Carcinoid syndrome (CS) is a debilitating disease caused by functional neuroendocrine tumors. Several treatment options are available to alleviate the hormonal symptoms, but their relative efficacy is unknown. Online databases were searched for publications on the treatment of CS symptoms. Independent reviewers assessed relevant publications for study quality and outcome. Meta-analysis of the outcomes of the intervention on CS-related symptoms was stratified by the type of treatment. We found 3682 therapeutic interventions on CS-specific outcomes were collected from 93 studies. Overall, the study qualities were poor with only six randomized controlled clinical trials. The somatostatin analogs octreotide and lanreotide induced symptomatic improvement in 65–72% and biochemical response in 45–46% of patients. An increase in dose or frequency or interclass switch led to a reduction of flushes and/or diarrhea in 72–84% of cases. Retrospective, institutional series showed that liver-directed therapy can improve symptoms in 82% of CS patients with a liver-dominant disease. The serotonin synthesis inhibitor telotristat ethyl reduced bowel movements in 40% of patients with diarrhea refractory to somatostatin analogs. Interferon-alpha controlled CS symptoms in 45–63% of cases. Favorable response has been noted after radionuclide therapy in subgroup analyses of studies not specifically involving CS patients. Chemotherapy and everolimus did not induce a significant response in the CS. We conclude that several treatment lines can be offered to patients suffering from the carcinoid syndrome. Initiation of randomized controlled trials with a primary outcome on carcinoid syndrome symptoms is strongly recommended.
Johannes Hofland, Aura D Herrera-Martínez, Wouter T Zandee and Wouter W de Herder
Aura D Herrera Martínez, Rosanna van den Dungen, Fadime Dogan, P M van Koetsveld, Michael Culler, Wouter W de Herder, Raul M Luque, R A Feelders and Leo Hofland
Control of symptoms related to hormonal hypersecretion by functioning neuroendocrine tumors (NETs) is challenging. New therapeutic options are required. Since novel in vitro tumor models seem to better mimic the tumor in vivo conditions, we aimed to study the effect of somatostatin and dopamine receptor agonists (octreotide and cabergoline, respectively) and novel somatostatin-dopamine chimeric multi-receptor drugs (BIM-065, BIM-23A760) using 2D (monolayer) and 3D (spheroids) cultures.
Methods: Dose-response studies in 2D and 3D human pancreatic NET cell cultures (BON-1 and QGP-1) were performed under serum-containing and serum-deprived conditions. Cell proliferation, somatostatin and dopamine receptors expression (sst and D2R), apoptosis, lactate dehydrogenase, as well as serotonin and chromogranin-A (CgA) release were assessed.
Results: 3D-cultures of BON-1/QGP-1 allowed better cell survival than 2D-cultures in serum-deprived conditions. Sst and D2R mRNA levels were significantly higher in the 3D-model vs. 2D-model. Octreotide/cabergoline/BIM-065/BIM-23A760 treatment did not affect cell-growth or spheroid size. In BON-1 2D-cultures, only BIM-23A760 significantly inhibited CgA release, being this effect more pronounced in 3D-cultures. In BON-1 2D-cultures, cabergoline/BIM-065/BIM-23A760 treatment decreased serotonin release (maximal effect up to 40%), being this effect again more potent in 3D-cultures (up to 67% inhibition; with BIM-23A760 having the most potent effects). In QGP-1, cabergoline/BIM-065 treatment decreased serotonin release only in the 3D-model.
Conclusions: Cultures of NET 3D-spheroids represent a promising method for evaluating cell-proliferation and secretion in NET cell-line models. Compared to 2D-models, 3D-models grow relatively serum-independent. In 3D-model, sst-D2R multi-receptor targeting drugs inhibit CgA and serotonin secretion, but not NET cell-growth.
Aura D Herrera-Martínez, Leo J Hofland, María A Gálvez Moreno, Justo P Castaño, Wouter W de Herder and Richard A Feelders
Some biomarkers for functioning and non-functioning neuroendocrine neoplasms (NENs) are currently available. Despite their application in clinical practice, results should be interpreted cautiously. Considering the variable sensitivity and specificity of these parameters, there is an unmet need for novel biomarkers to improve diagnosis and predict patient outcome. Nowadays, several new biomarkers are being evaluated and may become future tools for the management of NENs. These biomarkers include (1) peptides and growth factors; (2) DNA and RNA markers based on genomics analysis, for example, the so-called NET test, which has been developed for analyzing gene transcripts in circulating blood; (3) circulating tumor/endothelial/progenitor cells or cell-free tumor DNA, which represent minimally invasive methods that would provide additional information for monitoring treatment response and (4) improved imaging techniques with novel radiolabeled somatostatin analogs or peptides. Below we summarize some future directions in the development of novel diagnostic and predictive/prognostic biomarkers in NENs. This review is focused on circulating and selected tissue markers.