Current status of medical treatment for gastroenteropancreatic neuroendocrine neoplasms and future perspectives.
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ABSTRACT:
SUBMITTER: Hijioka S
PROVIDER: S-EPMC8326384 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare and heterogeneous group of tumors presenting as localised or metastatic disease and in a subset with distinct clinical syndromes. Treatment is aimed at controlling the functional syndrome, eradicating the tumor, and/or preventing further tumor growth. Surgery is the treatment of choice in removing the primary tumor and/or reducing tumor burden but cannot be applied to all patients. Somatostatin analogs (SS-analogs) obtain control of functional syndromes in the majority of GEP-neuroendocrine tumors (NETs); phase III trials have shown that SS-analogs can be used as first-line antiproliferative treatment in patients with slow-growing GEP-NETs. The role of the recently approved serotonin inhibitor, telotristat ethyl, and gastrin receptor antagonist, netazepide, is evolving. Streptozotocin-based chemotherapy has been used for inoperable or progressing pancreatic NENs but the orally administered combination of capecitabine/temozolomide is becoming more popular due to its better tolerability and potential effect in other GEP-NENs. Phase III trials have shown efficacy of molecular targeted therapies in GEP-NETs and of radionuclide treatment in patients with midgut carcinoid tumors expressing somatostatin receptors. Most patients will develop disease progression necessitating further therapeutic options. A combination of currently available treatments along with the molecular signature of each tumor will guide future treatment.
| S-EPMC5733630 | biostudies-other
Project description:Neuroendocrine neoplasms (NENs) are a highly heterogeneous class of tumors arising from neuroendocrine cells and peptidergic neurons. After failure of first-line treatment, patients have poor prognosis and limited treatment options. Immune checkpoint inhibitors (ICIs) may be a powerful means of increasing therapeutic efficacy for such patients, but ICIs alone have low response rates and short disease control durations in most NENs and may be effective for only a portion of the population. ICIs combined with other immunotherapies, targeted therapies, or cytotoxic drugs have achieved some efficacy in patients with NENs and are worthy of further exploration to assess their benefits to the population. In addition, accumulating experimental and clinical evidence supports that the interaction between neuroendocrine and immune systems is essential to maintain homeostasis, and assessment of this broad neuroendocrine-immune correlation is essential for NEN treatment. In this review, we summarize the immune microenvironment characteristics, advances in immunotherapy, predictive biomarkers of ICI efficacy for NENs, and the effects of common endocrine hormones on the immune system, highlighting possible new application areas for this promising treatment in neglected NENs.
| S-EPMC9755960 | biostudies-literature
Project description:Treatment of the clinically and prognostically heterogeneous neuroendocrine neoplasms (NEN) should be based on a multidisciplinary approach, including surgical, interventional, medical and nuclear medicine-based therapeutic options. Medical therapies include somatostatin analogues, interferon-a, mTOR inhibitors, multikinase inhibitors and systemic chemotherapy. For the selection of the appropriate medical treatment the hormonal activity, primary tumor localization, tumor grading and growth behaviour as well as the extent of the disease must be considered. Somatostatin analogues are mainly indicated in hormonally active tumors for symptomatic relief, but antiproliferative effects have also been demonstrated, especially in well-differentiated intestinal NET. The efficacy of everolimus and sunitinib in patients with pancreatic neuroendocrine tumors (pNET) has been demonstrated in large placebo-controlled clinical trials. pNETs are also chemosensitive. Streptozocin-based chemotherapeutic regimens are regarded as current standard of care. Temozolomide in combination with capecitabine is an alternative that has shown promising results that need to be confirmed in larger trials. Currently, no comparative studies and no molecular markers are established that predict the response to medical treatment. Therefore the choice of treatment for each pNET patient is based on individual parameters taking into account the patient's preference, expected side effects and established response criteria such as proliferation rate and tumor load. Platin-based chemotherapy is still the standard treatment for poorly differentiated neuroendocrine carcinomas. Clearly, there is an unmet need for new systemic treatment options in patients with extrapancreatic neuroendocrine tumors.
| S-EPMC3712673 | biostudies-literature
Project description:Poorly differentiated gastroenteropancreatic neuroendocrine carcinomas (GEPNECs) are a rare neoplasm with a bleak prognosis. Currently there are little prospective data available for optimal treatment. This review discusses the current available regimens and the future direction for the treatment of GEPNECs. Treatment plans for GEPNECs are often adapted from those devised for small cell lung cancer; however, differences in these malignancies exist, and GEPNECs require their own treatment paradigms. As such, current first-line treatment for GEPNECs is platinum-based chemotherapy with etoposide. Studies show that response rate and overall survival remain comparable between cisplatin and carboplatin versus etoposide and irinotecan; however, prognosis remains poor, and more efficacious therapy is needed to treat this malignancy. Additional first-line and second-line treatment options beyond platinum-based chemotherapy have also been investigated and may offer further treatment options, but again with suboptimal outcomes. Recent U.S. Food and Drug Administration approval of peptide receptor radionuclide therapy in low- and intermediate-grade neuroendocrine tumors may open the door for further research in its usefulness in GEPNECs. Additionally, the availability of checkpoint inhibitors lends promise to the treatment of GEPNECs. This review highlights the lack of large, prospective studies that focus on the treatment of GEPNECs. There is a need for randomized control trials to elucidate optimal treatment regimens specific to this malignancy. IMPLICATIONS FOR PRACTICE: There are limited data available for the treatment of poorly differentiated gastroenteropancreatic neuroendocrine carcinomas (GEPNECs) because of the rarity of this malignancy. Much of the treatment regimens used in practice today come from research in small cell lung cancer. Given the poor prognosis of GEPNECs, it is necessary to have treatment paradigms specific to this malignancy. The aim of this literature review is to summarize the available first- and second-line GEPNEC therapy, outline future treatments, and highlight the vast gap in the literature.
| S-EPMC6693730 | biostudies-literature
Project description:Our understanding about the epidemiological aspects, pathogenesis, molecular diagnosis, and targeted therapies of neuroendocrine neoplasms (NENs) have drastically advanced in the past decade. Gastroenteropancreatic (GEP) NENs originate from the enteroendocrine cells of the embryonic gut which share common endocrine and neural differentiation factors. Most NENs are well-differentiated, and slow growing. Specific neuroendocrine biomarkers that are used in the diagnosis of functional NENs include insulin, glucagon, vasoactive intestinal polypeptide, gastrin, somatostatin, adrenocorticotropin, growth hormone releasing hormone, parathyroid hormone-related peptide, serotonin, histamine, and 5-hydroxy indole acetic acid (5-HIAA). Biomarkers such as pancreatic polypeptide, human chorionic gonadotrophin subunits, neurotensin, ghrelin, and calcitonin are used in the diagnosis of non-functional NENs. 5-HIAA levels correlate with tumour burden, prognosis and development of carcinoid heart disease and mesenteric fibrosis, however several diseases, medications and edible products can falsely elevate the 5-HIAA levels. Organ-specific transcription factors are useful in the differential diagnosis of metastasis from an unknown primary of well-differentiated NENs. Emerging novel biomarkers include circulating tumour cells, circulating tumour DNA, circulating micro-RNAs, and neuroendocrine neoplasms test (NETest) (simultaneous measurement of 51 neuroendocrine-specific marker genes in the peripheral blood). NETest has high sensitivity (85%-98%) and specificity (93%-97%) for the detection of gastrointestinal NENs, and is useful for monitoring treatment response, recurrence, and prognosis. In terms of management, surgery, radiofrequency ablation, symptom control with medications, chemotherapy and molecular targeted therapies are all considered as options. Surgery is the mainstay of treatment, but depends on factors including age of the individual, location, stage, grade, functional status, and the heredity of the tumour (sporadic vs inherited). Medical management is helpful to alleviate the symptoms, manage inoperable lesions, suppress postoperative tumour growth, and manage recurrences. Several molecular-targeted therapies are considered second line to somatostatin analogues. This review is a clinical update on the pathophysiological aspects, diagnostic algorithm, and management of GEP NENs.
| S-EPMC7993001 | biostudies-literature
Project description: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.
| S-EPMC6338796 | biostudies-literature
Project description:Pancreatic neuroendocrine neoplasms (panNENs) are relatively rare but their incidence has increased almost sevenfold over the last four decades. Neuroendocrine neoplasms are classified according to their histologic differentiation and their grade. Their grade is based on their Ki-67 proliferation index and mitotic index. Their prognosis is highly variable according to these elements and treatments also vary according to their classification. Surgery is the only curative treatment for localized and advanced panNENs and offers a better prognosis than non-surgical treatments. In the case of an advanced panNEN without the possibility of resection and/or ablation, medical treatment remains the cornerstone for improving survival and preserving quality-of-life. PanNENs are considered as chemosensitive tumors, unlike midgut neuroendocrine tumors. Thus, panNENs can be treated with chemotherapy, but targeted therapies and somatostatin analogs are also treatment options. The scarcity and heterogeneity of NENs make their management difficult. The present review aims to clarify the medical treatments currently available for advanced panNENs, based on their characteristics, and to propose a treatment algorithm.
| S-EPMC7355438 | biostudies-literature
Project description:Neuroendocrine carcinomas (NECs) are poorly differentiated and highly aggressive epithelial neuroendocrine neoplasms. The most common primary site is the lung, but they may arise in every organ. Approximately 37% of extrapulmonary NECs (EP-NECs) occur in the gastroenteropancreatic (GEP) tract, followed by the genitourinary (GU) system and gynecological tract. As a result of their rarity, there is scant evidence to guide treatment recommendations, and a multidisciplinary approach is essential for the management of such patients. Platinum-based chemotherapy currently represents the standard of care for EP-NECs of any site, mirroring the management of small-cell lung cancer (SCLC), but further approaches are still under investigation. Indeed, ongoing trials evaluating targeted therapies, immune checkpoint inhibitors (ICIs), and radionuclide therapy could provide potentially breakthrough therapeutic options. Given the relative dearth of evidence-based literature on these orphan diseases, the aim of this review is to provide an overview of the pathology and current treatment options, as well as to shed light on the most pressing unmet needs in the field.
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Project description:The increased incidence and prevalence of neuroendocrine tumors (NETs) over the past few decades has been accompanied by an improvement in overall survival. There are differences in the management of small bowel NETs versus pNETs. The management of all patients with NETs must be individualized based on patient characteristics as well tumor-related factors. This article reviews the role of somatostatin analogues, historical results with chemotherapy in gastroenteropancreatic NETs (GEPNETs), and more recent evidence for the use of cytotoxic chemotherapy in GEPNETs. The article also discusses molecular targeted therapies approved for use in GEPNETs and some ongoing clinical trials.
| S-EPMC7700751 | biostudies-literature
Project description:Gastroenteropancreatic neuroendocrine neoplasms grade 3 (GEP-NENs G3) are rare tumors. These highly aggressive neoplasms are traditionally treated with platinum-based chemotherapy in combination with etoposide. Immune checkpoint proteins such as programmed cell death ligand (PD-L1) may have a role in different cancers allowing them escape the immune system and hence, progress. We aimed to investigate the immunohistochemical expression of PD-L1 in GEP-NEN G3 and evaluate its correlation to clinical parameters. In a cohort of 136 patients, 14 (10%) expressed PD-L1 immunoreactivity; four (3%) patients in the tumor cells and 10 (7%) had immunoreactive immune cells. PD-L1 expression did not correlate to clinical parameters, progression-free survival or overall survival. We conclude that PD-L1 expression is present only in a subset of GEP-NEN G3 patients. Further studies are needed to fully understand the role of PD-L1 in patients with GEP-NEN G3, including the future possibility for treatment with immune checkpoint inhibitors.
| S-EPMC7735636 | biostudies-literature