and Therapy of Neuroendocrine Tumors of the Abdomen

Fig. 1 a–o

Well-differentiated neuroendocrine neoplasm (NEN) of pancreatic tail, status post extended pancreatectomy and partial omentectomy, initial tumor stage (Union for International Cancer Control, UICC) pT2 (Ø 3.2 cm) pN1 (6/12) cM1 R0, Lx Vx, G2, proliferation rate (Ki-67) 10%, immunohistochemical expression of chromogranin A, synaptophysin, and somatostatin receptors (SSTRs), underwent peptide-receptor radionuclide therapy (PRRT). a–e Strongly SSTR-positive liver metastasis in S1 [standardized uptake value (SUV) 26.1] on gallium- 68 DOTA-D-Phe1-Tyr3-octreotide (⁶⁸Ga-DOTATOC) positron emission tomography computed tomo graphy (PET/CT) before therapy (a, coronal fused; c, transverse fused), hypodense on CT (b, transverse view), seen on T2-weighted magnetic resonance imaging (MRI) (d, transverse view), and importantly, ametabolic on ¹⁸F-2-fluoro- 2-deoxyglucose (¹⁸F-FDG) PET/CT with complete mismatch (e, transverse fused image). f–h The ⁶⁸Ga-DOTATOC PET maximum intensity projection (MIP) image before PRRT (f) shows, in addition to the receptor-positive lesion in S1, discrete tracer uptake in S6. The ¹⁷⁷Lu- DOTATOC whole-body planar scan 44 h after therapy also demonstrates an intense uptake in the liver metastasis described above. There was an excellent response after one PRRT cycle, as seen on the ⁶⁸Ga-DOTATOC PET image after therapy (h). i–o Posttherapy ⁶⁸Ga-DOTATOC PET/CT after one PRRT cycle (i, coronal fused; m, transverse fused and n coronal PET slice) compared with pretherapy SSTR PET (o, coronal PET before PRRT) shows complete remission

Targeted Imaging

NETs of the abdomen, i.e., gastroenteropancreatic (GEP) NETs, are relatively rare neoplasms typified by their endocrine metabolism and a distinct histological pattern [1]. Functional GEP-NETs cause symptoms due to secretion of neuroamines. On the other hand, many tumors are clinically silent, until they are identified later with mass effects. Therefore, better tumor localization and identification of small lesions is necessary. The morphologically oriented imaging modalities of ultrasound (US) (trans-abdominal, endoscopic, color Doppler), CT, and magnetic resonance imaging (MRI) provide valuable anatomical information and are therefore crucial for staging and restaging NETs. However, their shortcomings are in diagnosing an unknown neuroendocrine primary tumor and defining NET prognosis, where molecular imaging using radionuclides plays an important role.

Radionuclide imaging with gamma-emitting tracers, e.g., indium-labeled SMS analogs, and molecular imaging using diverse PET radiopharmaceuticals, e.g., galliumlabeled SMS analogs [2], is used for diagnostic workup of patients with NETs [3]. The foundation upon which molecular imaging of NETs is based, is the targeting of a metabolic pathway or a genuine molecular event (e.g., receptor binding of a peptide) that is specific for a certain kind of tumor or tissue/cells.

Based on Somatostatin Receptor Expression of Neuroendocrine Tumors

Targeting NETs for THERANOSTICS is enabled by SSTR expression, mainly subtype 2, on their cell surfaces. Indium-111 diethylene triamine penta-acetic acid (DTPA)-D-Phe1-octreotide (¹¹¹In-pentetreotide; Octreo – Scan, Mallinckrodt, Inc, St. Louis, MO, USA) was the first radiolabeled SMS analog to be approved for NET scintigraphy and was shown in large clinical studies to be well suited for scintigraphic localization of primary and metastatic NETs [4]. Among ^99mTc-labeled SMS analogs, ^99mTc-EDDA-HYNIC-TOC (or -TATE) has been shown in a larger patient population to be superior to ¹¹¹In-pentetreotide for detecting SSTR-positive tumors and metastases [5]. The next generation of SMS analogs, e.g., DOTA-D-Phe¹-Tyr³-octreotide (DOTATOC) and DOTAD- Phe¹-Tyr³-Thr⁸-octreotide (DOTATATE) were developed and labeled with different radionuclides for THERANOSTICS, i.e., diagnosis using PET/CT, as well as for therapy [6]. The advantage of PET/CT is its ability to quantify the disease at a molecular level. Therefore, SSTR PET/CT using ⁶⁸Ga, a generator-produced radionuclide with convenient radiochemical characteristics for labeling with SMS analogs, clearly has an edge over single-photon- emission CT/CT (SPECT/CT) using gamma-emitting radionuclides. Hofmann et al. demonstrated this for the first time with ⁶⁸Ga-DOTATOC as compared to 111In-octreotide SPECT (CT taken as reference) in detecting upper abdominal metastases [7]. In a more recent study, ⁶⁸Ga-DOTATOC PET was proven to be superior to ¹¹¹Inoctreotide for detecting NET metastases in lung, bone, liver, and brain [8]. In our own experience with >8,000 SSTR PET/CT studies (currently >20 per week) performed at the Zentralklinik Bad Berka, ⁶⁸Ga-SSTR PET is able to detect many lesions that are not routinely detected by CT, MRI, skeletal scintigraphy, or US. Our group [9] demonstrated for the first time a close correlation between maximum standard uptake value (SUV_max) and immunohistochemical scores for SSTR (particularly subtype 2A) quantification in NET tissue [8]. In a bicentric study, ⁶⁸Ga-DOTA-1-Nal3-octreotide (DOTANOC) PET/CT localized the primary tumor in 59% of cases with cancer of unknown provenience (CUP-NET), significantly higher than the detection rate (39%) reported in the literature for ¹¹¹In-Octreoscan [10].

Based on the Serotonin Production Pathway

Most clinical symptoms of NET are due to the excessive production of serotonin, i.e., 5-hydroxytryptamine (5- HT). The precursor for the production of 5-HT is tryptophan. One of the intermediates in the production pathway, 5-hydroxytryptophan labeled with carbon-11 ([¹¹C]), can be used for functionally active and serotonin-producing NETs, which accumulate the radiopharmaceutical, leading to visualization on PET images.

Based on Biogenic Amine Production and Storage Mechanism

NETs are characterized by the production and storage of several biogenic amines. One of the radiopharmaceuticals, metaiodobenzylguanidine (MIBG), labeled with iodine- 131 (¹³¹I) or with ¹²³I, utilizes the structural resemblance of MIBG to norepinephrine (NE) [11]. As with NE, MIBG is taken up in an active amine uptake mechanism by the cell membrane of sympathomedullary tissue and by intracellular granules, which results in prolonged retention of the radiopharmaceutical in NETs. ¹²³I is the preferred radionuclide for labeling MIBG because of its better physical imaging characteristics and ability to perform SPECT, whereas ¹³¹I-MIBG can also be used for therapy. ¹²⁴I MIBG could be advantageous over ¹²³I-MIBG in PET imaging. Carbon-11 (¹¹C)- or fluorine-18 (¹⁸F)-labeled l-dihydroxyphenylalanine (DOPA) may be useful based on the increased activity of L-DOPA decarboxylase, one of the hallmarks of NETs [12].

Based on the Catecholamine Transport Pathway

Pheochromocytoma, neuroblastoma, and other chromaffin tumor tissues, due to their ability to produce epinephrine and NE, concentrate many synthetic amine precursors using catecholamine transporters. ¹¹C-epinephrine and ¹¹C-hydroxyepiphedrine (¹¹C-HED) are catecholamine analogs, and ¹⁸F-fluorodopamine is a catecholamine precursor, all of which concentrate, and thus help detect NETs [13].

Based on Increased Glucose Metabolism

The utilization of ¹⁸F-2-fluoro-2-deoxyglucose (¹⁸F-FDG) for tumor imaging is based on the high glucose metabolism of many cancer cells for meeting their energy demand. ¹⁸F-FDG enters the glycolytic pathway like glucose in cytoplasm, where it is phosphorylated by the enzyme hexokinase to ¹⁸F-FDG-6-phosphate; however, it is not significantly metabolized, resulting in further accumulation (trapping) inside the cancer cell. ¹⁸F-FDG PET has a role in comprehensive tumor assessment in intermediateand high-grade tumors: intense metabolic activity of tumors/ metastases indicates a poor prognosis due to the presence of aggressive tumor clones [14].

Both conventional and functional imaging tools play a critical role in the diagnosis of NETs. CT or MRI alone cannot provide specific information regarding the functional status of the tumor. As knowing the functional status is essential in most cases prior to starting any of the available therapies, the current medical consensus should be to use PET/CT (or SPECT/CT or SPECT when PET is not available) at all tumor stages, and add MRI or other specific imaging modalities only when needed. Clinical indications for PET/CT in NETs are the following:

Diagnosis and staging
Follow-up of patients after surgery
Follow-up of patients after octreotide, chemotherapy or targeted therapy (kinase inhibitors)
Choosing the appropriate therapeutic regime of PRRT
Predicting response to PRRT
Defining patient prognosis.

Targeted Radionuclide Therapy

Following scintigraphic localization of NETs with radio-labeled SST analogs, therapeutic approaches with radio-labeled peptides were developed. PRRT comprises systemic administration of a specific, well-defined radio-pharmaceutical composed of a therapeutic radionuclide (e.g., a β-emitting radionuclide ¹⁷⁷Lu or ⁹⁰Y) chelated to a peptide for the purpose of delivering cytotoxic radiation to a tumor. The biological basis of PRRT is the SSTR 2A-mediated internalization and intracellular retention of the radiopeptide. PRRT can deliver adequate radiation doses to tumors to achieve volume reduction or even cure. Several clinical trials indicate that PRRT with radiolabeled SST analogs is among the most promising newly developed targeted tools for NETs [15–19]. PRRT is ideal for well-differentiated GEP and bronchial NETs (G1 or G2) according to the World Health Organization (WHO) 2010 classification [20]. Recently, as a joint effort of the International Atomic Energy Agency (IAEA), European Association of Nuclear Medicine (EANM), and Society of Nuclear Medicine and Molecular Imaging (SNMMI), practical guidelines on PRRT in NETs were formulated based on recent literature and opinions of leading experts covering rationale, indications, and contraindications for PRRT, treatment response assessment, and patient follow-up [21].

Prerequisites for PRRT are as follows:

Histologically proven NET
High SSTR expression determined by functional imaging with OctreoScan (Krenning score) or ⁶⁸Ga SSTR PET/CT
Patient condition: Karnofsky-Lansky Performance Status >60% or Eastern Cooperative Oncology Group (ECOG) <2
Tumor differentiation, preferably G1 or G2
Proliferation rate (Ki-67/mitotic index) of the tumor, preferably ⩽20%.