Therapeutic Options for Neuroendocrine Tumors

Kaderli, Reto; Spanjol, Marko; Kollár, Attila; Bütikofer, Lukas; Gloy, Viktoria; Dumont, Rebecca A.; Seiler, Christian; Christ, Emanuel; Radojewski, Piotr; Briel, Matthias; Walter, Martin A.

doi:10.1001/jamaoncol.2018.6720

Cited by 77 publications

(47 citation statements)

References 68 publications

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“…Among the therapies showing good efficacy, SSA in combination with 177 Lu-dototate showed a better profile in term of toxicity in respect to Everolimus (94% AE, 41% grade 3-4). Interferon and SSA caused AE in 21% of the patient and a small percentage of a grade 3-4 (3%) while SSA alone caused AE in 69.8% of the cases and 20.9% of AE of grades 3-4 (105). A metaanalysis of individual patient data showed that a 2-fold increase in Everolimus Cmin delayed NET disease progression with improved tumor size reduction.…”

Section: Meta-analysismentioning

confidence: 99%

mTOR Pathway in Gastroenteropancreatic Neuroendocrine Tumor (GEP-NETs)

et al. 2020

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Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) originate from neuroendocrine cells in the gastrointestinal tract. They are heterogeneous, and though initially considered rare tumors, the incidence of GEP-NENs has increased in the last few decades. Therapeutic approaches for the metastatic disease include surgery, radiological intervention by chemoembolisation, radiofrequency ablation, biological therapy in addition to somatostatin analogs, and PRRT therapy (177Lu-DOTATATE). The PI3K-AKT-mTOR pathway is essential in the regulation of protein translation, cell growth, and metabolism. Evidence suggests that the mTOR pathway is involved in malignant progression and resistance to treatment through over-activation of several mechanisms. PI3K, one of the main downstream of the Akt-mTOR axis, is mainly involved in the neoplastic process. This pathway is frequently deregulated in human tumors, making it a central target in the development of new anti-cancer treatments. Recent molecular studies identify potential targets within the PI3K/Akt/mTOR pathway in GEP-NENs. However, the use of target therapy has been known to lead to resistance due to several mechanisms such as feedback activation of alternative pathways, inactivation of protein kinases, and deregulation of the downstream mTOR components. Therefore, the specific role of targeted drugs for the management of GEP-NENs is yet to be well-defined. The variable clinical presentation of advanced neuroendocrine tumors is a significant challenge for designing studies. This review aims to highlight the role of the PI3K/Akt/mTOR pathway in the development of neuroendocrine tumors and further specify its potential as a therapeutic target in advanced stages.

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Section: Meta-analysismentioning

confidence: 99%

mTOR Pathway in Gastroenteropancreatic Neuroendocrine Tumor (GEP-NETs)

et al. 2020

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“…Furthermore, the addition of SSAs would appear to promote a synergistic effect, increasing the DCR in this patient subgroup. A recently published network meta-analysis supports this hypothesis of the additional effect of the SSA combination with other therapies (33).…”

Section: Summary Of Main Findingsmentioning

confidence: 78%

Phase-II Trials of Pazopanib in Metastatic Neuroendocrine Neoplasia (mNEN): A Systematic Review and Meta-Analysis

et al. 2020

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Background: Several phase-II trials have been designed to evaluate tyrosine kinase inhibitors (TKIs), in particular, pazopanib in neuroendocrine neoplasia (NEN), but its efficacy has not yet been demonstrated in a randomised-controlled Phase III trial. A systematic review of the published clinical trials of metastatic NEN patients could reduce the possible bias of single phase II studies. The present systematic review focuses on the efficacy and safety of pazopanib in patients with metastatic and locally advanced NEN. Methods: A systematic search in the major databases Medline/PubMed, Cochrane and Embase and in supplementary material from important international Meetings was performed to identify publications on pazopanib for the treatment of neuroendocrine neoplasia. English language was defined as a restriction. Four authors of the present review independently performed the study selection, assessed the risk of bias and extracted study data. Four published clinical trials and 2 abstracts were identified. One trial was excluded because the topic was Von-Hippel Landau disease and one abstract was eliminated because of the lack of information on meeting proceedings. Results: In all of the trials pazopanib was orally administered at a dose of 800 mg daily continuously with a 28-day cycle. The intention-to-treat population for efficacy was composed of 230 patients with a median age of 62 years. The partial response rate was 10.7% (95% confidence interval 2.6-20.5). The rate for stable disease was 79.6% (range: 61.7-92.1%) with a disease control rate (DCR) of 90.3%. Progressive disease was reported in 9.7% (range 5.2-17.6) of patients. No complete responses were observed. Median progression-free survival was 11.6 months (95% CI: 9.2-13.9). Overall survival from all the trials was 24.6 (95% CI: 18.7-40.8) months. Severe adverse events (grade III-IV) included hypertension 31%, 16% increase in AST/ALT, diarrhoea 10% and fatigue 10%. Bongiovanni et al. Systematic Review on Pazopanib in mNEN Conclusions: Pazopanib monotherapy achieved a DCR of 90.3% in patients with locally advanced and/or metastatic neuroendocrine neoplasia, with an overall response rate comparable to other TKIs and mTOR inhibitors and a safety profile similar to that of drugs of the same class.

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“…In the randomized clinical trials (RCT) of neuroendocrine tumors, 22 different therapy strategies were compared, stating that there are a number of effective therapies with different safety profiles available to patients, suggesting an overall superiority of combination therapies [62]. For patients with advanced NETs as a best second-and third-line treatment, respectively, to progression-free survival (PFS), PRRT, SSA + bevacizumab, and SSA + interferonalfa should be considered [63].…”

Section: The Treatment Of Neuroendocrine Neoplasmsmentioning

confidence: 99%

The Neuroendocrine Neoplasms of the Digestive Tract: Diagnosis, Treatment and Nutrition

et al. 2020

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Nuroendocrine neoplasms (NENs) are a group of rare neoplasms originating from dispersed neuroendocrine cells, mainly of the digestive and respiratory tract, showing characteristic histology and immunoprofile contributing to classification of NENs. Some NENs have the ability to produce biogenic amines and peptide hormones, which may be associated with clinical syndromes like, e.g., the carcinoid syndrome caused by unmetabolized overproduced serotonin, hypoglycemic syndrome in case of insulinoma, or Zollinger-Ellison syndrome accompanying gastrinoma. Diagnostics for these include ultrasound with endoscopic ultrasound (EUS), computed tomography (CT), magnetic resonance imaging (MRI), and positron-emission tomography/computed tomography (PET/CT). Different nuclear medicine procedures can also be used, like somatostatin analogues scintigraphy (SRS) and 68Ga-Dota-Peptide PET/CT, as well as biochemical methods to determine the level of general neuroendocrine markers, such as chromogranin A (CgA), 5-hydroxyindolacetic acid (5-HIAA), synaptopfysin and cell type-specific peptide hormones, and neurotransmitters like gastrin, insulin, serotonin, and histamine. NENs influence the whole organism by modulating metabolism. The treatment options for neuroendocrine neoplasms include surgery, somatostatin analogue therapy, radionuclide therapy, chemotherapy, molecular targeted therapies, alpha-interferon therapy, and inhibitors of serotonin production. In the case of hypersensitivity to biogenic amines, a diet that limits the main sources of amines should be used. The symptoms are usually connected with histamine, tyramine and putrescine. Exogenic sources of histamine are products that take a long time to mature and ferment. Patients with a genetic insufficiency of the diamine oxidase enzyme (DAO), and those that take medicine belonging to the group of monoamine oxidases (MAO), are particularly susceptible to the negative effects of amines. Diet plays an important role in the initiation, promotion, and progression of cancers. As a result of the illness, the consumption of some nutrients can be reduced, leading to nutritional deficiencies and resulting in malnutrition. Changes in metabolism may lead to cachexia in some patients suffering from NENs. The aim of this narrative review was to advance the knowledge in this area, and to determine possibilities related to dietary support. The authors also paid attention to role of biogenic amines in the treatment of patients with NENs. We can use this information to better understand nutritional issues faced by patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), and to help inform the development of screening tools and clinical practice guidelines.

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Therapeutic Options for Neuroendocrine Tumors

Cited by 77 publications

References 68 publications

mTOR Pathway in Gastroenteropancreatic Neuroendocrine Tumor (GEP-NETs)

mTOR Pathway in Gastroenteropancreatic Neuroendocrine Tumor (GEP-NETs)

Phase-II Trials of Pazopanib in Metastatic Neuroendocrine Neoplasia (mNEN): A Systematic Review and Meta-Analysis

The Neuroendocrine Neoplasms of the Digestive Tract: Diagnosis, Treatment and Nutrition

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