Well-differentiated Gastroenteropancreatic Neuroendocrine Tumors Research Articles

The factors associated with all-cause in-hospital mortality in patients with malignant well-differentiated gastroenteropancreatic neuroendocrine tumors: A retrospective analysis of National Inpatient Survey (NIS) 2020 dataset.

e16292 Background: Neuroendocrine tumors (NET) affect less than 200,000 (52 per 100,000) of the US population, with malignant well-differentiated gastroenteropancreatic (GEP) NETs accounting for about 65% of the cases. Owing to its rarity, the evidence on factors associated with all-cause mortality is limited. To address this gap, this study aims to identify socio-demographic and clinical factors associated with all-cause in-hospital mortality for patients with malignant well-differentiated GEP NET. Methods: We analyzed data from 2020 Nationwide Inpatient Sample survey on patients hospitalized with malignant well-differentiated GEP NET. Using ICD10 code, we identified patients hospitalized with any diagnosis of malignant well-differentiated GEP NET. In-hospital mortality was assessed based on the patient final disposition on discharge and dichotomized. Exposure variables analyzed included age, sex, tumor site, history of essential hypertension, COVID-19, hyperlipidemia, insurance status, length of hospital stay, and number of comorbidities present on the patients record. Multivariable logistic regression was used to assess for factors associated with mortality. Results: Of the 956 patients in this study, most were white (73.43%), male (48.28%) and mean age was 65 years (SD 13.59). Affected sites include small intestine (57.25%), pancreas (13.56%), colon (8.47%), appendix (8.26%), stomach (8.68%) and rectum (3.51%). Our results revealed that females were less likely to die in the hospital compared to their male counterpart hospitalized with malignant well-differentiated GEP NET (aOR = 0.42; 95% CI: 0.19 - 0.95). The presence of hyperlipidemia was significantly associated with in-hospital mortality (aOR = 0.24; 95% CI: 0.08 - 0.75). For every unit increase in the number of comorbidities, there is 12% increased risk of mortality (aOR = 1.12; 95% CI: 1.05 -1.19). The associations of age, race, tumor site, history of hypertension, insurance status or length of stay with in-hospital mortality were not statistically significant. Conclusions: Our study found significant associations of sex, hyperlipidemia, number of comorbidities and in-hospital mortality among patients with malignant well-differentiated GEP NET. Findings from this study highlight that factors such as sex, hyperlipidemia and number of comorbidities may be critical when developing prognostic tools that can be used to determine the risk of mortality among hospitalized patients hospitalized with these tumors.

Safety and time to response of [177Lu]Lu-DOTATATE in patients with newly diagnosed advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors: Sub-analysis of the phase 3 randomized NETTER-2 study.

4131 Background: NETTER-2 (NCT03972488) is the first randomized study to evaluate radioligand therapy ([177Lu]Lu-DOTA-TATE; hereafter 177Lu-DOTATATE) at first line (1L) in patients (pts) with advanced, well-differentiated higher grade (G2 and G3) gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Significant improvements in progression-free survival and objective response rate (ORR) were observed for pts receiving 177Lu-DOTATATE. This sub-analysis of NETTER-2 assessed safety and time to response (TTR). Methods: Eligible pts (n=226) were newly diagnosed with somatostatin receptor-positive high G2 or G3 (Ki67 ≥10% and ≤55%) advanced GEP-NETs and were randomized (2:1) to receive 4 cycles of 177Lu-DOTATATE (4 × 7.4 GBq every 8 weeks [Q8W]) plus 30 mg octreotide long-acting repeatable (LAR) Q8W during 177Lu-DOTATATE treatment then Q4W (177Lu-DOTATATE arm), or 60 mg octreotide LAR Q4W (control arm). Hematologic adverse events (AEs) and laboratory toxicities were scored according to CTCAE grade. Response was assessed centrally based on conventional imaging (RECIST 1.1 criteria). Results: The AE pattern in the 177Lu-DOTATATE arm was consistent with the established safety profile. Among laboratory abnormalities, grade 3/4 decreases in lymphocytes (38.1% vs 2.7%), leukocytes (4.1% vs 0), neutrophils (3.4% vs 0), platelets (2.0% vs 0) and hemoglobin (1.4% vs 2.7%) were observed in 177Lu-DOTATATE (n=147) and control (n=73) arms, respectively; median time to first occurrence of hematologic toxicities was 4.4 months among pts with immediate hematotoxicities. These events were transient and manageable. There was no notable difference in infection rates between treatment arms (31.3% 177Lu-DOTATATE and 27.4% control). One case of myelodysplastic syndrome was observed (177Lu-DOTATATE arm ~14 months after first cycle). Five fatal AEs occurred during the randomized treatment period; all considered unrelated to treatment and attributed to GEP-NET progression. AEs leading to 177Lu-DOTATATE dose interruption, reduction and discontinuation occurred in 14 (9.5%), 2 (1.4%) and 3 (2.0%) pts, respectively. Among 65 responders in the 177Lu-DOTATATE arm (ORR 43 %), median TTR (Q1, Q3) was 5.7 months (4.1, 8.3). Most responses occurred during the 4-cycle treatment with 177Lu-DOTATATE. Conclusions: In pts with advanced G2 and G3 (Ki67 ≥10% and ≤55%) GEP-NETs treated with 177Lu-DOTATATE at 1L the most common hematologic toxicity was lymphopenia, but infection rates were similar vs control. With a median TTR of 5.7 months, most responses to 177Lu-DOTATATE occurred during scheduled treatment. Overall, the study confirmed the safety profile of 177Lu-DOTATATE and supports its use at 1L for this pt population. Clinical trial information: NCT03972488 .

211MO First-line efficacy of [177Lu]Lu-DOTA-TATE in patients with advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors by tumor grade and primary origin: Subgroup analysis of the phase III NETTER-2 study

211MO First-line efficacy of [177Lu]Lu-DOTA-TATE in patients with advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors by tumor grade and primary origin: Subgroup analysis of the phase III NETTER-2 study

177Lu]Lu-DOTA-TATE in newly diagnosed patients with advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors: Primary analysis of the phase 3 randomized NETTER-2 study

177Lu]Lu-DOTA-TATE in newly diagnosed patients with advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors: Primary analysis of the phase 3 randomized NETTER-2 study

177Lu]Lu-DOTA-TATE in newly diagnosed patients with advanced grade 2 and grade 3, well-differentiated gastroenteropancreatic neuroendocrine tumors: Primary analysis of the phase 3 randomized NETTER-2 study.

LBA588 Background: Currently, there is no universally accepted first line (1L) therapy for higher grade, well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and an unmet medical need remains in these patients (pts). Radioligand therapy (RLT) is an innovative cancer treatment that crosses the traditional domains of systemic, radiation or surgical therapies. The Phase 3 NETTER-2 study (NCT03972488) evaluated [177Lu]Lu-DOTA-TATE (hereafter 177Lu-DOTATATE) as 1L treatment in pts with Grade (G) 2 and G3 advanced GEP-NETs. This is the first trial to assess 1L RLT in any solid tumor. Methods: Eligible pts were newly diagnosed with somatostatin receptor-positive high G2 or G3 (Ki-67 ≥10% and ≤55%) advanced GEP-NETs within the last 6 months prior to enrollment. Pts were randomized (2:1) to receive 4 cycles of 177Lu-DOTATATE (4 × 7.4 GBq) plus 30 mg octreotide long-acting release (LAR) at 8-weekly intervals during 177Lu-DOTATATE treatment then every 4 weeks (177Lu-DOTATATE arm), or 60 mg octreotide LAR every 4 weeks (control arm), stratified by grade (G2 vs G3) and tumor origin (pancreas vs other). The primary endpoint was progression-free survival (PFS), centrally assessed using RECIST 1.1. Objective response rate (ORR), a key secondary endpoint, was tested hierarchically after PFS. Results: Overall, 226 pts were randomized to the 177Lu-DOTATATE (n = 151) or control (n = 75) arms. Most tumors originated in the pancreas (54.4%) or small intestine (29.2%); G3 tumors were reported in 35.0% of pts. Median cumulative dose of 177Lu-DOTATATE was 29.2 GBq, with 87.8% of pts receiving all 4 doses. Median PFS (95% confidence interval [CI]) was significantly prolonged by ~14.3 months from 8.5 months (7.7, 13.8) in the control arm to 22.8 months (19.4, not estimable) in the 177Lu-DOTATATE arm; stratified hazard ratio 0.276 (95% CI: 0.182, 0.418; p < 0.0001). The ORR was significantly higher in the 177Lu-DOTATATE arm (43.0%) vs the control arm (9.3%); stratified odds ratio 7.81 (95% CI: 3.32, 18.4; p < 0.0001). PFS and ORR results were consistent across all pre-specified demographic and prognostic subgroups. Among adverse events of special interest to RLT, G3/4 leukopenia, anemia and thrombocytopenia occurred in ≤3 pts each in the 177Lu-DOTATATE arm. One case of myelodysplastic syndrome was reported (177Lu-DOTATATE arm). Conclusion: 177Lu-DOTATATE significantly prolonged PFS and demonstrated a clinically meaningful ORR, compared with high-dose octreotide LAR, in pts with newly diagnosed advanced G2 and G3 GEP-NETs. Safety was in line with the established profile of 177Lu-DOTATATE. This is the first randomized study to demonstrate efficacy of RLT as 1L treatment in any malignancy and will change clinical practice. Further investigations of RLT as a therapeutic option in other settings is warranted. Clinical trial information: NCT03972488 .

Radiation Exposure from GEP NET Surveillance.

Neuroendocrine tumors (NET) are neoplasms that secrete peptides and neuroamines. For gastroenteropancreatic (GEP) NET, surgical resection represents the only curative option. Ten-year imaging surveillance programs are recommended due to long time-to-recurrence following resection. We performed retrospective chart review evaluating radiation exposure and practice patterns from surveillance of completely resected GEP NET. We performed a retrospective cohort study of cases with well-differentiated GEP NET from January 2005 to July 2020. Location of primary, modality of imaging, and duration of follow-up were collected. Dosimetry data was collected to calculate effective dose. 62 cases were included with 422 surveillance scans performed. Cross-sectional imaging was used in 82% and functional imaging was used in 18% of scans. Mean number of scans per year was 1.25 (0.42-3). Mean total effective dose was 56.05 mSv (SD 45.56; 0 to 198 mSv) while mean total effective dose per year was 10.62 mSv (SD 9.35; 0 to 45 mSv). Over the recommended ten years of surveillance the estimated total effective dose was 106 mSv. Surveillance of completely resected GEP NET results in cumulative radiation doses in the range associated with secondary malignancy development. Strategies to minimize radiation exposure in surveillance should be considered in future guideline development.

Methodology of the SORENTO clinical trial: a prospective, randomised, active-controlled phase 3 trial assessing the efficacy and safety of high exposure octreotide subcutaneous depot (CAM2029) in patients with GEP-NET

BackgroundThe current standard of care (SoC) for the initial treatment of unresectable or metastatic well-differentiated gastroenteropancreatic neuroendocrine tumours (GEP-NET) requires initiation of first-generation somatostatin receptor ligand (SRL) therapy, octreotide and lanreotide, which provide safe and efficacious tumour/symptom control in most patients. However, disease progression can occur with SoC SRL treatment and the optimal dose response of SRL remains unknown. Octreotide subcutaneous depot (CAM2029) is a novel, long-acting, high-exposure formulation that has shown greater bioavailability and improved administration than octreotide long-acting release (LAR) with a well-tolerated safety profile. Retrospective data have highlighted a potential benefit of high-exposure SRL for improved disease control in patients who did not adequately respond to the current SoC SRL treatment. This trial will investigate the efficacy and tolerability of CAM2029 compared to the current SoC, including octreotide LAR and lanreotide autogel (ATG).MethodsSORENTO is a prospective, multicentre, randomised, active-controlled, open-label phase 3 trial aiming to demonstrate superiority of treatment with 20 mg octreotide subcutaneous depot (CAM2029) every 2 weeks (Q2W) compared to treatment with the Investigator’s choice of SRL therapy at standard doses for tumour control (octreotide LAR 30 mg or lanreotide ATG 120 mg every 4 weeks [Q4W]) as assessed by progression-free survival (PFS) in approximately 300 patients with unresectable/metastatic and well-differentiated GEP-NET. Upon confirmation of disease progression (determined by a Blinded Independent Review Committee [BIRC] and defined as per RECIST 1.1), patients may enter an open-label extension treatment period with once weekly dosing, to investigate the effects of higher frequency dosing. Overall survival follow-up will end a maximum of 2 years after primary analysis. The primary endpoint will be analysed after 194 confirmed PFS events.DiscussionThis is the first trial investigating the efficacy of CAM2029 versus SoC SRL therapy using a head-to-head, superiority trial design. It is expected to be the first trial to investigate the efficacy of increased dosing frequency of a high-exposure SRL. A BIRC will limit bias and measurement variability and ensure high-quality efficacy data. Additionally, inclusion of patients with well-differentiated Grade 3 NET may elucidate treatment strategies for this rarely investigated patient population.Trial registrationClinicalTrials.gov NCT05050942. Registered on 21st September 2021.

PP047 Concomitant 177Lu-DOTATATE and low dose capecitabine versus 177Lu-DOTATATE alone in patients with advanced well-differentiated gastroenteropancreatic neuroendocrine tumours – a randomized controlled trial

PP047 Concomitant 177Lu-DOTATATE and low dose capecitabine versus 177Lu-DOTATATE alone in patients with advanced well-differentiated gastroenteropancreatic neuroendocrine tumours – a randomized controlled trial

Intertumoral lineage diversity and immunosuppressive transcriptional programs in well-differentiated gastroenteropancreatic neuroendocrine tumors.

Neuroendocrine tumors (NETs) are rare cancers that most often arise in the gastrointestinal tract and pancreas. The fundamental mechanisms driving gastroenteropancreatic (GEP)-NET growth remain incompletely elucidated; however, the heterogeneous clinical behavior of GEP-NETs suggests that both cellular lineage dynamics and tumor microenvironment influence tumor pathophysiology. Here, we investigated the single-cell transcriptomes of tumor and immune cells from patients with gastroenteropancreatic NETs. Malignant GEP-NET cells expressed genes and regulons associated with normal, gastrointestinal endocrine cell differentiation, and fate determination stages. Tumor and lymphoid compartments sparsely expressed immunosuppressive targets commonly investigated in clinical trials, such as the programmed cell death protein-1/programmed death ligand-1 axis. However, infiltrating myeloid cell types within both primary and metastatic GEP-NETs were enriched for genes encoding other immune checkpoints, including VSIR (VISTA), HAVCR2 (TIM3), LGALS9 (Gal-9), and SIGLEC10. Our findings highlight the transcriptomic heterogeneity that distinguishes the cellular landscapes of GEP-NET anatomic subtypes and reveal potential avenues for future precision medicine therapeutics.

Systemic Therapy for Tumor Control in Metastatic Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors: ASCO Guideline.

To develop recommendations for systemic therapy for well-differentiated grade 1 (G1) to grade 3 (G3) metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). ASCO convened an Expert Panel to conduct a systematic review of relevant studies and develop recommendations for clinical practice. Eight randomized controlled trials met the inclusion criteria for the systematic review. Somatostatin analogs (SSAs) are recommended as first-line systemic therapy for most patients with G1-grade 2 (G2) metastatic well-differentiated GI-NETs. Observation is an option for patients with low-volume or slow-growing disease without symptoms. After progression on SSAs, peptide receptor radionuclide therapy (PRRT) is recommended as systematic therapy for patients with somatostatin receptor (SSTR)-positive tumors. Everolimus is an alternative second-line therapy, particularly in nonfunctioning NETs and patients with SSTR-negative tumors. SSAs are standard first-line therapy for SSTR-positive pancreatic (pan)NETs. Rarely, observation may be appropriate for asymptomatic patients until progression. Second-line systemic options for panNETs include PRRT (for SSTR-positive tumors), cytotoxic chemotherapy, everolimus, or sunitinib. For SSTR-negative tumors, first-line therapy options are chemotherapy, everolimus, or sunitinib. There are insufficient data to recommend particular sequencing of therapies. Patients with G1-G2 high-volume disease, relatively high Ki-67 index, and/or symptoms related to tumor growth may benefit from early cytotoxic chemotherapy. For G3 GEP-NETs, systemic options for G1-G2 may be considered, although cytotoxic chemotherapy is likely the most effective option for patients with tumor-related symptoms, and SSAs are relatively ineffective. Qualifying statements are provided to assist with treatment choice. Multidisciplinary team management is recommended, along with shared decision making with patients, incorporating their values and preferences, potential benefits and harms, and other characteristics and circumstances, such as comorbidities, performance status, geographic location, and access to care.Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines.

Bone fragility in well-differentiated gastroenteropancreatic-neuroendocrine tumors: Results from a retrospective two-centered study

Bone fragility in well-differentiated gastroenteropancreatic-neuroendocrine tumors: Results from a retrospective two-centered study

Combination Systemic Therapies in Advanced Well-Differentiated Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs): A Comprehensive Review of Clinical Trials and Prospective Studies.

There is an evolving landscape of systemic combination regimens for patients with advanced well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). In this review, we provide a comprehensive outline of the existing clinical trials/prospective studies investigating these combinations. PubMed was searched using key relevant terms to identify articles referring to GEP-NETs and combination treatments. No systematic search of the literature or metanalysis of the data was performed, and we focused on the most recent literature results. Primarily, phase 1 and 2 clinical trials were available, with a smaller number of phase 3 trials, reporting results from combination treatments across a wide range of antiproliferative agents. We identified significant variability in the anti-tumor activity of the reported combinations, with occasional promising results, but only a very small number of practice-changing phase 3 clinical trials. Overall, the peptide receptor radionuclide therapy (PRRT)-based combinations (with chemotherapy, dual PPRT, and targeted agents) and anti-vascular endothelial growth factor (VEGF) agent combinations with standard chemotherapy were found to have favorable results and may be worth investigating in future, larger-scale trials. In contrast, the immune-checkpoint inhibitor-based combinations were found to have limited applicability in advanced, well-differentiated GEP-NETs.

Prevalence of Endocrine Manifestations and GIST in 108 Systematically Screened Patients With Neurofibromatosis Type 1.

In patients with neurofibromatosis type 1 (NF1), guidelines suggest screening for pheochromocytoma by metanephrine measurement and abdominal imaging, which may lead to the discovery of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and their differential diagnosis, gastrointestinal stromal tumors (GISTs). Other endocrine manifestations such as follicular thyroid carcinoma and primary hyperparathyroidism have also been reported in a few cases. This study aimed to describe prevalence and clinical presentation of these manifestations through systematic screening in a large cohort of patients. In this monocentric retrospective study, 108 patients with NF1 were included and screened for endocrine manifestations and GISTs. Clinical, laboratory, molecular profile, pathology, and morphologic (abdominal computed tomography scan and/or magnetic resonance imaging) and functional imaging were collected. Twenty-four patients (22.2% of the cohort, 16 female, mean age 42.6 years) presented with pheochromocytomas that were unilateral in 65.5%, benign in 89.7%, and with a ganglioneural component in 20.7%. Three female patients (2.8% of the cohort, aged 42-63 years) presented with well-differentiated GEP-NETs, and 4 (3.7%) with GISTs. One patient had primary hyperparathyroidism, 1 patient had medullary microcarcinoma, and 16 patients had goiter, multinodular in 10 cases. There was no correlation between pheochromocytoma and other NF1 tumoral manifestations, nor correlations between pheochromocytoma and NF1 genotype, despite a familial clustering in one-third of patients. The pheochromocytoma prevalence in this NF1 cohort was higher (>20%) than previously described, confirming the interest of systematic screening, especially in young women. The prevalence of GEP-NETs and GISTs was about 3%, respectively. No phenotype-genotype correlation was observed.

Chromogranin A as surveillance biomarker in patients with carcinoids: CASPAR.

e16242 Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare cancers with highly heterogeneous growth rates, yielding very broad ranges of radiographic imaging intervals in standard guidelines, with a multitude of risk for patients. Better tools are needed to reduce risks for these patients. Chromogranin A (CgA) is released by GEP-NET cells and has been associated with increased tumor burden. The European Neuroendocrine Tumor Society (ENETS) considers CgA to be the most practical and useful general serum tumor marker in patients with NETs. However, clinical utility has been limited by the lack of prospective validation studies and by different sensitivity of CgA according to NET tumor type and volume. Accordingly, expert consensus guidelines have offered varying advice regarding the use of CgA to practicing clinicians. The aim was to evaluate the performance of the B·R·A·H·M·S CgA II KRYPTOR immunoassay to monitor the course of disease in patients with well-differentiated GEP-NETs (grade 1 and grade 2). This is the first prospective validation of a clinical algorithm for the interpretation of CgA values in patients with advanced GEP-NETs. Methods: This prospective, multi-center, observational study was designed to validate the performance of the B·R·A·H·M·S CgA II KRYPTOR assay in monitoring disease progression in a defined population of GEP-NET patients with minimal confounding from end organ dysfunction or concomitant medications (e.g. PPIs). Patients were followed for up to 36 months including the evaluation of tumor burden with RECIST 1.1 categorization by imaging (CT/MRI scans). A clinical cut-off for changes in CgA levels over time to indicate the risk that a tumor progression occurred was derived from a retrospective, bicentric observational pilot study. A change in CgA levels between visits was considered positive, if the CgA concentration increased by more than 50% to an absolute value of >100 ng/ml. Results: A total of 175 adult patients were enrolled, and 153 patients had measurable disease at baseline and ≥1 follow-up visit. Using the cut-off for CgA increase defined above resulted in a sensitivity of 34.4% (95%-CI: 25.6% - 44.3%, p < 0.001) and a specificity of 93.4% (95%-CI: 90.4% – 95.5%, p < 0.001). Positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+) and negative likelihood ratio (LR-) to diagnose whether a tumor progression occurred according RECIST 1.1 criteria were 57.9% (95% CI: 45.0-69.8), 84.3% (95% CI: 80.5-87.6), 5.20 (95% CI: 3.23-8.36), and 0.70 (95% CI: 0.61-0.81), respectively. The AUC was estimated at 0.731 (95% CI: 0.670-0.793). Conclusions: B·R·A·H·M·S CgA II KRYPTOR can be used in conjunction with other clinical methods as an aid in monitoring of disease progression during the course of disease and treatment in patients with gastroentero-pancreatic neuroendocrine tumors (GEP-NETs, grade 1 and grade 2).

Clinical and radiological response to locoregional and systemic treatments in well-differentiated gastroenteropancreatic neuroendocrine tumors with liver metastases treated at a reference center in Mexico.

644 Background: liver metastases (LM) from well-differentiated gastroenteropancreatic neuroendocrine tumors (wd-GEP-NET) can develop in 28-77% of patients (pts) in their lifetime. Multiple treatments can provide radiological and symptomatic response. Our aim was to evaluate responses to locoregional (LRT) and systemic (SYST) treatments in wd-GEP-NET with LM. Methods: we included consecutive records of pts with confirmed histological diagnosis of wd-GEP-NET and radiological LM, treated at our institution between 2008-2019. Relevant variables were retrospectively extracted from electronic records. Radiological response was assessed with RECIST 1.1 by radiological independent review. Results: 55 pts, 45.5% male. Median age at LM diagnosis 49 years (IQR 41-63). Primary tumor sites: 49% pancreatic, 27.3% small intestine, 11% unknown, 12.7% others. WHO 2019 grade 1, 2 and 3 in 52.7, 41.8 and 1.8%, respectively. Twentynine tumors (52.7%) were functional, with carcinoid syndrome in n20. At LM diagnosis, 91% of pts had symptomatic disease: hormonal n8, local n4, systemic n4, hormonal + local n4, local + systemic n22, hormonal + systemic n5, hormonal + local + systemic n5. LM tumoral burden was <10% in 22%, 11-50% in 43.6, > 50% in 30.9% of pts. 49.1% of pts had extra hepatic metastatic disease. LRT to LM was administered to 32 pts: TAE/TACE n26, ablation n8. SYST to 22 pts: somatostatin analog n15, Lutetium-177 n4, chemotherapy n2, everolimus n1. 1 pt did not receive treatment. Response to treatments is shown. In the LRT group, -- pts developed complications: n16 postembolization syndrome, n2 infections, n3 liver failure, n7 others. There was 1-procedure-related death. Conclusions: Patients treated with LRT at our institution achieved similar efficacy and safety results compared to those reported by previous studies.[Table: see text]

A Clinical Guide to Peptide Receptor Radionuclide Therapy with 177Lu-DOTATATE in Neuroendocrine Tumor Patients

Peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-[DOTA0,Tyr3]-octreotate (177Lu-DOTATATE) has become an established second- or third-line treatment option for patients with somatostatin receptor (SSTR)-positive advanced well-differentiated gastroenteropancreatic (GEP) neuroendocrine tumors (NETs). Clinical evidence of the efficacy of PRRT in tumor control has been proven and lower risks of disease progression or death are seen combined with an improved quality of life. When appropriate patient selection is performed, PRRT is accompanied by limited risks for renal and hematological toxicities. Treatment of NET patients with PRRT requires dedicated clinical expertise due to the biological characteristics of PRRT and specific characteristics of NET patients. This review provides an overview for clinicians dealing with NET on the history, molecular characteristics, efficacy, toxicity and relevant clinical specifics of PRRT.

Outcomes in patients with advanced well-differentiated gastroenteropancreatic neuroendocrine tumours receiving PRRT early versus later

Outcomes in patients with advanced well-differentiated gastroenteropancreatic neuroendocrine tumours receiving PRRT early versus later

Inflammatory Cytokines Associated with Diagnosis, Tumor Grade and Prognosis in Patients with Neuroendocrine Tumors.

Background and aims: Inflammatory cytokines represent diagnostic and prognostic biomarkers in manifold cancers. Recent data suggest a pivotal role of these cytokines in different biological processes involved in the development of neuroendocrine tumors (NETs). However, their role as biomarkers in NETs is only poorly understood. Methods: We analyzed serum concentrations of 13 inflammation-related cytokines at different time points in 43 patients with well-differentiated gastroenteropancreatic NETs (G1/G2) treated at Charité Berlin and compared them to 40 healthy controls. The results were correlated with clinical records. Results: Serum concentrations (Median (Interquartile Range (IQR)) in pg/mL) of IL-1β (124 (82) vs. 68 (61) pg/mL; p = 0.0003), IL-6 (111(122) vs. 88 (32) pg/mL; p = 0.0086), IL-8 (1058 (768) vs. 210 (90) pg/mL; p < 0.0001), IL-18 (2936 (1723) vs. 1590 (704) pg/mL; p < 0.0001), and TNF (271 (260) vs. 42 (25) pg/mL; p < 0.0001) were significantly elevated in NET patients, whereas IL-10 (43 (44) vs. 105 (48) pg/mL; p < 0.0001) showed lower concentrations in NETs when compared to controls. Cytokine levels significantly correlated with tumor grade (IL-6; p = 0.0070), prevalence of distant metastasis (IL-18; p = 0.0313), and disease progression over time (IL-10; p = 0.0033) but not tumor location. Chromogranin A (CgA) and the NETest are currently used to monitor treatment response. A more accurate prediction could possibly be achieved by employing a subset of cytokines. Our data clearly warrants further functional investigation into the role of the immune response and cytokine release in NETs. Conclusion: A biologically plausible panel of cytokines might be added to the diagnostic and prognostic tools currently employed in patients with NETs. Combining different markers into a score would elevate diagnostic accuracy compared to single markers.

Patterns of Lymph Node Metastasis and Optimal Surgical Strategy in Small (≤20 mm) Gastroenteropancreatic Neuroendocrine Tumors.

BackgroundRegional lymph node metastasis (LNM) is crucial for planning additional lymphadenectomy, and is directly correlated with poor prognosis in gastroenteropancreatic neuroendocrine tumors (GEP-NETs). However, the patterns of LNM for small (≤20 mm) GEP-NETs remain unclear. This population-based study aimed at evaluating LNM patterns and identifying optimal surgical strategies from the standpoint of lymph node dissemination.MethodsThis retrospective cohort study retrieved data from the Surveillance, Epidemiology, and End Results (SEER) 18 registries database for 17,308 patients diagnosed as having localized well-differentiated GEP-NETs ≤ 20 mm between January 1, 2004, and December 31, 2017. The patterns of LNM were characterized in 6,622 patients who underwent extended resection for adequate lymph node harvest.ResultsOf 6,622 patients with localized small GEP-NETs in the current study, 2,380 (36%) presented with LNM after regional lymphadenectomy. Nodal involvement was observed in approximately 7.4%, 49.1%, 13.6%, 53.7%, 13.8%, 7.8%, and 15.4% of gastric (g-), small intestinal (si-), appendiceal (a-), colonic (c-), rectal (r-), non-functional pancreatic (nfp-), and functional pancreatic (fp-) NETs ≤ 20 mm. Patients with younger age, larger tumor size, and muscularis invasion were more likely to present with LNM. Additional lymphadenectomy conferred a significant survival advantage in NETs (≤10 mm: HR, 0.47; 95% CI, 0.33–0.66; p < 0.001; 11–20 mm: HR, 0.54; 95% CI, 0.34–0.85; p = 0.008) and fp-NETs ≤ 20 mm (HR, 0.08; 95% CI, 0.02–0.36; p = 0.001), as well as g-NETs (HR, 0.39; 95% CI, 0.16–0.96; p = 0.041) and c-NETs of 11–20 mm (HR, 0.07; 95% CI, 0.01–0.48; p = 0.007). Survival benefits of additional lymphadenectomy were not found in a-NETs, r-NETs, and nfp-NETs with a small size.ConclusionsGiven the increased risk for nodal metastasis, primary tumor resection with regional lymphadenectomy is a potential optimal surgical strategy for si-NETs and fp-NETs ≤ 20 mm, as well as g-NETs and c-NETs of 11–20 mm. Local resection is an appropriate and reliable surgical approach for a-NETs, r-NETs, and nfp-NETs ≤ 20 mm.

Methodology of the SORENTO clinical trial: Assessing the efficacy and safety of high exposure octreotide subcutaneous depot in patients with GEP-NETs.

TPS4178 Background: Somatostatin receptor ligands (SRLs) are first-line standard of care therapies for gastroenteropancreatic neuroendocrine tumors (GEP-NETs), showing efficacy in tumor/symptom control with an established safety profile. Yet, disease progression may occur despite standard-dose SRL treatment, requiring more aggressive and toxic therapies. Retrospective/non-randomized data suggest higher-dose SRLs may benefit patients with GEP-NETs who do not respond to standard-dose treatment and provide improved disease control. Octreotide depot (CAM2029) is a novel high-exposure, subcutaneous (SC) formulation. Clinical trials showed ̃500% higher CAM2029 bioavailability versus octreotide long-acting release (LAR) (Tiberg et al. 2015), and maintenance/reduction of NET symptoms (Pavel et al. 2019). Prospective, randomized data are needed to confirm the efficacy/safety of novel SRLs with higher bioavailability such as CAM2029, vs standard-dose SRLs including octreotide LAR and lanreotide Autogel (ATG). Methods: SORENTO is a randomized, multi-center, open-label, active-controlled Phase 3 trial, aiming to enroll 302 adults with GEP-NETs. Key eligibility criteria: advanced, well-differentiated NET of GEP/presumed GEP origin; ≥1 measurable SR positive (by nuclear imaging) lesion according to RECIST 1.1; no or &lt; 6 months consecutive treatment with long-acting SRLs. Notably, patients with Grade 3 GEP-NETs (excluded by CLARINET/PROMID trials) are eligible. Patients will be randomized 1:1 to CAM2029 20 mg Q2W, or active comparator (octreotide LAR 30 mg intramuscular or lanreotide ATG 120 mg SC, Q4W). CAM2029 self/carer administration is allowed after ≥3 successful supervised administrations. Randomization stratified by: histological grade, tumor origin, intended comparator. Primary outcome: progression free survival (PFS; time from randomization to date of first documented disease progression [RECIST 1.1] or death), assessed by a Blinded Independent Review Committee. The study is powered to detect a hazard ratio of 0.65. Key secondary outcomes: overall survival; response rate; rescue medication use; patient satisfaction; adverse events. After primary PFS analysis, patient overall survival will be followed for up to 2 years. If CAM2029 displays superiority in the primary analysis, the comparator group may switch to CAM2029 20 mg Q2W. Patients in any treatment group experiencing progressive disease in the randomized part of the study may proceed to an open-label extension with intensified CAM2029 treatment, to investigate effects of higher frequency dosing. First patient randomized in Nov-2021, with readout (following 194 events) expected by 2024 end. This novel head-to-head superiority trial is anticipated to demonstrate the potential benefits of CAM2029 as a first line-therapy in patients with well-differentiated GEP-NETs. Clinical trial information: NCT05050942.