Neuroendocrine tumors (NETs) are tumors originated from neuroendocrine cells in the body. The localization and the detection of the extent of NETs are important for diagnosis and treatment, which should be individualized according to the tumor type, burden, and symptoms. Molecular imaging of NETs with high sensitivity and specificity is achieved by nuclear medicine method using single photon-emitting and positron-emitting radiopharmaceuticals. Somatostatin receptor imaging (SRI) using SPECT or PET as a whole-body imaging technique has become a crucial part of the management of NETs. The radiotherapy with somatostatin analogues labeled with therapeutic beta emitters, such as lutetium-177 or yttrium-90, has been proved to be an option of therapy for patients with unresectable and metastasized NETs. Molecular imaging can deliver an important message to improve the outcome for patients with NETs by earlier diagnosis, better choice of the therapeutic method, and evaluation of the therapeutic response.
Neuroendocrine tumors (NETs) are unique tumors that originate almost everywhere in the body from neuroendocrine cells [
Overall, 5- and 10-year survival rates of NETs were 78 and 63%, respectively [
SST is produced by neuroendocrine, immune, and inflammatory cells in response to many kinds of factors, such as ions, nutrients, neuropeptides, neurotransmitters, and thyroid [
There is significant variation in SSTR subtype expression between the tumors of the same type [
Characteristics of radionuclides used for SRI and PRRT.
Radionuclide | Type of decay | Type of rays | Half-life | Energy | Producer |
---|---|---|---|---|---|
111In | EC |
|
2.8 days | 173 KeV | 111Cd (p, n) |
247 KeV | |||||
18F |
|
|
109.8 min | 511 KeV |
20Ne (d, |
EC | 18O (p, n) | ||||
68Ga |
|
|
68.3 min | 511 KeV | 68Ge-68Ga generator |
90Y |
|
|
64 h | 2.288 MeV | 90Sr-90Y generator |
177Lu |
|
|
6.7 days | 0.5 MeV |
176Lu (n, |
176Yb (n, | |||||
64Cu |
|
|
12.7 h | 0.58 MeV |
63Cu (n, |
|
0.653 MeV | 64Zn (n, p) | |||
EC |
|
1.346 MeV |
SRI is widely used for the diagnosis, as well as staging and restaging of NETs [
The tracer used for SPECT and PET in NETs and for gene imaging.
Types of imaging | Radiotracer |
---|---|
SPECT | 111In-pentetreotide |
111In-DTPAOC | |
123I-octreotide | |
111In-DOTA-lanreotide | |
111In-DOTA-NOC-ATE | |
111In-DOTA-BOC-ATE | |
| |
PET | 68Ga-DOTATATE |
68Ga-DOTATOC | |
68Ga-DOTANOC | |
64Cu-DOTATATE | |
18F-FP-Gluc-TOCA | |
| |
Gene imaging | 94mTc-Demotate 1 |
99mTc-P2045 | |
99mTc-P829 |
111In-pentetreotide used to be the first choice for the visualization of receptor for SST analogues. Tumors and metastases that express the SSTR subtypes SSTR2, SSTR3, or SSTR5 can also be visualized in vivo after injection of 111In-pentetreotide [
There is an overall high sensitivity of SRI to localize NETs. The value of SRI in patients with NETs has been proven [
68Ga-labeled somatostatin analogues are widely used [
Lesions have exclusive higher uptake in 68Ga-DOTATOC than 68Ga-DOTATATE imaging. (a) From left to right: 68Ga-DOTATOC PET maximum-intensity projection, 68Ga-DOTATOC PET, CT, and PET/CT fusion. (b) From left to right: 68Ga-DOTATATE PET maximum-intensity projection, 68Ga-DOTATATE PET, and PET/CT fusion. The arrow refers to ileal carcinoid (SUVmax 68Ga-DOTATOC, 21.0; SUVmax 68Ga-DOTATATE, 8.2) [
A case reported that, in a patient who had synchronous colorectal cancer and pancreatic NET, the 68Ga-DOTATATE PET and 18F-FDG PET imaging showed two different tumor types within the liver metastases. This case suggested that combinational 68Ga-DOTATATE PET and 18F-FDG PET imaging modalities are of potential use in understanding the biology of the NETs and managing the NETs [
Several novel agents have been developed. DOTANOC is the first compound for PET imaging and is reported to have a higher affinity for SSTR2 as well as for SSTR5 [
A study concluded the sensitivity and specificity of SSTR PET or PET/CT in detecting thoracic and/or GEP-NETs, which were 93% and 91%, respectively [
The treatment of the NETs includes peptide receptor therapy, somatostatin analogues, and surgery [
90Y-DOTATOC is a potential choice which can deliver high absorbed doses to tumors expressing SST2 receptors, and the therapeutic response is achieved in about 25% of patients [
Antitumor effects of 90Y-DOTATOC have been reported considerably different between various studies [
177Lu-DOTATATE, another radiopharmaceutical for treatment purpose, was used in GEP-NET patients. It was reported that CR and PR occurred in 2% and 28% of patients, respectively, and minor tumor response occurred in 16%. There was a 40 to 72 months survival benefit from diagnosis when compared with historical controls [
(a)–(c) Planar scans of the abdomen, 3 days after the injection of 200 mCi 177Lu-octreotate in a patient with liver metastases of an operated neuroendocrine pancreatic tumor. (a) After the first treatment; (b) after the second treatment; (c) after the fourth treatment. Note the loss of intensity of uptake in the liver lesions (arrows in (a)). This sign virtually always indicates a tumor volume response. (d) and (e). CT scans of the same patient: (d) before treatment; (e) 3 months after the last treatment. Tumor (arrows in (d)) is not demonstrated on (e). Neither MRI nor octreoscan could demonstrate definite tumor deposits at that time [
With 177Lu-DOTATATE treatments, tumor regression of 50% or more was achieved in 28% of patients. In 19% of patients, tumor regression was in 25% to 50%, SD showed in 35%, and PD showed in 18% of patients [
Oh et al. evaluated the effect of PRRT on the glucose metabolism and SSTR density assessed by 18F-FDG PET/CT and 68Ga-DOTANOC PET/CT, respectively. Only 56% (77/138) of the lesions show matched SSTR expression and glucose metabolism; the relationship is complicated [
Radiolabeled octreotide analogues therapy is effective in patients with NETs [
The radioagent used in PRRT and the efficacy of the therapy.
Therapeutic agents | Subjects | Dosage | Duration | Main findings | References |
---|---|---|---|---|---|
90Y-DOTATATE | 46 NETs | 7.4 GBq/m2 | 3–5 cycles | PFS 37.4 months | [ |
90Y-DOTATOC | 116 Metastatic NETs | 162–200 mCi/m2 | 2–4 cycles | Significant reduction of symptoms was found in 83% of patients | [ |
177Lu-DOTATATE | 310GEP-NETs | 750 to 800 mCi | 4 cycles | Survival benefit of 40 to 72 months from diagnosis | [ |
177Lu-DOTATOC | 27 relapse NETs | 7,400 MBq | Once | 2 PR, 5 MR, 12 SD, and 8 PD | [ |
Dose-limiting factors for PRRT are kidney and/or bone marrow dose [
The human SSTR subtype 2 (hSSTr2), as a reporter gene, is under research for molecular imaging applications which have several features for potential translation to human studies [
The imaging of gene expression is critical to monitor gene transfer. There are great benefits for gene therapy trials from the use of noninvasive imaging to determine the location and time course of gene transfer [
A study used a tumor model with an adenoviral vector encoding the human type 2 SSTR (Ad5-CMVhSSTr2) and a radiolabeled somatostatin-avid peptide (P829) to evaluate the level and location of the expression of the transferred gene [
Significant advances have been made in the imaging of NETs, but the challenge is to find the ideal imaging method with increased sensitivity and better tomographic localization of the primary and metastatic disease [
Despite the fact that most GEP-NETs are slow growing, OS in NET patients with liver metastases is 2 to 4 years. In metastatic cases, there are limits of cytoreductive therapeutic options [
Beta particles with higher energies and longer range emitted by 90Y may be preferable for larger tumors, while 177Lu that emits beta particles with shorter range and longer half-life may be a good choice for small tumors. In patients with tumors of nonhomogeneous receptor distribution and various sizes, a combination of radionuclide might be useful [
68Ga-DOTATOC is a specific ligand for hSSTr2 reporter system and so that for hSSTr2 reporter gene PET imaging. Because DOTATOC has been tested clinically, this reporter system can be used for translation to human studies [
The SSTR-based molecular imaging is a noninvasive and quantitative method to diagnose the NETs and evaluate the therapeutic efficacy for NETs. The development of radiolabeled SST analogues has affected the clinical management of patients with NETs. PET/CT can be useful in the early prediction of the treatment outcome of NET patients who underwent PRRT. Furthermore, the clinical management of NETs will be further improved if better radioligands are developed and more technologies are used to identify the radiotherapy treatment response in patients with NETs.
Dual therapy is a promising method to treat NETs. The combination of PRRT and EBRT can increase the dose delivered to the tumor and reduce the dose for organs at risk. The clinical use of molecular imaging is not only in diagnosis and treatment efficacy evaluation, but also in patient selection. Still, it plays an important role in the reporter gene research. Personalized diagnosis and treatment of NETs will be established based on increased understanding of molecular mechanisms of NETs.
Neuroendocrine tumors
Gastroenteropancrea
Somatostatin receptors
Somatostatin
Sst subtype 2
Somatostatin receptor imaging
Single photon emission computed tomography
[111In-DTPA(0)]octreotide
Positron emission tomography
68Ga-DOTA(0), Tyr(3)octreotate
Somatostatin receptor scintigraphy
Computed tomography
Peptide receptor radionuclide therapy
Standard uptake value
18F-fluoropropionyl-Lys0-Tyr3-octreotate
Somatostatin receptor targeted radionuclide therapy
Response evaluation criteria in solid tumors
Partial response
Stable disease
Progressive disease
Progression-free survival
Overall survival
Complete response
Human somatostatin receptor subtype 2
Adeno-associated viral
Selective internal radiation therapy.
The authors declare that they have no conflict of interests.
This work is partly sponsored by Grants from the Zhejiang Provincial Natural Science Foundation of China (Z2110230), Health Bureau of Zhejiang Province (2011ZDA013), and National Science Foundation of China (NSFC) (no. 30672396). This work was reprinted by permission of SNMMI from Poeppel et al. [