Search Results (41)

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a family of tumors that arise throughout the gastrointestinal tract. These tumors are heterogeneous, with complex clinical symptoms and tumor behaviors, and demonstrate rising incidence rates worldwide. In addition to their nature, GEP-NETs possess limited diagnostic and therapeutic options, which results in poor survival rates for patients with metastatic tumors. Given these findings, a further analysis of these tumors’ biology is needed to determine new therapeutic strategies. The tumor microenvironment (TME) consists of several residual cell populations and non-cellular components whose altered behavior creates a tumor-supportive niche. Studies from other cancers demonstrate the TME’s significance in tumor initiation, progression, and spread. In this review, we discuss efforts to characterize the TME in GEP-NETs. Preliminary studies of the immune system in GEP-NETs have led to several major clinical trials, with limited success. Efforts to target signaling crosstalk between cancer-associated fibroblasts, vascular endothelial cells, and tumor cells has led to major discoveries and multiple approved therapies. Finally, alterations to the extracellular matrix may lead towards an improved understanding of GEP-NET development, behavior, and improved detection methods. While research has rapidly expanded our knowledge within the last decade, further work is needed to bring our understanding of the GEP-NET TME in line with other rare cancers. Full article

Background/Objectives: Neuroendocrine tumors (NETs) can arise in any organ and are most commonly found in the lungs and gastroenteropancreatic (GEP) system. GEP-NETs represent a small percentage of gastrointestinal cancers, and therefore, the standard treatment is not well-defined, especially for advanced disease. Our objective is to review GI NETs among veterans and analyze their therapeutic outcomes. Methods: A total of 61 GI NET cases were identified from our institution from 2019–2024. In total, twenty-seven review papers, ten population-based/multicenter/outcome studies, six case reports, and one case series were reviewed for the literature review. Results: The incidence of GI NETs at our institution was higher than the known epidemiology of GI NETs. Small intestine NETs were one of the most common sites of GEP-NETs at our institution, with only one of nineteen cases being grade 3 poorly differentiated neuroendocrine carcinoma. All cases of colonic and rectal NETs had good clinical outcomes consistent with findings from the literature. Most of the gastric NETs were type 1 and had benign courses of disease, except for one case with an intermediate grade and metastatic liver lesions. One case of esophageal neuroendocrine carcinoma (E-NEC) showed a complete response to chemotherapy despite a significant tumor burden on presentation and high-grade pathology, while another case of ENEC had recurrent disease despite systemic therapy. Conclusions: While the role of surgery or endoscopic resection is limited to localized tumors, combined treatment with chemoradiation can significantly improve patient outcomes, especially in high-grade, poorly differentiated tumors. Further studies are needed to establish systemic (i.e., chemotherapy and radiation) treatment strategies for poorly differentiated GI NETs. Full article

The Eastern Canadian Gastrointestinal Cancer Consensus Conference was an annual meeting that was held in St. John’s, Newfoundland and Labrador, from 26 to 28 September 2024. This included experts in medical oncology, radiation oncology, surgical oncology, nuclear medicine, and general practitioners in oncology (GPO) from across the eastern Canadian provinces who are involved in the management of patients with gastrointestinal malignancies. This consensus statement generated by the conference addresses multiple topics, including the management of localized rectal cancer, liver-limited colorectal cancer, systemic therapy for advanced biliary tract cancers, radioligand therapy for gastroenteropancreatic neuroendocrine tumors (GEP-NETs), systemic therapy for pancreatic and midgut well-differentiated NETs, and systemic therapy for HER2-positive gastroesophageal cancers. Full article

Background: Neuroendocrine carcinomas (NECs) are treated with a frontline platinum–etoposide combination with no standard second-line therapies. We explored a novel combination of nanoliposomal irinotecan (Nal-IRI), 5-fluorouracil (5-FU), and leucovorin (LV) in advanced refractory NECs and investigated the impact of UGT1A1*28 polymorphism on treatment outcomes and toxicity. Methods: We conducted an open-label, single-arm, multi-center Phase 2 trial in advanced NEC patients of gastroenteropancreatic (GEP) or unknown origin with progression or intolerance to first-line therapy. Eligible patients received nal-IRI 70 mg/m² and leucovorin 400 mg/m², followed by 5-FU 2400 mg/m² biweekly till disease progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. Next-generation sequencing (NGS) was performed on blood/tissue samples at baseline and during treatment. Results: Eleven patients were enrolled, with nine evaluable for the primary endpoint. Seven were male, the median age was 66.7 years, and the median Ki-67 was 90%. We observed partial response in one patient, stable disease in six patients, and progressive disease in two patients. The median OS was 9.4 months (95% CI 2.9–29.3), and the median PFS was 4.4 months (95% CI 1.7–6.7). The most common adverse events were diarrhea (45%), nausea (45%), vomiting (45%), and fatigue (45%). The most common genetic mutations on NGS were TP53 (88.9%), CHEK2 (88.9%), and APC (33.3%). Patients with CHEK2 and APC mutation had longer PFS (p = 0.005 and p = 0.013, respectively). UGT1A1*28 polymorphism was not associated with OS, PFS, or toxicity. Conclusion: Nal-IRI with 5-FU/LV is a safe and effective treatment for refractory high-grade NECs of GEP or unknown origin. Future studies should explore novel combinations with Nal-IRI in high-grade NECs both in frontline and refractory settings. Full article

Background: Sarcopenia is a muscle disease that occur across a lifetime. It is commonly described in the aging population but can occur earlier in life in patients with cancer. Previous studies demonstrated sarcopenia is highly prevalent in patients with gastroenteropancreatic neuroendocrine tumours (GEP-NETs). In solid organ cancers, such as colorectal or pancreatic cancer, the presence of sarcopenia is associated with surgical complications. It is unknown if sarcopenia in patients with GEP-NETs is a risk factor for surgical complications. Methods: A multicentre retrospective study was performed in patients with a recently diagnosed GEP-NET and surgery to the primary tumour. CT scans were analysed for body composition analyses to assess for the presence of sarcopenia. Data regarding surgical procedures and complications were collected. Any major surgical complication was considered as Clavien–Dindo score ≥ 3. Results: This study included 180 patients, with 83 being male (46%) with a median age of 62 years (IQR 54–69). Most patients (n = 138, 77%) had a small intestinal NET, while 36 patients (20%) had pancreatic NETs. Sarcopenia was present in 109 patients (61%). In 43 patients (24%), surgical complications were recorded, and 21 complications (49%) were considered as major. Any type of surgical complication was not statistically different between patients without sarcopenia (n = 17, 24%) and with sarcopenia (n = 26, 24%)—a p-value of 0.36. This was the same for major complications; between patients without sarcopenia (n = 5, 24%) and with sarcopenia (n = 16, 76%)—a p-value of 0.18. Conclusions: Sarcopenia is highly prevalent in patients with a recently diagnosed GEP-NET, but this is not associated with major surgical complications. Future studies should include pathophysiological mechanisms that could be used to identify the causes of sarcopenia, its effect on quality of life and other oncological outcomes. Full article

There are several well-described molecular mechanisms that influence cell growth and are related to the development of cancer. Chemokines constitute a fundamental element that is not only involved in local growth but also affects angiogenesis, tumor spread, and metastatic disease. Among them, the C-X-C motif chemokine ligand 12 (CXCL12) and its specific receptor the chemokine C-X-C motif receptor 4 (CXCR4) have been widely studied. The overexpression in cell membranes of CXCR4 has been shown to be associated with the development of different kinds of histological malignancies, such as adenocarcinomas, epidermoid carcinomas, mesenchymal tumors, or neuroendocrine neoplasms (NENs). The molecular synapsis between CXCL12 and CXCR4 leads to the interaction of G proteins and the activation of different intracellular signaling pathways in both gastroenteropancreatic (GEP) and bronchopulmonary (BP) NENs, conferring greater capacity for locoregional aggressiveness, the epithelial–mesenchymal transition (EMT), and the appearance of metastases. Therefore, it has been hypothesized as to how to design tools that target this receptor. The aim of this review is to focus on current knowledge of the relationship between CXCR4 and NENs, with a special emphasis on diagnostic and therapeutic molecular targets. Full article

Neuroendocrine tumors (NETs) are a heterogeneous class of cancers, predominately occurring in the gastroenteropancreatic system, which pose a growing health concern with a significant rise in incidence over the past four decades. Emerging from neuroendocrine cells, these tumors often elicit paraneoplastic syndromes such as carcinoid syndrome, which can manifest as a constellation of symptoms significantly impacting patients’ quality of life. The prognosis of NETs is influenced by their tendency for metastasis, especially in cases involving the liver, where the estimated 5-year survival is between 20 and 40%. Although surgical resection remains the preferred curative option, challenges emerge in cases of neuroendocrine tumors with liver metastasis (NELM) with multifocal lobar involvement, and many patients may not meet the criteria for surgery. Thus, minimally invasive and non-surgical treatments, such as locoregional therapies, have surfaced. Overall, these approaches aim to prioritize symptom relief and aid in overall tumor control. This review examines locoregional therapies, encompassing catheter-driven procedures, ablative techniques, and radioembolization therapies. These interventions play a pivotal role in enhancing progression-free survival and managing hormonal symptoms, contributing to the dynamic landscape of evolving NELM treatment. This review meticulously explores each modality, presenting the current state of the literature on their utilization and efficacy in addressing NELM. Full article

Somatostatin, a somatotropin release inhibiting factor (SST, SRIF), is a widely distributed multifunctional cyclic peptide and acts through a transmembrane G protein-coupled receptor (SST1-SST5). Over the past decades, research has begun to reveal the molecular mechanisms underlying the anticancer activity of this hormonal peptide. Among gastrointestinal tract (GIT) tumors, direct and indirect antitumor effects of SST have been documented best in gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and less well in non-endocrine cancers, including sporadic colorectal cancer (CRC). In the latter, the signaling pathways involved in the antitumor function of SST are primarily MAPK/ERK/AKT and Wnt/β–catenin. Direct (involving the MAPK pathway) and indirect (VEGF production) antiangiogenic effects of SST in CRC have also been described. The anti-inflammatory role of SST in CRC is emphasized, but detailed molecular mechanisms are still being explored. The role of SST in tumor genome/tumor microenvironment (TME)/host’s gut microbiome interactions is only partially known. The results of SST analogues (SSAs)’ treatment of sporadic CRC in monotherapy in vivo are not spectacular. The current review aims to present the state-of-the-art mechanisms and antitumor activity of endogenous SST and its synthetic analogues in CRC, with particular emphasis on sporadic CRC. Full article

Introduction: The COVID-19 pandemic resulted in an unprecedent shift towards virtual cancer care, including the care of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The aim of this study was to evaluate the use of virtual care for GEP-NETs during the COVID-19 pandemic at a high-volume academic cancer center. Methods: This retrospective, observational study performed at the Ottawa Hospital Cancer Center in Canada evaluated adult patients with GEP-NETs seen in consultation by medical oncology between 1 June 2019 and 31 December 2022. Demographic, clinicopathologic, cancer treatment and visit data were collected. Univariable and multivariable analyses assessed the relationship between patient characteristics and virtual care use. Results: A total of 103 patients with well-differentiated GEP-NETS were included. Overall, 18/103 (17.5%) consults and 594/781 (76.1%) follow-ups were performed virtually. All consultation visits returned to in-person assessment by 2022, while 67.0% and 41.4% follow-ups remained virtual in 2022 and 2023, respectively. The year of follow-up, sex, employment and Charlston comorbidity index were associated with virtual follow-up use in the multivariable analysis. Discussion: Virtual care remained a predominant method of GEP-NET patient assessment in the peri-pandemic period. These results highlight an opportunity to improve access to subspecialty neuroendocrine cancer care through the continued use of virtual care. Full article

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. Full article

Bone metastases from gastroenteropancreatic neuroendocrine neoplasms (GEPNENs) have been associated with poor prognosis, but it is unclear whether patients with concurrent bone metastases who receive liver-directed therapy (LDT) would derive survival benefit. The California Cancer Registry dataset, merged with data from the California Office of Statewide Health Planning and Development, was used to perform a retrospective study of GEPNENs metastatic to both liver and bone between 2000 and 2012. A total of 203 patients were identified. Of these, 14.8% underwent LDT after bone metastasis diagnosis, 22.1% received LDT prior to that diagnosis, and 63.1% never received LDT. The median overall survival from the time of bone metastasis diagnosis was significantly longer in those that received LDT after diagnosis when compared with those that never received LDT (p = 0.005) and was not significantly different from the median overall survival of those that had received LDT prior to diagnosis (p = 0.256). LDT may still be associated with improved survival even after a diagnosis of bone metastasis. Full article

Gastroentero-pancreatic Neuroendocrine Neoplasms (GEP-NENs) are a diverse group of rare tumors that arise from neuroendocrine cells in the gastrointestinal tract and pancreas, and they can vary significantly in terms of clinical behavior and prognosis. Immunotherapy, particularly immune checkpoint inhibitors, has shown remarkable success in various malignancies by harnessing the body’s immune system to target and eliminate cancer cells. Immune checkpoint inhibitor clinical studies in GEP-NENs have yielded promising outcomes, particularly in individuals with advanced and refractory disease. Objective responses and disease stabilization have been observed in some cases, even in those previously unresponsive to traditional treatments like chemotherapy or targeted therapies. However, it’s important to note that the efficacy of immunotherapy in GEP-NENs can vary widely depending on tumor characteristics, the immune microenvironment, and patient factors. As such, identifying predictive biomarkers to select the most suitable patients for immunotherapy remains an ongoing challenge. Immunotherapy has considerable potential for treating GEP-NENs, but research is still in its early stages. Several combinations are being explored to enhance the effectiveness of immunotherapy and improve the outcomes of treatment, such as combining immunotherapy with other targeted therapies or chemotherapy. Full article

¹⁷⁷Lu-iPSMA is a novel radioligand developed at ININ-Mexico with a high affinity for the PSMA protein heavily expressed in cancer cells of approximately 95% of patients with metastatic castration-resistant prostate cancer (mCRPC). ¹⁷⁷Lu-DOTATOC is a patent-free radioligand, molecularly recognized by somatostatin receptors (SSTR-2) overexpressed in cancer cells of about 80% of patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NET). This translational research aimed to determine the efficacy and safety of ¹⁷⁷Lu-iPSMA and ¹⁷⁷Lu-DOTATOC developed as GMP pharmaceutical formulations for treating progressive and advanced mCRPC and NET. One hundred and forty-five patients with mCRPC and one hundred and eighty-seven subjects with progressive NET (83% GEP-NET and 17% other NET), treated with ¹⁷⁷Lu-iPSMA and ¹⁷⁷Lu-DOTATOC, respectively, were evaluated. Patients received a mean dose of 7.4 GBq per administration of ¹⁷⁷Lu-iPSMA (range 1–5 administrations; 394 treatment doses) or ¹⁷⁷Lu-DOTATOC (range 2–8 administrations; 511 treatment doses) at intervals of 1.5–2.5 months. Efficacy was assessed by SPECT/CT or PET/CT. Results were stratified by primary tumor origin and number of doses administered. Patients with mCRPC showed overall survival (OS) of 21.7 months with decreased radiotracer tumor uptake (SUV) and PSA level in 80% and 73% of patients, respectively. In addition, a significant reduction in pain (numerical scale from 10–7 to 3–1) was observed in 88% of patients with bone metastases between one and two weeks after the second injection. In the GEP-NET population, the median progression-free survival was 34.7 months, with an OS of >44.2 months. The treatments were well tolerated. Only ten patients experienced grade ≥ 3 myelosuppression (3% of all patients). The observed safety profiles and favorable therapeutic responses demonstrated the potential of ¹⁷⁷Lu-iPSMA and ¹⁷⁷Lu-DOTATOC to improve overall survival and quality of life in patients with progressive and advanced mCRPC and NET. Full article

Peptide receptor radionuclide therapy (PRRT) using Lutetium-177 (¹⁷⁷Lu) based radiopharmaceuticals has emerged as a therapeutic area in the field of nuclear medicine and oncology, allowing for personalized medicine. Since the first market authorization in 2018 of [¹⁷⁷Lu]Lu-DOTATATE (Lutathera®) targeting somatostatin receptor type 2 in the treatment of gastroenteropancreatic neuroendocrine tumors, intensive research has led to transfer innovative ¹⁷⁷Lu containing pharmaceuticals to the clinic. Recently, a second market authorization in the field was obtained for [¹⁷⁷Lu]Lu-PSMA-617 (Pluvicto®) in the treatment of prostate cancer. The efficacy of ¹⁷⁷Lu radiopharmaceuticals are now quite well-reported and data on the safety and management of patients are needed. This review will focus on several clinically tested and reported tailored approaches to enhance the risk–benefit trade-off of radioligand therapy. The aim is to help clinicians and nuclear medicine staff set up safe and optimized procedures using the approved ¹⁷⁷Lu based radiopharmaceuticals. Full article

Tumour heterogeneity is a common phenomenon in neuroendocrine neoplasms (NENs) and a significant cause of treatment failure and disease progression. Genetic and epigenetic instability, along with proliferation of cancer stem cells and alterations in the tumour microenvironment, manifest as intra-tumoural variability in tumour biology in primary tumours and metastases. This may change over time, especially under selective pressure during treatment. The gastroenteropancreatic (GEP) tract is the most common site for NENs, and their diagnosis and treatment depends on the specific characteristics of the disease, in particular proliferation activity, expression of somatostatin receptors and grading. Somatostatin receptor expression has a major role in the diagnosis and treatment of GEP-NENs, while Ki-67 is also a valuable prognostic marker. Intra- and inter-tumour heterogeneity in GEP-NENS, however, may lead to inaccurate assessment of the disease and affect the reliability of the available diagnostic, prognostic and predictive tests. In this review, we summarise the current available evidence of the impact of tumour heterogeneity on tumour diagnosis and treatment of GEP-NENs. Understanding and accurately measuring tumour heterogeneity could better inform clinical decision making in NENs. Full article