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. Author manuscript; available in PMC: 2018 Feb 1.
Published in final edited form as: Curr Opin Endocrinol Diabetes Obes. 2017 Feb;24(1):15–24. doi: 10.1097/MED.0000000000000300

Molecular imaging in neuroendocrine tumors: Recent advances, controversies, unresolved issues, and roles in management

Tetsuhide Ito 1, Robert T Jensen 2
PMCID: PMC5195891  NIHMSID: NIHMS823788  PMID: 27875420

Abstract

Purpose

To review recent advances in molecular imaging of neuroendocrine tumors (NETs), discuss unresolved issues, and review how these advances are affecting clinical management.

Recent findings

Molecular imaging of NETs underwent a number of important changes in the last few years, leading to some controversies, unresolved issues, and significant changes in clinical management. The most recent changes are reviewed in this article. Particularly important is the rapid replacement in somatostatin receptor scintigraphy (SRS) of 111In-DTPA-SPECT/CT by 68Ga-DOTA-peptide-PET/CT imaging, which is now approved in many countries including the US. Numerous studies in many different types of NETs demonstrate the greater sensitivity of 68Ga-DOTA-peptide-PET/CT, its high specificity, and its impact on management. Other important developments in SRS/molecular imaging include demonstrating the prognostic value of both 68Ga-DOTA-peptide-PET/CT and 18F-FDG –PET/CT; how their use can be complementary; comparing the sensitivities and usefulness of 68Ga-DOTA-peptide-PET/CT and 18F-FDOPA PET/CT; introducing new linkers and radiolabeled ligands such as 64Cu-DOTA-peptides with a long half-life, enhancing utility; and the introduction of somatostatin receptor antagonists which show enhanced uptake by NETs. In addition, novel ligands which interact with other receptors (GLP1, Bombesin, CCK, GIP, integrin, chemokines) are described which show promise in the imaging of both NETs and other tumors.

Summary

Molecular imaging is now required for all aspects of the management of patients with NETs. It results are essential not only for the proper diagnostic management of the patient, but also for assessing whether the patient is a candidate for peptide receptor radionuclide therapy (PRRT) with 177Lu and also for providing prognostic value.

Keywords: somatostatin, somatostatin-receptor scintigraphy, 68Gallium PET/CT, Carcinoid, pancreatic neuroendocrine tumor

Introduction

Neuroendocrine tumor (NET) is now the recommended term to include both pancreatic (neuro)endocrine tumors (pNETs/PETs) and NETs in other locations, including gastrointestinal NETs (GI-NETs) (carcinoids), comprising 70% of all NETs[1•]. NETs present many unique problems in their management, because they differ from adenocarcinomas in their pathogenesis, diagnosis, clinical presentations, and treatment approaches[1•, 2••, 3]. NETs are increasing in frequency in almost all countries and present two management problems: the management of the NET itself, because a proportion pursue aggressive growth, and management of the hormone excess-state which occurs in up 30% of pNETs and 3–13% of patients with GI-NETs (carcinoids)[3, 4]. Curative resection would treat both problems, however in many cases, because of the extent of disease, this is not possible, and therefore treatment must be directed at each of these two problems[3–5].

The steps in the management of patients with NETs include suspecting and establishing the diagnosis, determining whether an inherited genetic syndrome is present (MEN1, MEN2, VHL, NF1, etc.), controlling the hormone-excess state, assessing the location and extent of the tumor burden, assessing the histological features of the tumor (proliferative indices, degree of differentiation) and treatment of the tumor either medically or surgically[2••, 3, 5, 6]. An essential aspect of the management is tumor imaging to assess location and extent, which presents a number of unique features, not seen in other tumors[3, 7••, 8]. Particularly important in these tumors is the increasingly important role of molecular imaging. A number of recent reviews and other studies have covered various aspects of imaging including the important role of cross-sectional imaging (CT, MRI, Ultrasound), hormonal sampling, endoscopic procedures, and other localization methods unique to these tumors, including aspects of molecular imaging[3, 8–11, 12•, 13, 14]. Molecular imaging of NETs has been a particular active area of investigation and resulting in changes which are unique to NETs, but which also has widespread implications for other neoplasms[14–16]. This review will highlight recent advances in this area (Table 1), the controversies and unresolved issues that have arisen (Table 2), and how these affect management, focusing primarily on advances in the last 3–5 years.

Table 1.

Molecular imaging in Neuroendocrine tumors (NETs). Recent advances

  1. Development of 68Gallium(68Ga)-labeled somatostatin analogues with PET/CT

  2. Investigation of the role of 18F-FDG PET/CT imaging either alone or combined with 68Ga-peptide PET/CT

  3. Studies of results of 18F-DOPA (18F-dihydroxyphenylalanine) PET/CT either alone or compared to 68Ga-peptide PET/CT

  4. Development of radiolabeled somatostatin receptor antagonists with enhanced sensitivity

  5. Development of other, novel radiolabeled somatostatin receptor ligands: 64Cu-labeled ligands for PET/CT; ligands with different linkers; alpha emitting ligands for enhanced Peptide radio-receptor therapy (PRRT)

  6. Development of novel radiolabeled ligands interacting with other receptors for imaging NETs or other tumors: radiolabeled GLP-1 receptor ligands; CCK2 receptor ligands: Bombesin receptor ligands (BB1, BB2, BB3); GIP receptor ligands and chemokine receptor CXCR4.

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Table 2.

Molecular imaging in Neuroendocrine tumors (NETs). Controversies/unresolved issues

  1. What is current role of 18F-FDG PET/CT imaging? Is it complementary enough to 68Ga-peptide PET/CT that it should be routinely used? If not, in what subgroup?

  2. Is there still a role for 111In-DTPA-peptide-SPECT/CT or has it been completely replaced by 68Ga-peptide PET/CT?

  3. Is there still a role for 18F-DOPA (18F-dihydroxyphenylalanine) PET/CT or is it completely replaced by 68Ga-peptide PET/CT?

  4. Should 64Cu-peptide PET/CT replace 68Ga-peptide PET/CT?

  5. What is the role of 68Ga-labeled sst antagonist-PET/CT and should it replace 68Ga-labeled-sst peptide agonist PET/CT?

  6. What is the role of new, novel radiolabeled ligands interacting with other receptors for imaging NETs or other tumors: radiolabeled GLP-1 receptor ligands; CCK2 receptor ligands: Bombesin receptor ligands (BB1, BB2, BB3); GIP receptor ligands and chemokine receptor CXCR4?

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Why imaging is important in NETs and frequently difficult

Accurate tumor imaging is essential to planning the approach in all phases of management of patients with NETs. First, surgical resection remains the only curative procedure and thus should be carried out whenever it can be safely undertaken and has a high promise of a curative result[2••, 3, 5, 7••, 17]. To increase the possibility of successful surgery and prevent unnecessary surgery, accurate information on the location of the primary tumor and extent of the disease prior to surgery is essential[2••, 3, 5, 7••, 17]. In patients with unresectible disease, accurate imaging is essential to determine timing of antitumor therapies, the response to treatment, and the possible need for new approaches during treatment[2••, 7••, 8]. In patients with hormone excess-states unresponsive to medical therapy, imaging studies are essential in planning possible cytoreductive surgery, chemotherapy or treatment modalities directed at liver-predominant disease (embolization, chemoembolization, radioembolization), all of which have been successful in various series[18, 19].

Tumor imaging has been particularly difficult in a number of subgroups of patients with NETs. Patients with functional pNETs (F-pNETs) characteristically present with symptoms of the hormone excess-state[5, 6] with small primary tumors (<1 cm) which are frequently missed by conventional imaging studies. The success of cross-sectional imaging studies is very much affected by tumor size: detecting 10–30% of NETs <1–1.5 cm, whereas they detect >80% of those >3 cm[3, 5, 12•]. Measurments of hormonal gradients is more sensitive[•12, 20–22], but is usually performed with angiography (insulinomas, gastrinomas), is invasive and uncommonly performed nowadays, except to localize insulinomas in specialized centers in the uncommon patient when all other studies are negative, or in patients with MEN1[3, 12•]. Patients with GI-NETs (carcinoids) and carcinoid syndrome have liver metastases in >95% of cases at the time of presentation [3]. In some of these patients, as well as patients presenting with metastatic nonfunctional NETs, the primary tumor can be small and difficult to localize, but its localization is important in selecting the proper antitumor treatment[15, 23–26]. Lastly, both malignant pNETs as well as GI-NETs frequently metastasize to adjacent lymph nodes, which are not seen on cross-sectional imaging and which can be difficult to localize at surgery[5, 17, 27]. Each of these points argue for the need for more sensitive imaging modalities in patients with NETs.

Molecular imaging of neuroendocrine tumors

General aspects

There are a number of molecular imaging approaches for NETs that are increasingly being used. These include somatostatin-receptor scintigraphy (SRS) using ligands that are targeted to somatostatin-receptors (primarily sst2) overexpressed by NETs[7••, 28]. This method is now approved in many countries including the United States and utilizes primarily 111In-DPTA-peptides, with SPECT/CT-imaging or using 68Ga-DOTA-peptides with positron emission tomography (PET) combined with CT-imaging (PET/CT) or magnetic resonance imaging (PET/MRI)[7••, 8, 29•, 30–32]. Other molecular imaging approaches include the use of 18F-FDG with PET/CT imaging which assesses glucose uptake by tumors[8, 29•, 31, 32, 33•]; 125I-MIBG(123I-metaiodobenyzl-guanidine)-scintigraphy which utilitizes an analogue of guanidine, which is taken up by cells of sympathomedullary tissues and retained intracellularly by storage in catecholamine storage granules[8, 29•, 32]; and the use of 18F-DOPA(18F-dihydroxyphenylalanine)PET or 11C-5-hydroxy-L-tryptophan(5-HTP)(11C-5-HTP)- PET which takes advantage of the fact that NETs take up and decarboxylate amine precursors[8, 29•, 31, 32, 34]. 11C-5-hydroxy-L-tryptophan(5-HTP)(11C-5-HTP)-PET/CT is rarely used and only available in a few clinical centers.

Initially, beginning in the 1990s the most widely used approach was SRS with 111In-DPTA-labeled-somatostatin agonist analogues, which had high affinity primarily for the somatostatin receptor subtype sst2[8, 9, 35]. For well-differentiated NETs, 80–100% express at least one of the 5 somatostatin receptor subtypes (sst1-5), with the most frequent being sst2 (>80%).This approach has greater sensitivity than conventional imaging studies, generally ranging from 60–90% for both pNETs and GI-NETs[8, 9, 35–37]. It has proven especially useful for allowing whole body imaging at one time and for detecting distant metastases, whereby its use resulted in management changes in 25–50% of cases[35, 38, 39]. This approach is limited by the size of NET (identify <50% <1 cm)[8, 40] and by the degree of differentiation of the NET, because poorly differentiated tumors frequently either do not express somatostatin receptors or do so only at low densities[8, 35, 36]. However, this aproach allows an assessment of magnitude of uptake by the tumor and establishes the presence of somatostatin-receptors in the NET, which can be used to plan therapy with other radiolabeled-somatostatin analogues(90Y-,177Lu-labeled-analogues), using peptide receptor radionuclide radiotherapy (PRRT)[8, 35, 36].

PRRT will not be generally discussed in this review, however, it is receiving much attention as a therapeutic, targeted approach for patients with advanced NETs, and thus plays a role in the utilization of SRS, to assess whether this approach might be considered, by establishing the presence of somatostatin receptors on NET tissue [30, 32, 35, 41••, 42]. A recent prospective, randomized clinical trial (NETTER)[ 43•] using 177Lu-DOTATATE in patients with unresectable advanced ileal NETs has been reported in preliminary communications to be effective with an acceptable safety profile. Therefore the availability of PRRT in the future will be a major factor in determining the use of SRS.

Over the last 3–5 years there have been considerable advances in molecular imaging of NETs, both in describing new approaches, new ligands, as well as comparison of different methods and studies leading to a better definition of their potential place in standard medical practice (Table 1). In some cases this had led to controversies and unresolved issues (Table 2) and changes in clincial management. These will be briefly reviewed in the following sections.

Rise of 68Ga-DOTA-peptide-PET/CT imaging

Molecular imaging with 68Ga-DOTA-labeled-somatostatin analogues has a number of advantages over imaging with 111In-DTPA-peptide-SPECT/CT and is now becoming the standard, which is recommended in most current guidelines and is approved in many countries, including recently in the United States[2••, 5, 7••, 8, 29•, 31, 44–47]. The use of 68Ga allows PET-imaging with greater spatial resolution(0.5 cm vs 1.5 cm for 111In-DTPA-peptides/SPECT); has a shorter half-life of 68 min, allowing rapid scanning (1–3 hrs post injection versus 24–48 hr for 111In); it is produced from a generator rather than a cyclotron; its effective dose is less than onehalf of that using 111In-DTPA-peptides and the tissue contrast is better with PET/CT than with SPECT/CT-imaging[7••, 36, 46].

There are numerous recent studies [48••, 49–54] demonstrating imaging superiority of 68Ga-DOTA-labeled-somatostatin analogues in patients with various NETs over conventional cross-sectional imaging studies and SRS with 111In-DTPA-peptides with SPECT/CT-imaging. These recent studies support the superiority of 68Ga-DOTA-PET/CT in pNETs/GI-NETs (carcinoids) [48••, 49–54] in MEN1 patients[12•, 49], in head and neck paragangliomas[55, 56], medullary thyroid cancer[50], pheochromocytomas[56, 58], and ectopic Cushing’s syndrome[57]. Furthermore, a meta-analysis in 2012[59] involving 16 studies (567 NET patients including patients with thoracic NETs) reported a sensitivity of 93% on a per-lesion basis (91% per-patient basis) with excellent specificity. A more recent meta-analysis[48] summarizing 42 studies supported the superiority of 68Ga-DOTA-PET/CT over conventional imaging or 111In-DTPA-SPECT/CT demonstrating a high sensitivity (90%), specificity (91%), and its safety. Occasional false-negatives were observed and occurred primarily in poorly-differentiated NETs or insulinomas that have no or low somatostatin receptor sst2 expression and with small lesions (<0.7 cm)[59]. During interpretation of the 68Ga-DOTA-peptide-PET/CT images, numerous studies have pointed out false-positives can occur due to uptake in the uncinate process of the pancreas, the adrenal gland or due to high somatostatin receptor expression in the spleen and splenosis, with inflammatory processes, or with increased osteoblastic activity[60, 61]. The use of 68Ga-DOTA-PET/CT has been reported to change clinical management in 20–70% of NET patients[62, 63, 64••, 65, 66•, 67, 68].

The uptake of 68Ga-DOTA-peptides by NETs strongly correlates with the tumor expression of sst2[50, 69, 70]. A number of recent studies[53, 71–74]have reported that the maximum standardized uptake value(SUV/max) of 68Ga-DOTA-peptide-PET/CT-imaging of NETs has important prognostic and predictive value. In well-differentiated NETs it was an independent predictor of progression-free survival(PFS)[53, 74]. In another study[71] a cutoff-value of 16.4 for 68Ga-DOTA-peptide-PET/CT was found predictive of a tumor response with PRRT using either 90Y- or 177Lu-labeled somatostatin analogues. SUV/max on 68Ga-DOTA-peptide-PET/CT has also been reported to be predictive in patients with advanced NETs regarding their response to octreotide therapy with a SUV/MAX>29.4 associated with a longer PFS[72]. In patients with well-differentiated G1/G2 pNETs[73], a SUV/Max >37.8 on 68Ga-DOTA-peptide-PET/CT was an independent predictor of PFS.

Three different 68Ga-linker-somatostatin labeled analogues have been used in different studies including 68Ga-DOTATATE (the most commonly used), 68Ga-DOTATOC, and 68Ga-DOTANOC[47, 50, 75]. These differ in their affinities for the different somatostatin receptor subtypes (sst1-5), but all have high affinity for sst2. Each of these performs better than SRS with 111In-DTPA-peptide-SPECT/CT[32, 47, 75]. They have been directly compared in relatively few studies with one suggesting uptake was better with 68Ga-DOTATATE[76] and a second reported the sst2,3,5-specific 68Ga-DOTANOC detected more lesions[75]. Reviews of all studies comparing these different ligands concluded that overall there seemed to be no or little major difference in their performance[32, 47].

Comparison of 68Ga-DOTA-PET/CT and 18F-FDG-PET/CT

Whereas 68Ga-DOTA-peptide-PET/CT assesses NET somatostatin receptor expression, 18F-FDG-PET/CT studies metabolic-activity by assessing glucose-uptake, and therefore these two imaging modalities assess different characteristics of NETs. Older studies suggested that 18F-FDG-PET/CT had minimal utility in NETs, however, more recent studies show a percentage of NETs have high 18F-FDG-PET/CT activity[74, 77–84]. Recently there have been a number of studies attempting to define the potential usefulness of 18F-FDG-PET/CT and 68Ga-DOTA-peptide-PET/CT either alone or together[74, 77, 79, 80]. In general, these studies support the conclusion that 68Ga-DOTA-peptide-PET/CT demonstrated superior imaging in well-differentiated G1/G2 NETs compared to 18F-FDG-PET/CT, whereas 18F-FDG-PET/CT demonstrates higher uptake in poorly-differentiated G3 NETs than 68Ga-DOTA-peptide-PET/CT[77, 79]. A similar pattern is seen with lung carcinoids with 68Ga-DOTA-peptide-PET/CT being more sensitive than 18F-FDG-PET/CT for detecting typical carcinoids, whereas the reverse was true for atypical lung carcinoids[85•]. The presence of 18F-FDG-PET/CT in NETs has been shown to correlate strongly with high rate of progression and to have prognostic significance[77, 78, 81, 83, 84]. In one study patients with a positive 18F-FDG-PET/CT with a SUV ratio of 2.5 of greater had a 4-yr survival rate of 0%[81]. Furthermore, in a number of studies, some patients with G1/G2 tumors had positive 18F-FDG-PET/CT uptake which had important predictive value[33•, 77, 82]. A number of studies have concluded that the results of 18F-FDG-PET/CT and 68Ga-DOTA-peptide-PET/CT in patients with NETs are complementary in providing different information that is clinically relevant[77, 79, 80]. In one study their combined impact was to change the therapeutic decision in 59% of the patients[79].

In well-differentiated NETs the maximal standardized uptake value (SUV/Max) for 68Ga-DOTA-PET/CT is superior to that for 18F-FDG-PET/CT as an independent prognostic factor for PFS[53].

SRS with 111In-DPTA-SPECT/CT has also been compared to 18F-FDG-PET/CT in studies[81, 82, 86]. Similar, although less dramatic results compared with those seen with the comparison of 68Ga-DOTA-PET/CT and 18F-FDG-PET/CT reviewed above, were obtained. SRS with 111In-DPTA-peptide-SPECT/CT had greater sensitivity for well-differentiated NETs than 18F-FDG-PET/CT, and the reverse was true for poorly-differentiated NETs[82]. The sensitivity of 111In-DPTA-peptide-SPECT/CT and 18F-FDG-PET/CT were very much affected by the tumor grade, being 79% vs 52% for Grade 1, 85% vs 86% for Grade 2, and 57% vs 100% for Grade 3[82]. 111In-DPTA-peptide-SPECT/CT negativity and 18F-FDG-PET/CT positivity correlate with early tumor progression[86], and 18F-FDG-PET/CT positivity[78, 86] correlated with shortened PFS and overall survival.

Comparison of 68Ga-DOTA-PET/CT and 18F-FDOPA PET/CT

18F-FDOPA PET/CT takes advantage of the fact that NETs take up and decarboxylate amine precursors by assessing the ability of the tumor cells to be taken up by a neutral-amino acid-transporter (LAT1/4F2hc)[87•]. In contrast, 68Ga-DOTA-peptide-PET/CT assesses NET somatostatin receptor expression, and therefore, these two imaging modalities assess different characteristics of NETs. A number of studies have recently compared these two radiolabeled peptides in patients with different NETs[56]. In patients with pheochromocytomas and paragangliomas, 68Ga-DOTA-peptide-PET/CT is more sensitive than 18F-FDOPA-PET/CT in detecting head and neck paragangliomas, especially in patients with SDHD (succinate dehydrogenase-subunit b mutations)[56]. 18F-FDOPA-PET/CT is reported to be a good modality for detecting medullary thyroid cancer, investigating hyperinsulinemic states, and is more sensitive than SRS with 111In-DTPA-SPECT/CT in detecting and staging carcinoid tumors, but not pNETs[8, 34, 87•, 88].

In one comparative study 18F-FDOPA PET/CT was less sensitive than 68Ga-DOTA-peptide-PET/CT in detecting NETs((70% pNETs)[89].

Similar to 68Ga-DOTA-peptide-PET/CT, 18F-FDOPA PET/CT is of limited value in localizing insulinomas[46, 90–92]. Carbidopa is an inhibitor of peripheralaromaticamino-acid decarboxylase, and its administration has been shown to increase the sensitivity of 18F-FDOPA PET/CT detection of insulinomas to 70%[93]. In another study[94] carbidopa premedication increased the sensitivity of 18F-FDOPA PET/CT to 90% for localizing NF-pNETs, which was superior to the 68% seen with 111In-DTPA-SPECT/CT-imaging.

Use of radiolabeled antagonists rather than agonists

Initially only radiolabeled somatostatin receptor agonists were used for SRS/PRRT because it was assumed that cellular internalization of ligand by the tumor was essential for both imaging and for PRRT, because with numerous G-protein-coupled receptors, peptide agonists, but not antagonists are internalized[95, 96]. However, in preclinical studies in animals, 111In labeled sst2/sst3 peptide receptor antagonists showed superior binding in both amount and in retention-time with cells expressing these receptors, than seen with 111In-labeled-agonists[96], even though the antagonists were not internalized. Analysis of the binding characteristics demonstrated the antagonist showed a 10-times higher number of binding sites than seen with the agonist[96], possibly because it was interacting with predominately low-affinity receptor-sites ,whereas the agonist may have interacted with predominately high-affinity receptor-states.

Subsequently, in a study of 5 patients with metastatic thyroid cancers or NETs[95], a radiolabeled-antagonist, 111In-DOTA-BASS, showed higher tumor-uptake and lower renal retention than the radiolabeled-agonist, and imaged more lesions.

These promising results have been extended to the investigation of the relative value of radiolabeled-somatostatin analogues that are agonists or antagonists, for their tumoricidal effects on sst2-containing tumor cells by PRRT[97]. In a preclinical study the radiolabeled antagonist, 177Lu-DOTA-JR11, demonstrated 5-times greater tumor cell-associated radioactivity than the agonist, 177Lu-DOTA-octreotate, caused more double-stranded DNA breaks in the tumor, showed in biodistribution studies a 4-times greater radiation-dose with the antagonist and in an in vivo study, and resulted in a longer tumor-growth delay. These promising results were extended recently to investigate the comparative effect of these two ligands for PRRT in 4 patients with advanced NETs[98••]. 177Lu-DOTA-JR11 delivered 1.7–10.6-fold higher tumor doses than 177Lu-DOTATATE, and the tumor-kidney and tumor to bone marrow dose was 1.1–7.2 times higher. The radiolabeled antagonist caused a partial remission in 2/4 patients, stable disease in 1 patient and a mixed response in the 4th patient[98••]. These results demonstrate that radiolabeled-somatostatin receptor antagonists show promise of being superior agents to the currently widely used radiolabeled-agonists, for both imaging and for PRRT.

Development of other radiolabeled ligands for imaging

68Ga has a short half-life of 68 min which can lead to logistic problems with many patients examined daily and it has a limited spatial resolution, which can be overcome by the use of 64Cu (half-life −12.7 hrs), allowing once-daily preparation for multiple uses, and it has lower positron energy than 68Ga which should translate into better spatial resolution[99–101]. In 14 patients with NETS 64Cu-DOTATATE imaging was investigated using both SPECT/CT and PET/CT[100]. Images of excellent quality with high spatial resolution were obtained and in 43% of patients additional lesions were found using PET/CT compared to SPECT/CT[100]. In a second study[99] 64Cu-DOTATATE-PET/CT was compared prospectively to 111In-DTPA-Octreotide in 112 patients with confirmed NETs. The diagnostic sensitivity of 64Cu-DOTATATE-PET/CT was 97%/97% which was significantly better than 111In-DTPA-Octreotide(87%/87%) and with 64Cu-DOTATATE-PET/CT twice as many lesions were detected including in 36% of patients in organs thought not involved by 111In-DTPA-Octreotide imaging[99]. A recent study [102••] reports a prospective, head-to-head comparison of 64Cu-DOTATATE-PET/CT and 68Ga-DOTATATE-PET/CT in 59 NET patients and found they had equal sensitivity on a per patient-basis, but 64Cu-DOTATATE-PET/CT identified significantly more lesions and its longer half-life made it easier to use in a clinical setting.

A preclinical study reports[103]excellent imaging of HEK-sst2 containing xenografts by two sst2-radiolabeled antagonists, 64Cu- and 68Ga-NODAGA-LM3. The authors conclude that these ligands are promising candidates for imaging with favorable pharmacokinetics and high-image contrast on PET/CT[103].

Using somatostatin receptor overexpression to deliver cytotoxic doses of radiolabeled somatostatin receptor ligands(PRRT) has received the most attention using β-emitting isotopes(90Y,177Lu), however a significant number of patients do not show tumor shrinkage and new approaches are being considered. One approach is to use 213Bi-DOTATOC, which allows target alpha-particle therapy[104]. In one study of 7 patients refractory to 90Y/177Lu-DOTATATE, all demonstrated enduring responses with favorable acute and midterm toxicity with 213Bi-DOTATOC[104]. Other approaches being taken to increase the cytotoxicity of 90Y-/177Lu in PRRT include the use of combination therapies including using 90Y-/177Lu-DOTATATE together[105]; combined with PARP inhibitors to potentiate the accummulation of double-stranded DNA breaks and cytoxicity[106]; with peptide-degradation inhibitors such as phosphoramidon to increase tissue uptake[107, 108] or with chemotherapeutics to increase sensitivity such as temozolomide, or capecitabine and other anti-tumor agents such as everolimus[30, 109–112].

Novel ligands and approaches

In addition to ligands for somatostatin receptors, a number of other molecular imaging probes are in development, which may prove to be useful not only in NETs, but also a wide group of other tumors. These include: radiolabeled GLP-1 receptor ligands[90, 113•, 114] which show particular promise in imaging insulinomas and adult nesidioblastosis; radiolabeled-agonists interacting with the chemokine-receptor, CXCR4, which is frequently overexpressed in proliferating and advanced tumors including SCLC cells and NETs[16, 115]; 68Ga-DOTA-labeled CCK2 receptor ligands for imaging medullary thyroid cancer and SCL cancer[116–118]; radiolabeled-bombesin receptor ligands (agonists/ antagonists)(BB1, BB2,BB3-receptor) which can image a large range of tumors (prostate, colon, breast, CNS, NETs)[15, 119•]; radiolabeled-ligands which interact with VIP-PACAP receptors (VPAC1,VPAC2,PAC) which also can image a wide range of tumors[120•], and radiolabeled-ligands interacting with the glucose-dependent insulinotrophic-polypeptide receptor(GIPR) which is overexpressed by a number of tumors including NETs and whose expression correlates with the proliferative-index ,whereas sst expression does not[121–126]. A recent study demonstrated that a combination of GIP, somatostatin, and GLP-1 agonists identified all NETs, because at least one is overexpressed by all tumors and therefore it was proposed, triple peptide receptor targeting (GIPR, sst, GLP1R) should be considered for enhanced sensitivity[121, 123]. An additional area of molecular imaging receiving increased attention is the targeting of tumor’s angiogenesis, including NETs, which are vascular tumors, using increased expression of integrin-receptors[127, 128•, 129–132].

Conclusion

Molecular imaging by performing somatostatin receptor scintigraphy(SRS) (using 111In-DTPA-peptide-SPECT/CT or 68Ga-DOTA-peptide-PET/CT) is now an essential component in almost all steps in the management of patients with NETs. Both are approved in the US and many countries. However, numerous studies now demonstrate in many different types of NETs, that 68Ga-DOTA-peptide-PET/CT is the preferred modality because of its greater sensitivity, excellent specificity, better resolution and its use changes patient management in 20–70% of cases. Recent studies demonstrate that 68Ga-DOTA-peptide-PET/CT also has prognostic value and that it and 18F-FDG -PET/CT can be complementary. Recent studies have helped to define the role of 18F-FDOPA PET/CT and reported novel ligands for SRS which show promise, include antagonists, which show enhanced imaging of NETs. Furthermore, other molecular receptor ligands for imaging are being studied (CCK, GLP1, GIP, chemokines, integrins, bombesin) which show promise in both NETs and other tumors.

KEY POINTS.

  • ●

    There have been numerous advances in Molecular imaging of NETs over the last few years.

  • ●

    Molecular imaging in NET patients currently consists of somatostatin-receptor scintigraphy (using 111In-DTPA-peptide-SPECT/CT ,68Ga-DOTA-peptide-PET/CT)[approved in US/many countries]; 18F-FDG -PET/CT; 18F-FDOPA PET/CT; with less frequent general use of 125I-MIBG or 11C-5-hydroxy-L-tryptophan(5-HTP)(11C-5-HTP)- PET/CT.

  • ●

    68Ga-DOTA-peptide-PET/CT is rapidly replacing 111In-DTPA-peptide-SPECT/CT because of its greater resolution resulting in greater sensitivity and changes in patient management.

  • ●

    Recent studies have compared these different modalities, helping to define their place in management, which has resulted in some being complementary (68Ga-DOTA-peptide-PET/CT/18F-FDG) and also leading to some controversies and unresolved issues.

  • ●

    Newer, novel ligands with different linkers and radiolabeles are being described include somatostatin-receptor antagonists which show enhanced imaging.

  • ●

    Ligands for other receptors(CCK, GLP1, GIP, Bombesin, chemokines, integrins) are reported, that also show promise for imaging NETs and other tumors.

Acknowledgments

Financial support

This research was supported by the intramural program on NCI and NIDDK of the NIH.

Footnotes

Conflicts of Interest

None

References

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