Targeted Systemic Treatment of Neuroendocrine Tumors: Current Options and Future Perspectives

Abstract

Neuroendocrine tumors (NETs) originate from the neuroendocrine cell system in the bronchial and gastrointestinal tract and can produce hormones leading to distinct clinical syndromes. Systemic treatment of patients with unresectable NETs aims to control symptoms related to hormonal overproduction and tumor growth. In the last decades prognosis has improved as a result of increased detection of early stage disease and the introduction of somatostatin analogs (SSAs) as well as several new therapeutic options. SSAs are the first-line medical treatment of NETs and can control hormonal production and tumor growth. The development of next-generation multireceptor targeted and radiolabelled somatostatin analogs, as well as target-directed therapies (as second-line treatment options) further improve progression-free survival in NET patients. To date, however, a significant prolongation of overall survival with systemic treatment in NET has not been convincingly demonstrated. Several new medical options and treatment combinations will become available in the upcoming years, and although preliminary results of preclinical and clinical trials are encouraging, large, preferrably randomized clinical studies are required to provide definitive evidence of their effect on survival and symptom control.

Biological and Biochemical Basis of the Differential Efficacy of First and Second Generation Somatostatin Receptor Ligands in Neuroendocrine Neoplasms

“…First, the in vitro activity of OCT was tested in BON-1 cells, which express SST 1 , SST 2 , and SST 5 : OCT inhibited cAMP accumulation, CgA secretion, and MAP kinase activity [164], Akt-phosphorylation and cell growth [36], and tumor growth [165]. On the contrary, other studies reported the lack of significant anti-proliferative effects in both BON-1 and QG-1 cells [166,167] neither in 2D cultures nor in 3D-spheroid models [168], as well as in mice bearing BON-1 xenografts [166]. The BON-1 cell line has been also proposed as a model mimicking the IGF system on GEP-NETs and a model used to test the activation of IGF-related factors upon treatment with OCT and PAS [169].…”

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

“…Nutrition care plans are an integral part of the multidisciplinary management of patients with NETs. Nutritionists with expertise in NETs can provide dietary approaches to improve the quality of life and nutritional status during therapeutic modalities used for patients with NETs and particular in palliative care [73]. Unfortunately, there are not enough registered physicians and dieticians who have expertise in the nutritional management of NETs [74].…”

“…Factors such as unhealthy diets, tobacco, alcoholism, infections and occupational exposures contribute to the formation of neoplasms [75]. The need for consistent dietary guidelines for NEN patients and collaboration with nutritionists in multidisciplinary healthcare teams in NET management have been emphasized by other authors [69][70][71][72][73][74][75][76]. Recommendations for a healthy diet are based on the 2015-2020 Dietary Guidelines Advisory Committee for patients with newly diagnosed asymptomatic NETs [77].…”

Targeted therapy for upper gastrointestinal tract cancer: current and future prospects

“…For years, somatostatin analogues such as octreotide and lanreotide formed the mainstay of siteagnostic adjuvant therapy for advanced NETs. 101 Peptide receptor radionuclide therapy has recently been shown to improve PFS and OS in metastatic midgut NETs. 102,103 Specifically, 177 Lu-Dotatate particles are injected into the patient, with the Dotatate component having an affinity for somatostatin receptors on the tumours and the 177 Lu isotope delivering cytotoxic radiation.…”

“…Other targeted therapies under investigation for NETs include everolimus and sunitinib. 101,106 NETs should not be confused with poorly differentiated neuroendocrine carcinomas, which are rare, aggressive and primarily treated with platinum-based chemotherapy, 107 although sunitinib may also have some efficacy. 108 The selective transcription inhibitor lurbinectedin recently received US FDA approval for second-line treatment of metastatic small cell lung carcinoma based on encouraging results from a Phase II trial.…”