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Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare tumors that present many clinical features secreting peptides and neuroamines that cause distinct clinical syndromes such as carcinoid syndrome. However most of them are clinically silent until late presentation with mass effects. Surgical resection is the first line treatment for a p...
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Neuroendocrine neoplasms (NEN) are rare malignancies with a wide spectrum of metastatic potential which originate from the endocrine cells of the body and express somatostatin receptors. The (68)gallium somatostatin receptor positron emission tomography-computed tomography (PET/CT) technique is the most sensitive method of assessment of well-differ...
Citations
... The development of radiolabelled small peptides for diagnostic imaging and radionuclide therapy in nuclear oncology has seen significant progress in recent years (Baldelli 2014). This progress is attributed to the higher expression of peptide receptors in many tumour cells compared to normal tissues. ...
Targeted alpha therapy (TAT) has emerged as a viable therapeutic option for cancer management, due to its high target specificity and superlative ability to effectively disrupt the genetic make-up of the cancerous cells, thereby impeding their aggressive growth. TAT belongs to the category of radioligand therapies in oncology wherein alpha-emitting radionuclides are delivered directly to tumours and the tumour microenvironment with little impact on surrounding healthy cells. This approach is facilitated by chelating the radionuclides with ligands or conjugating them to targeting vehicles which facilitate their biodistribution, localization, and accumulation in the target sites. Currently, TAT continues to exhibit promising therapeutic outcomes in both preclinical and clinical evaluations, with more exciting prospects for the future. Accordingly, this timely review focuses on the pertinent, appealing merits of TAT, elaborating on the favourable chemical properties of potent alpha-emitting radionuclides and their enhancement. The current review also delves into the radiobiology and dosimetry of alpha-particles, and their application to TAT. Recent preclinical and clinical reports have further supported the viability of TAT as a promising therapeutic intervention. More so, this review sheds light on the promising therapeutic possibilities that nuclear medicine, particularly TAT, can offer in oncology.
... Somatostatin synthetic analogs (SSAs) were initially introduced in 1987 for the management of carcinoid syndrome [94]. Around eighty percent of gastroenteropancreatic NETs express somatostatin receptors (SSR) [95]. By binding to somatostatin receptors, specifically somatostatin receptor 2, SSAs suppress excess hormone secretion and cell proliferation and can allow for stability or shrinkage of tumors. ...
Simple Summary
Liver metastases secondary to neuroendocrine tumors (NETs) are common at the time of diagnosis and are associated with worse quality of life and overall survival. This review focuses on the biomarkers and genetics associated with NETs, with a particular focus on disease diagnosis, prognosis, and treatment options. Specifically, liver-directed therapies are highlighted as meaningful treatment options for liver-dominant NETs.
Abstract
Neuroendocrine tumors (NETs) are considered rare tumors that originate from specialized endocrine cells. Patients often present with metastatic disease at the time of diagnosis, which negatively impacts their quality of life and overall survival. An understanding of the genetic mutations that drive these tumors and the biomarkers used to detect new NET cases is important to identify patients at an earlier disease stage. Elevations in CgA, synaptophysin, and 5-HIAA are most commonly used to identify NETs and assess prognosis; however, new advances in whole genome sequencing and multigenomic blood assays have allowed for a greater understanding of the drivers of NETs and more sensitive and specific tests to diagnose tumors and assess disease response. Treating NET liver metastases is important in managing hormonal or carcinoid symptoms and is imperative to improve patient survival. Treatment for liver-dominant disease is varied; delineating biomarkers that may predict response will allow for better patient stratification.
... Somatostatin is a 14-amino acid peptide that inhibits the secretion of other hormones such as serotonin, insulin, glucagon, gastrin and VIP and also has potent antiproliferative actions [112,113]. Due to the short half-life of native somatostatin, synthetic agents with longer half-life have been developed for therapeutic applications. Long-acting somatostatin analogues (SSAs) are peptide hormones that bind to somatostatin receptors (SSTR, mainly subtypes 2 & 5) to inhibit the secretion of other hormones and alleviate hormonal symptoms such as diarrhea and flushing [113][114][115]. ...
... Due to the short half-life of native somatostatin, synthetic agents with longer half-life have been developed for therapeutic applications. Long-acting somatostatin analogues (SSAs) are peptide hormones that bind to somatostatin receptors (SSTR, mainly subtypes 2 & 5) to inhibit the secretion of other hormones and alleviate hormonal symptoms such as diarrhea and flushing [113][114][115]. In addition, SSAs have also been shown to inhibit tumor growth in randomized phase III trials (PROMID and CLAIRNET) and therefore are considered the main foundation for treating metastatic well-differentiated NETs [116][117][118]. ...
Appendiceal neuroendocrine neoplasms (ANENs) usually present as incidental findings at the time of appendectomy for acute appendicitis. They are rare, accounting for only 0.5–1% of intestinal neoplasms; they are found in 0.3–0.9% of all appendectomy specimens. They are usually sporadic tumors. There are several histological types including well-differentiated neuroendocrine tumors (NETs), poorly differentiated neuroendocrine carcinomas (NECs), and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs). Histologic differentiation and the grade of well-differentiated NETs correlate with clinical behavior and prognosis. Management varies based on differentiation, aggressiveness, and metastatic potential. There is debate about the optimal surgical management for localized appendiceal NETs that are impacted by many factors including the tumor size, the extent of mesoappendiceal spread, lymphovascular invasion and perineural involvement. In addition, the data to guide therapy in metastatic disease are limited due to the paucity of these tumors. Here, we review the current advances in the management of ANENs within the context of a multidisciplinary approach to these tumors.
... They belong to the super-family of GPRC (G protein coupled receptor). There are five sub-types of SSTRs located in different chromosomes [77,78]. These receptors can be imaged, and their expression provides additional information in terms of treatment sensitivity/response, disease burden, extension, and location. ...
Simple Summary
Neuroendocrine neoplasms are a small group of malignancies with a diverse prognosis and behaviour. In order to offer an adequate treatment, physicians need to perform a proper diagnosis, staging and stratification. This review aims to help to integrate the information from pathology, immunohistochemistry, molecular biology and imaging to guide this process.
Abstract
Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumours with a diverse behaviour, biology and prognosis, whose incidence is gradually increasing. Their diagnosis is challenging and a multidisciplinary approach is often required. The combination of pathology, molecular biomarkers, and the use of novel imaging techniques leads to an accurate diagnosis and a better treatment approach. To determine the functionality of the tumour, somatostatin receptor expression, differentiation, and primary tumour origin are the main determining tumour-dependent factors to guide treatment, both in local and metastatic stages. Until recently, little was known about the biological behaviour of these tumours. However, in recent years, many advances have been achieved in the molecular characterization and diagnosis of NENs. The incorporation of novel radiotracer-based imaging techniques, such as ⁶⁸Gallium-DOTATATE PET-CT, has significantly increased diagnostic sensitivity, while introducing the theragnosis concept, offering new treatment strategies. Here, we will review current knowledge and novelties in the diagnosis of NENs, including molecular biology, pathology, and new radiotracers.
... SST analogue drugs have been widely used for clinical treatment of acromegaly caused by excessive release of growth hormone from the pituitary gland, NETs and carcinoid syndrome [30][31][32][33][34][35] . In addition, octreotide has also been approved for the treatment of TSH-secreting pituitary adenomas, liver fibrosis, refractory diarrhea and flushing 33,36,37 . ...
... SST analogue drugs have been widely used for clinical treatment of acromegaly caused by excessive release of growth hormone from the pituitary gland, NETs and carcinoid syndrome [30][31][32][33][34][35] . In addition, octreotide has also been approved for the treatment of TSH-secreting pituitary adenomas, liver fibrosis, refractory diarrhea and flushing 33,36,37 . Similarly, lanreotide is also clinically used to treat polycystic kidney disease, medullary thyroid cancer (MTC) and thyrotrophic adenoma with TSH secretion [38][39][40][41] . ...
The endogenous cyclic tetradecapeptide SST14 was reported to stimulate all five somatostatin receptors (SSTR1–5) for hormone release, neurotransmission, cell growth arrest and cancer suppression. Two SST14-derived short cyclic SST analogues (lanreotide or octreotide) with improved stability and longer lifetime were developed as drugs to preferentially activate SSTR2 and treat acromegalia and neuroendocrine tumors. Here, cryo-EM structures of the human SSTR2–Gi complex bound with SST14, octreotide or lanreotide were determined at resolutions of 2.85 Å, 2.97 Å, and 2.87 Å, respectively. Structural and functional analysis revealed that interactions between β-turn residues in SST analogues and transmembrane SSTR2 residues in the ligand-binding pocket are crucial for receptor binding and functional stimulation of the two SST14-derived cyclic octapeptides. Additionally, Q1022.63, N2766.55, and F2947.35 could be responsible for the selectivity of lanreotide or octreotide for SSTR2 over SSTR1 or SSTR4. These results provide valuable insights into further rational development of SST analogue drugs targeting SSTR2.
... [7] GEP-NETs express SSTR1, SSTR2, SSTR3, SSTR4, and SSTR5, with expression of these receptors varying based on the location of the tumor. [8] PRRT targets the SSTRs using radiolabeled SSAs such as 177 Lu-DOTA-DPhe-[Tyr 3 ] octreotate ( 177 Lu-DOTATATE, alternatively, Lutathera) to facilitate direct delivery of radiation to tumor cells. [9][10][11] In contrast to the 90 Y radionuclide that has a range of ∼12 mm in tissues and is better suited for larger tumors, Lutathera has a maximum particle range of 2 mm and is preferentially used for smaller tumors. ...
Neuroendocrine tumors (NETs) are rare, but the incidence and prevalence of NETs are increasing in the United States. While surgery is the preferred treatment for NETs, it is not a viable option for metastatic disease. Lutathera (¹⁷⁷Lu-DOTATATE) is approved by the United States Food and Drug Administration and the European Medicines Agency for the treatment of gastroenteropancreatic (GEP)-NETs in adults. There is limited information on GEP-NET treatment responses to Lutathera.
Our institution launched a peptide receptor radionuclide therapy (PRRT) service line using Lutathera with involvement from a multidisciplinary team and complete collaboration between hospital administration and clinical providers. A prospective registry study was also established in order to collect patient demographics and clinical data regarding the treatment of GEP primary NETs with Lutathera.
Between August 2018 and July 2020, 35 GEP-NET patients were treated with Lutathera, of which 65.71% received 4 complete cycles and 25.71% received 3 cycles; 5.71% and 2.86% received 2 and 1 cycles of PRRT, respectively. Most adverse events during the course of our study were low grade using the common terminology criteria for adverse events system. Of the patients who completed all 4 cycles: 22% showed partial response to Lutathera, 44% showed stable disease, and 13% showed disease progression based on a qualitative assessment of positron emission tomography/computed tomography imaging.
From our experience, Lutathera was well tolerated in patients with GEP-NET. Additional studies are needed to examine long-term clinical and patient-reported outcomes associated with GEP-NET treatment as well as financial considerations for hospitals embarking on a PRRT program.
... For example, in lung NETs: SST1-63% to 83%, SST2-43% to 96%, SST3-5% to 54%, SST4-0% to 14%, SST5-0% to 71% [10]. GEP-NETs (80%) present all five SST subtypes, in different proportion: SST1-68%, SST2-86%, SST3-46%, SST4-93%, SST5-57% [11]. The SST distribution in the human body can be accurately visualized by somatostatin receptors scintigraphy (SRS), using radiolabelled somatostatin analogues (RSA). ...
... For example, in lung NETs: SST 1 -63% to 83%, SST 2 -43% to 96%, SST 3 -5% to 54%, SST 4 -0% to 14%, SST 5 -0% to 71% [10]. GEP-NETs (80%) present all five SST subtypes, in different proportion: SST 1 -68%, SST 2 -86%, SST 3 -46%, SST 4 -93%, SST 5 -57% [11]. The SST distribution in the human body can be accurately visualized by somatostatin receptors scintigraphy (SRS), using radiolabelled somatostatin analogues (RSA). ...
Although neuroendocrine tumours (NETs) are intensively studied, their diagnosis and consequently personalised therapy management is still puzzling due to their tumoral heterogeneity. In their theragnosis algorithm, receptor somatostatin scintigraphy takes the central place, the diagnosis receptor somatostatin analogue (RSA) choice depending on laboratory experience and accessibility. However, in all cases, the results depend decisively on correct radiotracer tumoral uptake quantification, where unfortunately there are still unrevealed clues and lack of standardization. We propose an improved method to quantify the biodistribution of gamma-emitting RSA, using tissular corrected uptake indices. We conducted a bi-centric retrospective study on 101 patients with different types of NETs. Three uptake indices obtained after applying new corrections to areas of interest drawn for the tumour and for three reference organs (liver, spleen and lung) were statistically analysed. For the corrected pathological uptake indices, the results showed a significant decrease in the error of estimating the occurrence of errors and an increase in the diagnostic predictive power for NETs, especially in the case of lung-referring corrected index. In conclusion, these results support the importance of corrected uptake indices use in the analysis of 99mTcRSA biodistribution for a better personalised diagnostic accuracy of NETs patients.
... In one study, three out of ten patients with SSTR 2 negative and SSTR 5 positive NETs were responsive to SSA therapy [43]. Novel strategies such as SSTR 2 receptor gene transfer might prove useful as new therapies for unresectable tumors [44]. Diarrhea and weight loss, presenting signs in our patient and components of the somatostatinoma syndrome, ameliorated in the first couple of months as a result of SSA therapy. ...
Somatostatinomas are rare neuroendocrine tumors (NET) that arise in the gastrointestinal (GI) tract. Because of their insidious growth, they are usually asymptomatic until late stages, presenting as malignant disease. We report the case of a 50-year-old woman who presented with epigastric abdominal pain, diarrhea and significant weight loss in the last two years. On clinical examination the patient met the criteria for neurofibromatosis type 1 (NF1). Abdominal CT and MRI revealed an infiltrative duodenal mass, with pancreatic invasion, locoregional enlarged lymph nodes and disseminated hepatic nodules. Microscopy and immunohistochemistry uncovered a neuroendocrine tumor, staining positive for chromogranin A (CgA), synaptophysin and somatostatin, with a Ki67 = 1%. Somatostatin receptors (SSTRs) type 2 were negative and SSTRs type 5 were positive in less than 50% of tumoral cells. Our patient was classified as a T3N1M1 stage IV metastatic duodenal grade 1 somatostatinoma and treatment with somatostatin analogues and chemotherapy with capecitabine and temozolomide was started, with so far abdominal imaging follow-up showing stable disease. When a patient is diagnosed with a rare NET, such as a somatostatinoma, it is of utmost importance to determine if it is a sporadic tumor or just a feature of a genetic disorder.
... In general, the treatment of well-differentiated metastatic disease (G1, G2 or G3 NET) is usually similar to other NETs, taking into account the patient's performance, available drugs, toxicity profile, the volume and extent of the metastatic disease, the expression of somatostatin receptors in functional images (Octreoscan or 68 Ga-Dotatate) and the presence/lack of a functioning syndrome. Surgical resection of metastases, local-regional therapies such as embolization or ablation when there is exclusive liver involvement, somatostatin analogs, targetmolecular drugs (everolimus), 177 Lu-OctreoTate or even chemotherapy regimens when G3 should be considered when possible [40] . Despite the low response rates, the somatostatin analogue (Octreotide or Lanreotide) is usually the initial treatment of choice because it is well tolerated [41,42] . ...
Gastric neuroendocrine tumors are gastric neoplasms originating from enterochromaffin type cells and are inserted in a larger group, named gastroenteropancreatic neuroendocrine tumors. They are considered rare and variable in terms of their clinical, morphological and functional characteristics and may be indolent or aggressive. They are classified into types I, II and III, according to their pathophysiology, behavior and treatment. Their diagnosis occurs, in most cases, incidentally during upper digestive endoscopies, presenting as simple gastric polyps. Most cases (type I and type II) are related to hypergastrinemia, can be multiple and are treated by endoscopic resection, whenever possible. The use of somatostatin analogs for tumor control may be one of the options for therapy, in addition to total or subtotal gastrectomy for selected cases. Adjuvant chemotherapy is only reserved for poorly differentiated neuroendocrine carcinomas. Although rare, gastric neuroendocrine tumors have an increasing incidence over the years, therefore deserving more comprehensive studies on its adequate treatment. The present study reviews and updates management recommendations for gastric neuroendocrine tumors.
... Although both, octreotide and lanreotide are SSTR2-preferential analogs, they also interact with SSTR5 and to a lesser extent with SSTR3 (73e75). The overall biochemical response rate is 30%; however, patient-reported clinical improvement of diarrhea and flushing reaches 75e80% (74,75). ...
... SSA are reasonably safe and well-tolerated, the most frequent side effects being gastro-intestinal discomfort and the generation of gallstones or biliary sludge (74,75). A non-negligible proportion of patients develop resistance and recurrence of symptoms after 9e12 months of treatment (74,75). ...
... SSA are reasonably safe and well-tolerated, the most frequent side effects being gastro-intestinal discomfort and the generation of gallstones or biliary sludge (74,75). A non-negligible proportion of patients develop resistance and recurrence of symptoms after 9e12 months of treatment (74,75). Increased dose or reduced intervals of administration have been reported as an option that is currently off label. ...
Although neuroendocrine neoplasms (NEN) were once thought to be rare and mostly “benign” diseases, they are now being redefined in light of recently discovered molecular information. NENs constitute a spectrum of variably differentiated neoplasms, ranging from well-differentiated tumors with a protracted course over many years to very aggressive neuroendocrine carcinomas. Although the majority of NEN are non-functional lesions, some of these tumors, do produce a hormonal hypersecretion syndrome. Their reappraisal has led scientist to unveil previously unknown oncogenic pathways and connections that resulted in a new category in the International Classification of Diseases (ICD-11) and a revised version of the World Health Organization Classification (WHO 2018). Complex diseases like NEN require a multidisciplinary approach that includes the perspectives of endocrinologists, medical and surgical oncologists, radiation oncologists, imaging specialists and pathologists. There are currently virtually thousands of ongoing trials evaluating the efficacy and safety of several molecular targeted therapies. The purpose of this review was to critically evaluate recent information regarding the pathogenesis, diagnosis and treatment of NEN.
