et al. 1999). However, clinical studies that

confirm these preclinical observations are lacking.

S36

90Y-labelled somatostatin analogues

The next generation of radiolabelled somatostatin

analogues was coupled to the b-emitting radionuclide 90Y.

DOTA-chelated somatosatin analogues were used for

more stable conjugation of analogue and radionuclide.

The different somatostatin analogues have different

affinities for the somatostatin receptor subtypes, which

can have accounted for the difference in reported

outcome as is shown in Table 4. However, since no

randomised trial has been performed, other differences,

such as used protocol, selected patient population and

the total administered activity, could have been

reponsible for the observed differences. In a small

group of patients, Otte et al. (1998). Reported two PRs

out of ten patients with somatostatin receptor-positive

tumours treated with [90Y-DOTA0,Tyr3]octreotide

(90Y-DOTATOC), whereas six patients had SD. In

the studies that followed, response rates (complete

response (CR) and PR) in patients with GEP-NETs,

who were either treated with upto 6.0 GBq/m2 (dose-

escalating study of four cycles) or 7.4 GBq/m2, were

10/37 (27%) and 8/37 (22%) respectively (Waldherr

www.endocrinology-journals.org

Table

3PRRTwith[111In-D

TPA0]octreotidein

patients

withgastroenteropancreaticneuroendocrinetumours

References

No.of

evaluable

patients

Progressivedisease

before

PRRT

Cumulativeactivity

(GBq)

Response

PR

MRa

SD

PD

Criteriab

Valkemaetal.(2002)

26

24/26(92%)(clinicaland/or

imagingbased)

4.7–160.0

02(8%)

15(58%)

9(35%)

SWOG

Anthonyetal.(2002)

26

100%

(clinicaland/or

imagingbased)

6.7–46.6

2(8%)

N/I

21(81%)

3(11%)

WHO

Buscombeetal.(2003)

12

100%

(biochemicalor

imagingbased)

3.1–36.6

2(17%)

N/I

7(58%)

3(25%)

RECIST

Delpassandetal.(2008)

29

100%

(imagingbased)

35.3–37.3

2(7%)

N/I

16/29(55%)

11/29(38%)c

RECIST

PRRT,peptidereceptorradionuclidetherapy;cumulativeactivity,totaladministeredactivityof[111In-D

TPA0]octreotide;N/I,notindicated.

aModificationofSouthwestOncologyGroup(SWOG)criteriaincludingMR

(minorremission),between25and50%

reductionoftumoursize.

bCriteriaoftumourresponse:S

WOG:P

R(partialremission),R

30%

reductionoftumoursize;M

R(m

inorremission),30%

reductionorincrease

ofS

D(stabledisease

),!30%

reductio

norincreaseof!

20%

oftumoursize;PD(progressivedisease),R

20%

increaseoftumoursizeornewlesion(s).WHO:PR,R50%

reductionoftumoursize;SD,!50%

reductionor

increaseof!25%

oftumoursize;PD,R

25%

increase

oftumoursizeornewlesion(s).Responseevaluationcriteriain

solid

tumours

(RECIST):PR,R

50%

reductio

noftumoursize;

SD,!25%

reductionorincreaseoftumoursize;PD,O

50%

increaseoftumoursize.

cFourpatients

deceasedbefore

theseco

ndcycle

given,seve

npatients

were

withdrawnfrom

thestudywithoutanyreasonmentioned.

Endocrine-Related Cancer (2011) 18 S27–S51

www.endocrinology-journals.org

et al. 2001, 2002a). In a preliminary subsequent

study the same total administered activity of

7.4 GBq/m2 was given in two cycles to determine

whether a decrease in the number of treatments could

increase PRRT efficacy in terms of objective responses

(Waldherr et al. 2002b). Twelve out of 35 patients

(34%) had CR or PR, which indicated a higher

percentage of tumour regression. No increase in side

effects was reported. Unfortunately, published random-

ised clinical studies to indicate a therapeutic benefit of

less cycles in PRRT are lacking.

Reported clinical studies of PRRT from Milan,

also used the radiolabelled somatostatin analogue90Y-DOTATOC to treat patients with various somato-

statin receptor-positive tumours (Paganelli et al.

2001, 2002, Chinol et al. 2002, Bodei et al. 2003,

2004). Objective tumour responses, including CR and

PR varied from 26 to 29%. Unfortunately, a clear

description of the tumour response in relation to a

specific tumour type on a per-patient basis was not

always given. Instead, it was reported that most of

the patients who had a favourable outcome, had

GEP-NETs.

In a multi-centre (Rotterdam, The Netherlands;

Brussels, Belgium; Tampa, USA) dose escalation

phase I study, also with 90Y-DOTATOC, escalating

administered activities up to 14.8 GBq/m2 in four

cycles or up to 9.3 GBq/m2 in a single cycle were given

to a total of 58 GEP-NET patients (Valkema et al.

2006). The maximum tolerated single dose was not

reached. The total administered activity was limited

according to a maximum estimated dose of 27 Gy to

the kidneys. Furthermore, concomitantly with the

therapy, an amino acid (lysine 2.5%/arginine 2.5%)

solution was administered for kidney protection. Five

out of 55 (9%) evaluable patients had PR, seven (13%)

had minimal response (MR) and 29 (53%) had SD.

Although a detailed QoL assessment was not

performed, 21 of the 36 patients (58%) had improve-

ment in Karnofsky performance score (KPS) or

symptoms.

In a recently published study, 90 GEP-NET patients

were treated with a fixed dose regimen of three cycles

of 4.4 GBq 90Y-DOTATOC (90Y-edotreotide, Onalta,

Molecular Insight Pharmaceuticals, Cambridge, MA,

USA; Bushnell et al. 2010). The maximum cumulative

administered activity of 13.3 GBq was chosen as it is

regarded as both safe and effective (Smith et al. 2000,

Valkema et al. 2006). Four out of 90 (4%) evaluable

patients had PR and 63 (70%) had SD. Median

progression-free survival was 16.3 months. The

number of patients who had PR and SD is comparable

with the results of the second largest (multi-centre)

S37

Table 4 Peptide receptor radionuclide therapy clinical trials with 90Y- or 177Lu-labelled somatostatin analogues in patients with

gastroenteropancreatic neuroendocrine tumours

References

No. of

evaluable

patients

Progression at

inclusion (%)

Reported response

CR PR MRa SD PD CRCPR Criteriab

[90Y-DOTA0,Tyr3]octreotide

Otte et al. (1999) 16 N/I 0 1 (6%) N/I 14 (88%) 1 (6%) 1/16 (6%) N/I

Waldherr et al. (2001) 37 84 1 (3%) 9 (24%) N/I 23 (62%) 4 (11%) 10/37 (27%) WHO

Waldherr et al. (2002a) 37 100 1 (3%) 7 (19%) N/I 6 (70%) 3 (8%) 8/37 (22%) WHO

Waldherr et al. (2002b) 36 100 2 (6%) 10 (28%) N/I 19 (54%) 4 (12%) 12/35 (34%) WHO

Bodei et al. (2003) 21 N/I 0 6 (29%) N/I 11 (52%) 4 (19%) 6/21 (29%) WHO

Valkema et al. (2006) 58 81 0 5 (9%) 7 (13%) 29 (53%) 14 (25%) 5/58 (9%) SWOG

Bushnell et al. (2010) 90 100 0 4 (4%) N/I 63 (70%) 23 (26%) 4/90 (4%) SWOG

[90Y-DOTA]lanreotide

Virgolini et al. (2002) 39 100 0 0 8 (20%) 17 (44%) 14 (36%) 0/39 (0%) WHO

[90Y-DOTA0,Tyr3]octreotate

Baum et al. (2004) 75 89 0 28 (37%) N/I 39 (52%) 8 (11%) 28/75 (37%) N/I

[177Lu-DOTA0,Tyr3]octreotate

Kwekkeboomet al. (2008) 310 38 5 (2%) 86 (28%) 51 (16%) 107 (35%) 61 (20%) 91/310 (29%) SWOG

Garkavij et al. (2010) 12 N/I 0 2 (17%) 3 (25%) 5 (50%) 2 (17%) 2/12 (17%) RECIST

N/I, not indicated or not specified to the number of evaluable patients.aModification of the Southwest Oncology Group (SWOG) criteria including MR (minor remission), between 25 and 50% reduction oftumour size.bCriteria of tumour response: SWOG: PR (partial remission),R30% reduction of tumour size; MR (minor remission), 30% reductionor increase of SD (stable disease),!30% reduction or increase of!20% of tumour size; PD (progressive disease),R20% increaseof tumour size or new lesion(s), measurements: bidimensional. WHO: PR,R50% reduction of tumour size; SD,!50% reduction orincrease of !25% of tumour size; PD, R25% increase of tumour size or new lesion(s), measurements: bidimensional. Responseevaluation criteria in solid tumours (RECIST): PR,R50% reduction of tumour size; SD,!25% reduction or increase of tumour size;PD, O50% increase of tumour size, measurements: unidimensional.

J J M Teunissen et al.: Imaging and treatment of NET

PRRT phase I study with 90Y-DOTATOC (Valkema

et al. 2006). Furthermore, in this study, a subgroup

analysis of 19 patients who received a cumulative

activity between 9.9 and 13.3 GBq 90Y-DOTATOC

was performed to mimic the cumulative activity

administered in the phase II studies. Median overall

survival (OS) in these 19 patients was 21.3 months,

which is in line with the reported OS of 26.9 months in

the larger group of 90 patients (Bushnell et al. 2010).

Also clinically used, is the 90Y-labelled somatostatin

analogue [DOTA0,Tyr3]octreotate (DOTATATE).

DOTATATE is formed by replacing the C-terminal

threoninol in DOTATOC with threonine. This small

change of molecular structure improved the binding

to somatostatin receptor-positive tissues in animals

(de Jong et al. 1998). Furthermore, a ninefold increase

in affinity for the sst2 for DOTATATE if compared

with DOTATOC was reported (Reubi et al. 2000).

After coupling of Yttrium to both analogues, an almost

sevenfold increase was preserved.

Preliminary results of the therapeutic efficacy of90Y-DOTATATE in patients with somatostatin

receptor-positive tumours was reported by Baum

et al. (2004) Twenty-eight out of 75 (37%) patients

had PR and 39/75 (52%) had SD after therapy.

Therefore, 90Y-DOTATATE might also be a promis-

ing 90Y-labelled somatostatin analogue. In analogy

S38

with [111In-DTPA0]octreotide therapy, transient, but

mild bone marrow suppression was the most often

observed side effect in patients treated 90Y-labelled

somatostatin analogues. Acute grades 3 and 4

haematologic toxicity was observed for platelets in

3–12% of the patients, 1–7% for haemoglobulin and

2–7% for white blood cells (Otte et al. 1999, Waldherr

et al. 2002a, Bodei et al. 2003, Valkema et al. 2006)

The latter toxicity has recently been addressed in

a study by Sierra et al. (2009) in which it was

concluded that the toxicity regarding the lymphocytic

subpopulation is mainly directed to the B-cell

subpopulation.

Despite the current use of kidney protection which

consists of coinfusion of an amino acid solution during

PRRT, the kidneys are often found to be dose-limiting.

Especially in patients treated with 90Y based somato-

statin analogues with and without kidney protection

renal toxicity has been reported in a limited number

of patients.

In an intra-patient dose-escalating study renal

toxicity was seen in four out of 29 (14%) treated

patients after administration of cumulative activities of

7.6–8.9 GBq/m2 90Y-DOTATOC (Otte et al. 1999).

None of these four patients received coinfusion of an

amino acid solution during and after PRRT. Two

of them needed haemodialysis treatment. No renal

www.endocrinology-journals.org

Endocrine-Related Cancer (2011) 18 S27–S51

toxicity was observed in the other patients who

received a maximum of administered cumulative

activity of 7.4 GBq/m2. A cumulative administered

activity of 7.5 GBq/m2 was, therefore, suggested to

be dose-limiting for the kidneys in PRRT with90Y-DOTATOC. However, a case report of a patient

treated with 5.6 GBq/m2 90Y-DOTATOC, who

developed end-stage renal disease, suggests that this

limit is not completely reliable to exclude renal toxicity

(Cybulla et al. 2001).

In a more detailed study focusing on renal function,

28 patients who had a cumulative radiation dose to the

kidneys up to 38.7 Gy and a median follow-up 2.9

years, had a median decline of creatinine clearance of

7.3%/year (Valkema et al. 2005). Furthermore, a

decline of O15% was reported in a subgroup of nine

patients of which five had hypertension and/or

diabetes. In this and another study by Bodei et al.

(2008), it was concluded that cumulative renal

radiation dose, per-cycle renal radiation dose, age,

hypertension and diabetes are probable contributing

factors responsible for the high rate of decline in

creatinine clearance after PRRT demonstrated in a

subgroup of patients.

All the clinical trials with 90Y-labelled somatostatin

analogues, despite the differences in analogues and

protocols used, report favourable outcome in terms of

percentages of patients with complete or PR ranging up

to 37% (Table 4) and, therefore, compare favourably

with [111In-DTPA0]octreotide based PRRT. Further-

more, survival data are encouraging in terms of a

longer documented OS. In the multi-centre study

comprising a group of 58 patients treated with90Y-DOTATOC, the OS compared favourably

with a historical group of patients treated with

[111In-DTPA0]octreotide with a median time of

survival of 3 years (versus 12 months; Valkema et al.

2002, 2006). Limitation of this comparison is the fact

that both were separate phase I studies and thus without

randomisation. However, the observed difference in

median survival can probably not be solely explained

by this.

177Lu-labelled somatostatin analogues

In preclinical studies by de Jong et al. (2002b),

different radiolabelled somatostatin analogues were

evaluated for future clinical therapeutic use. Besides

[111In-DTPA0]octreotide and 90Y-DOTATOC, the

b-emitting radionuclide 177Lu coupled to DOTATATE

(177Lu-DOTATATE) was used. 177Lu-DOTATATE

demonstrated the highest tumour uptake together

with excellent tumour-to-kidney ratios compared

www.endocrinology-journals.org

with [111In-DTPA0]octreotide and 90Y-DOTATOC.

Furthermore, in a clinical study by Esser et al. (2006)

was compared with 177Lu-DOTATOC in a thera-

peutical setting. A mean residence time ratio of 2.1 in

favour of 177Lu-DOTATATE for PRRT was reported.

Therefore, in our view for GEP-NETs 177Lu-

DOTATATE is the radiolabelled somatostatin

analogue of choice for PRRT.

The first reports on the results of the clinical use of177Lu-DOTATATE were promising with CR and PR

in 30%, MR in 12% and SD in 40% of the treated

GEP-NET patients (Kwekkeboom et al. 2003a). In a

more recent analysis these results were confirmed in a

large group of a total of 310 GEP-NET patients

(Kwekkeboom et al. 2008). Patients were treated up to

a total administered activity of 27.8–29.6 GBq, usually

in four treatment cycles, with treatment intervals of

6–10 weeks. Complete and partial tumour remissions

occurred in 2 and 28% of patients respectively. Factors

predictive of a favourable response with tumour

shrinkage (CR, MR and PR) were high uptake on

pre-PRRT [111In-DTPA0]octreotide scintigraphy and a

KPS higher than 70. Interestingly, a reduced tumour

uptake after the third or fourth treatment in comparison

with the scan after the first treatment was frequently

seen in patients who eventually had a tumour

regression during follow-up (Kwekkeboom et al.

2005). This phenomenon is illustrated in Fig. 3. In

line with these observations on post-PRRT scintigra-

phy, similar results of reduced somatostatin receptor

mediated uptake after PRRT was recently published by

Haug et al. (2010). In their study, decreased68Ga-DOTATATE uptake in tumours after the first

cycle of PRRT predicted the time to progression (TTP)

after completion of PRRT (one, two or three cycles)

and was correlated with improvement in clinical

symptoms. Most obvious cause of the observed

decrease in uptake is a decreased amount of viable

somatostatin receptor-expressing tumour cells and

thereby reflecting the cytotoxic therapeutic effect of

PRRT. Other suggested causes included the induction

of dedifferentiating of NET cells within the tumour as

somatostatin expression depends on the grade of

differentiation of NET (Miederer et al. 2009).

However, dedifferentiation is less likely because the

observed favourable effect on tumour response, TTP

and clinical symptoms in tumours with reduced uptake

in the tumours after PRRT. Also, the effect of PRRT on

receptor expression and density on a single tumour cell

is not know and has to be elucidated in further studies.

Four patients who were judged inoperable by the

surgeon, became operable after adequate reduction of

tumour mass, 6–12 months after PRRT. Three of these

S39

A Anterior Posterior

Cycle 3

Cycle 2

Cycle 1

Cycle 4

B Pre-PRRT Post-PRRT

Figure 3 (a) Posttherapy scans (anterior/posterior, abdominal spot view images) after each cycle of PRRT with 7400 MBq[177Lu-DOTA0,Tyr3]octreotate (top to bottom row indicates the first to last cycle) in a patient with rectal carcinoid with metastases whoeventually had partial remission as tumour outcome. Note the decrease of uptake in the liver lesions compared to physiological liveruptake with every post-therapy scan. (b) CT of the abdomen of the same patient before (left panel) and 3 months after (right panel)the last cycle.

J J M Teunissen et al.: Imaging and treatment of NET

patients were succesfully operated upon, whereas one

died of unfortunate postoperative complications.

Median TTP in the GEP-NET patients who did not

have PD (nZ249) was 40 months from start of the first

cycle. Median OS was 46 months and median disease-

related survival was O48 months. Median pro-

gression-free survival was 33 months (Kwekkeboom

et al. 2008). Not surprisingly, the most important factor

predicting increased survival was treatment outcome.

Patients with PD had significantly shorter survival

compared with patients with SD or tumour shrinkage.

Survival between other treatment outcomes did not

differ significantly (Fig. 4).

Furthermore, patients with a low KPS or extensive

tumour load within the liver had a less favourable

survival.

In 42 patients with metastasised bronchial or

GEP-NETs who had an objective tumour response of

tumour remission or SD with clearly clinical benefit

after the regular 177Lu-DOTATATE therapy, salvage

therapy, with two additional cycles of 7.4 GBq, was

evaluated (van Essen et al. 2010). On radiological

evaluation, eight (24%) out of 33 eligible patients had

tumour remission (MR or PR), ten (31%) had SD and

15 (45%) had PD 3 months after the last therapy.

The additional treatments were well tolerated with

acceptable haematological toxicity and without any

S40

serious delayed toxicity. A similar study was

performed by Forrer et al. (2005) in patients with

NETs previously successfully treated with 90Y-

DOTATOC. Twenty-seven patients received an

additional treatment of 7.4 GBq 177Lu-DOTATATE.

On radiological evaluation, seven (26%) had tumour

remission (MR or PR) and 12 (44%) had SD 8–12

weeks after therapy.

Published reports of PRRT with 177Lu-DOTATATE

in other clinical centres are in a small group of

patients or anecdotal. In the study by Muros et al.

(2009), PRRT with 177Lu-DOTATATE was performed

in two patients with advanced NETs in addition to

previously given treatments of 90Y-DOTATOC. In

both patients disease stabilisation was the maximum

achieved objective tumour response. In a recently

published study, which was mainly focused on

dosimetric issues instead of the therapeutic efficacy

of PRRT, two out of 12 (17%) patients, who were

evaluable and had completed the treatments (three and

four cycles of 7.4 GBq) with 177Lu-DOTATATE, had

PR, 3/12 (25%) had MR and 5/12 (42%) had SD

(Garkavij et al. 2010). Although a limited number of

patients studied, the results are in line with the large

series by Kwekkeboom et al. (2008).

Clinical PRRT studies with other 177Lu-labelled

somatostatin analogues are limited. The use of

www.endocrinology-journals.org

1.0

0.8

0.6

PD

SD

CR, PR and MR

0.4

Cum

ulat

ive

surv

ival

0.2

0 6 12 18 24 30 36

Time from treatment start (months)

42 48

Figure 4 Disease-related survival in 310 patients accordingto treatment outcome. Patients with progressive disease (PD)have significantly shorter survival. Survival between othertreatment outcomes did not differ significantly. CR, completeresponse; PR, partial response; MR, minimal response;SD, stable disease. Reproduced with permission. q 2008American Society of Clinical Oncology. Kwekkeboom et al.,Treatment with the radiolabelled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate: toxicity, efficacy, and survival, Journalof Clinical Oncology, volume 26, pp 2124–2130.

Endocrine-Related Cancer (2011) 18 S27–S51

DOTANOC is interesting because it has a high affinity

to the sst2, sst3 and sst5 (Wild et al. 2003). Therewith, a

broader affinity profile than DOTATATE, which has

predominantly high affinity to the sst2. In theory, the

broader affinity profile can be beneficial for patients

with tumours that express not only the sst2. In a recent

study, eight patients were treated with one cycle of

3600–7400 MBq 177Lu-DOTANOC (Wehrmann et al.

2007). PRRT was continued in three patients with177Lu-DOTATATE (Wehrmann et al. 2007). Because

the report was primarily conducted for dosimetric

comparison of 177Lu-DOTATATE with 177Lu-

DOTANOC, no tumour response outcome was

reported. From the results it was concluded that

DOTANOC coupled to 177Lu leads to a higher uptake

in normal tissue, and therefore an increase in the

whole-body dose. Together with the observed high

inter-patient variability this outcome indicates that

individual patient dosimetry is important to decide

whether to treat a patient with 177Lu-DOTATATE or177Lu-DOTANOC. In a preliminary report from

Rotterdam, four patients with thyroid carcinoma were

treated with 6.7–32.5 GBq 177Lu-DOTANOC

(Valkema et al. 2007). One patient with follicular

thyroid carcinoma had PR, one patient with Hurthle

cell thyroid carcinoma (HCTC) had clinical

www.endocrinology-journals.org

improvement whereas the other two patients (HCTC

and medullary thyroid carcinoma) had PD. Studies that

report tumour responses in patients with NETs with177Lu-DOTANOC therapy are lacking.

Side effects after PRRT with 177Lu-DOTATATE

were analysed in a total of 504 patients. Acute side

effects within 24 h after administration were reported

and included nausea (25%) and vomiting (10%) and

abdominal pain/comfort (10%). However, it is not

clear whether both nausea and vomiting are purely

related to the PRRT since both side effects can be

caused by the coinfusion of renal protective amino acid

solutions (Rolleman et al. 2003).

Acute haematological toxicity was often mild and

transient with grade 3 or 4 toxicity (WHO criteria) in

3.6% calculated on a per-cycle basis or 9.5% on a per-

patient basis (at least one of several cycles). Patients

had an increased risk of grade 3 or 4 haematological

toxicity when older than 70 years of age at the start of

PRRT, previous chemotherapy, low creatinine clear-

ance (%60 ml/min; Cockcroft’s formula estimation) or

the presence of bone metastases. Temporary mild hair

loss was noticed in 62% of the patients.

Serious late toxicity in the group of 504 patients

included MDS in four patients of which in three

probably PRRT-related, two patients with renal

insufficiency, both probably unrelated, and three

patients with serious liver toxicity.

Similar to PRRT with 90Y-labelled somatostatin

analogues, the kidneys are one of the dose-limiting

organs with 177Lu-DOTATATE. However, the study

by Valkema et al. (2005) indicated that the impact on

creatinine clearance rate is less pronounced than with90Y-DOTATOC with a median decline in creatinine

clearance of 3.8%/year.

Prolonged or (re-)hospitalisation after therapy

because of probably PRRT-induced hormonal crises

occurred in six (1%) patients (de Keizer et al. 2008).

All patients recovered after adequate care including

fluid infusion, high-dose i.v. administered somatostatin

analogue, corticosteroids and correction of electrolyte

disturbances.

PRRT-induced hormone disturbances such as tran-

sient inhibitory effect on inhibin that suggests an effect

on the spermatogenesis and mild decrease in gonado-

tropin hormones in postmenopausal women have been

described (Teunissen 2009). This could have clinical

relevance, especially in those patients with a favour-

able durable response. These endocrine effects are

similar with the reported experience of the use of 131I

treatment in men with differentiated thyroid carcinoma

(Wichers et al. 2000).

S41

J J M Teunissen et al.: Imaging and treatment of NET

Quality of life

Another study evaluated the QoL in patients with

metastatic somatostatin receptor-positive GEP-NETs

treated with 177Lu-DOTATATE (Teunissen et al.

2004). Fifty Dutch patients completed the European

Organization for the Research and Treatment of Cancer

Quality of Life Questionnaire C30 (Aaronson et al.

1993) before therapy and at follow-up visit 6 weeks

after the last cycle. A significant improvement in the

global health status/QoL scale was observed after

therapy with 177Lu-DOTATATE. Furthermore, signi-

ficant improvement was observed in the role, emotional

and social function scales. The symptom scores for

fatigue, insomnia and pain decreased significantly.

Patients with proven tumour regression most frequently

had an improvement of QoL domains. However,

because of the lack of a control group in this study,

some placebo effect cannot be ruled out completely.

Comparison of the various radiolabelled

somatostatin analogues used for PRRT

Treatment with 90Y- and 177Lu-labelled somatostatin

analogues is very encouraging in terms of tumour

shrinkage. However, studies that compare the different

radiopharmaceuticals in a direct randomised manner,

are lacking. Even comparison of studies using the same

compound (e.g. 90Y-DOTATOC, Table 4) is difficult

because of differences in the used PRRT such as the

amount of administered activity, number of cycles,

selection of patients and the tumour response criteria

used. These among other causes can be responsible for

the observed differences in treatment outcome. There-

fore, randomised controlled trials are necessary to

define the optimal PRRT and treatment scheme fur

future use. It may be kept in mind, however, that 50

years of experience of 131I treatment for thyroid

disease, has not lead to a general accepted consenses

on treatment protocols.

Comparison of PRRT with conventional therapy

At this moment the opportunity for a prospective

randomised comparison of PRRT with no further

treatment has passed. It seems unethical to perform

such a trial with the impressive reported results of

PRRT to date. Of interest is the use of ‘cold’

somastostatin analogues and interferon-a. In a group

of 80 progressive therapy-naive GEP-NET patients,

somatostatin analogues and/or interferon-a was started

(Faiss et al. 2003). Four (5%) patients had a tumour

remission and 19 (24%) had SD. In another recently

published prospective randomised trial, patients with

S42

metastatic mid-gut NET (carcinoids) were assigned to

either placebo or octreotide LAR 30 mg/month (Rinke

et al. 2009). Octreotide LAR significantly lenghtened

the TTP compared with placebo with 8–9 months, with

the most favourable effect in patients with low hepatic

tumour load and resected primary tumour. The next

logical step would be a similar randomised trial with

octreotide LAR versus PRRT.

Studies in which a direct comparison of PRRT with

chemotherapy was performed are lacking. However, in

a recent article (Kwekkeboom et al. 2005) the outcome

of historical studies with single or combination

chemotherapy regimens was used as a surrogate for

the comparison with the outcome of PRRT with177Lu-DOTATATE (Kwekkeboom et al. 2005).

Compared with these historical control groups, a

survival benefit of 40–72 months was observed.

Although comparison with historical controls always

has to be interpreted with caution, the consistent

differences with these studies is at least suggestive for a

better survival after 177Lu-DOTATATE therapy.

Options to improve PRRT

Various methods to improve the efficacy of PRRT have

been proposed. The combination of 90Y- and 177Lu-

labelled somatostatin analogues, which demonstrated

more favourable tumour responses in animal experi-

ments than either analogue tested as a single agent,

might be more effective (de Jong et al. 2002b).

However, an adequate prospective randomised trial

has not yet been performed.

Currently, locoregional administration of radio-

labelled somatostatin analogues administered via the

hepatic artery to increase the uptake in liver lesions is

studied. This therapeutic approach could be especially

effective when the major tumour bulk is within the

liver. Selective hepatic intra-arterial administrated

[90Y-DOTA]lanreotide proved to be both safe and

effective, resulting in PR in 3/19 (16%) and SD in

12/19 (63%) of patients. Comparison with the same

therapy i.v. administered, however, was impossible,

because of the absence of randomisation, limited

number of patients included and because locoregional

administration was performed with and without

embolisation (McStay et al. 2005).

Another study reported the results in 17 patients

after multiple cycles (maximum of 15 per patient) of

intra-arterially administered [111In-DTPA0]octreotide

(Limouris et al. 2008). An average of 6.3G2.3 GBq

per cycle was administered. The use of [111In-DTPA0]

octreotide in this therapeutic setting resulted in CR in

1/17 (6%), PR in 8/17 (47%) and SD in 3/12 (25%)

www.endocrinology-journals.org

Endocrine-Related Cancer (2011) 18 S27–S51

according to the response evaluation criteria in solid

tumours.

PRRT in combination with the chemosensitisation

agents 5-fluorouracil (5-FU) or its prodrug capecita-

bine, which was performed in analogy with radio-

immunotherapy (Wong et al. 2003) and (fractionated)

external beam radiotherapy (Rich et al. 2004), could

also be more effective than PRRT with a single agent.

A phase 1 feasibility study with the combination of177Lu-octreotate and relatively low doses (1650 mg/m2

per day for 2 weeks) of capecitabine, indicated that

treatment with this combination was feasible and safe

considering acute and subacute side effects (van Essen

et al. 2008). Subsequently, a randomised, controlled

clinical trial to compare this combination with177Lu-octreotate as a single agent was started.

As mentioned, the kidneys and bone marrow are the

dose-limiting organs in PRRT. To widen its therapeutic

window, both the reduction of the absorbed radiation

dose to these organs and a tumour-specific increase in

somatostatin receptor density are subjects of research.

Lastly, individualised tailored dosimetry for each

patient is the ideal method of treating patients with

PRRT, combining the highest possible radiation dose

to the tumour and a maximally well-tolerated dose to

the dose-limiting organs. Both kidneys and bone

marrow absorbed radiation dose vary widely between

patients (Kwekkeboom et al. 2001, Forrer et al. 2009).

Therefore, the administration of fixed activities to our

patients with relatively few side effects implicate that

some patients had suboptimal administered activities

and thus suboptimal doses to the tumours. This means

that with fixed dose regimens that show relatively few

side effects, a proportion of patients is undertreated.

The currently used method of tailored dosimetry

includes urine collection, repeated imaging and blood

sampling and is time-consuming. However, although

practically difficult, tailored dosimetry could indicate

the maximum cumulative activity that can be safely

administered to the patient and thereby increase the

effectiveness of PRRT. Studies into more accurate and,

if possible, simplified individualised dosimetry are

necessary to address this method of tailored PRRT.

MIBG therapy

Except for the diagnosis and staging of GEP-NETs,123I-MIBG scintigraphy can also be used to select

patients for 131I-MIBG therapy. In a similar approach as

with PRRT, 131I-MIBG therapy has the advantage that

the treatment targets all sites of disease, including

distant metastases, that were visible on 123I-MIBG

scintigraphy. Visualisation of disease on 123I-MIBG

www.endocrinology-journals.org

scintigraphy is therefore a prerequisite for the initiation

of treatment. Treatment protocols vary between

different centres. The usual prescribed activities range

between 7.4 and 11.2 GBq, administered at 3–6 months

intervals. Reported tumour responses after 131I-MIBG

therapy in patients with metastatic carcinoid disease

range from 13 to 35% (Hoefnagel 1994, Bomanji et al.

2003, Safford et al. 2004), with objective tumour

shrinkage (WHO criteria), evaluated with CT or MRI,

in 13 and 15% of patients in the two largest studies

comprising 75 and 52 evaluable patients respectively.

In general, biochemical response, which was defined

as O50% reduction in the tumour marker levels such

as CgA or 5-hydroxyindoleacetic acid (5-HIAA), was

demonstrated in 37–46% (Bomanji et al. 2003, Safford

et al. 2004). However, biochemical responses do not

correlate well with objective tumour responses.

Symptomatic control was reported in a higher

proportion of patients, being present in 49–87%131I-MIBG treated patients (Taal et al. 1996b,

Pathirana et al. 2001, Bomanji et al. 2003, Safford

et al. 2004). Reports on survival in patients with NETs

(including carcinoids) treated with 131I-MIBG are few.

Recently, two studies reported survival benefit when

patients with carcinoid tumour were treated with at

least 15 GBq 131I-MIBG given in a period of 6 months

(Safford et al. 2004, Sywak et al. 2004).

In general, 131I-MIBG treatment is well tolerated

with side effects limited to nausea or vomiting 24–72 h

after administration, mild hepatic dysfunction with

spontaneous recovery and temporary myelosuppression

4–6 weeks posttherapy. Only incidentally patients may

develop significant side effects such as severe myelo-

suppression, especially when extensive metastatic

spread within the bone marrow is present, or hepatic

failure in patients with widespread liver metastases

(Bongers et al. 1997). Furthermore, the frequency and

severity of most haematological side effects is clearly

dependent on the (cumulative) administered activity

(Bomanji et al. 2003, Safford et al. 2004).

In conclusion, in patients with GEP-NETs who have

low tumoural uptake on SRS and do not qualify

for PRRT, but have uptake on MIBG scintigraphy,131I-MIBG therapy can be an alternative treatment

option to offer possible tumour size reduction and/or

effective palliation. Furthermore, survival analyses

after 131I-MIBG suggest that there may be a survival

benefit.

Summary

Conventional imaging techniques such as CT, MRI and

US to image NETs have been improved over the years.

S43

J J M Teunissen et al.: Imaging and treatment of NET

Nonetheless, to image the small primary tumours and

metastases that can be encountered during the initial

diagnostic work up, nuclear medicine imaging with

SRS continues to play a pivotal role with

[111In-DTPA0]octreotide scintigraphy, including the

acquisition methodology of planar imaging, SPECT

and SPECT–CT as the gold standard. Different

alternative somatostatin analogues labelled with

g-emitting radionuclides have been proposed, and

although some of them are encouraging in terms of

imaging quality and sensitivity to detect GEP-NETs,

none of them is approved by the European Medicines

Agency (Daly et al. 2006) and/or FDA.

The same holds true for the very promising

somatostatin analogue-based PET radiopharmaceuti-

cals, such as 68Ga-DOTATOC, 68Ga-DOTATATE and68Ga-DOTANOC. Other interesting and promising

PET imaging modalities includes metabolic imaging

of GEP-NETs with 18F-DOPA and 11C-HTP.

Treatment with radiolabelled peptides or PRRT is a

promising new therapeutic option in the management

of inoperable or metastasised NETs. Symptomatic

control can be achieved with all 111In-, 90Y- and177Lu-labelled somatostatin analogue-based PRRT.

For objective response and long-lasting duration of

response, 90Y-DOTATOC and 177Lu- DOTATATE are

the most promising radiopharmaceuticals. Side effects

of PRRT are few and mild, if adequate kidney

protective measures are taken and dose-limits are

respected. In a minority of patients, when SRS fails to

identify neuroendocrine disease, MIBG scintigraphy

and subsequent 131I-MBG therapy might be an

alternative treatment option.

Declaration of interest

E P Krenning is a member of the advisory board of

BioSynthema, and a consultant of Biosynthema and

Covidien. He receives research or material support from

Covidien, Novartis and BioSynthema, and is a shareholder

in BioSynthema. D J Kwekkeboom is a shareholder in

BioSynthema.

Funding

This research did not receive any specific grant from any

funding agency in the public, commercial or not-for-profit

sector.

Acknowledgements

The images of Figs. 1 and 2 have been kindly provided by K P

Koopmans MD PhD, University Medical Centre Groningen,

The Netherlands.

S44

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